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Neuropathic pain caused by a lesion or disease of the somatosensory nervous system is a common chronic pain condition with major impact on quality of life. Examples include trigeminal neuralgia, painful polyneuropathy, postherpetic neuralgia and central poststroke pain. Most patients complain of an ongoing or intermittent spontaneous pain of e.g. burning, pricking, squeezing quality, which may be accompanied by evoked pain, particular to light touch and cold. Ectopic activity in e.g. nerve-end neuroma, compressed nerves or nerve roots, dorsal root ganglia, and the thalamus may in different conditions underlie the spontaneous pain. Evoked pain may spread to neighboring areas and the underlying pathophysiology involves peripheral and central sensitization. Maladaptive structural changes and a number of cell-cell interactions and molecular signaling underlies the sensitization of nociceptive pathways. These include alteration in ion channels, activation of immune cells, glial-derived mediators, and epigenetic regulation. The major classes of therapeutics include drugs acting on α δsubunits of calcium channels, sodium channels, and descending modulatory inhibitory pathways.
Learn More >Although pain is defined as a sensory and emotional experience, it is traditionally researched and clinically treated separately from emotion. Conceptual and mechanistic relationships between these constructs highlight the need for better understanding of their bi-directional influences and the value of bridging the pain and emotion research and clinical communities.
Learn More >Meissner corpuscles are mechanosensory end organs that densely occupy mammalian glabrous skin. We generated mice that selectively lacked Meissner corpuscles and found them to be deficient in both perceiving the gentlest detectable forces acting on glabrous skin and fine sensorimotor control. We found that Meissner corpuscles are innervated by two mechanoreceptor subtypes that exhibit distinct responses to tactile stimuli. The anatomical receptive fields of these two mechanoreceptor subtypes homotypically tile glabrous skin in a manner that is offset with respect to one another. Electron microscopic analysis of the two Meissner afferents within the corpuscle supports a model in which the extent of lamellar cell wrappings of mechanoreceptor endings determines their force sensitivity thresholds and kinetic properties.
Learn More >G-protein-coupled receptors (GPCRs) are key signaling proteins that mostly function as monomers, but for several receptors constitutive dimer formation has been described and in some cases is essential for function. Using single-molecule microscopy combined with super-resolution techniques on intact cells, we describe here a dynamic monomer-dimer equilibrium of µ-opioid receptors (µORs), where dimer formation is driven by specific agonists. The agonist DAMGO, but not morphine, induces dimer formation in a process that correlates both temporally and in its agonist- and phosphorylation-dependence with β-arrestin2 binding to the receptors. This dimerization is independent from, but may precede, µOR internalization. These data suggest a new level of GPCR regulation that links dimer formation to specific agonists and their downstream signals.
Learn More >The medial prefrontal cortex (mPFC) is a brain region involved in the affective components of pain and undergoes plasticity during the development of chronic pain. Dopamine (DA) is a key neuromodulator in the mesocortical circuit and modulates working memory and aversion. Although DA inputs into the mPFC are known to modulate plasticity, whether and how these inputs affect pain remains incompletely understood. By using optogenetics, we find that phasic activation of DA inputs from the ventral tegmental area (VTA) into the mPFC reduce mechanical hypersensitivity during neuropathic pain states. Mice with neuropathic pain exhibit a preference for contexts paired with photostimulation of DA terminals in the mPFC. Fiber photometry-based calcium imaging reveals that DA increases the activity of mPFC neurons projecting to the ventrolateral periaqueductal gray (vlPAG). Together, our findings indicate an important role of mPFC DA signaling in pain modulation.
Learn More >Chronic pain is a major comorbidity of chronic inflammatory diseases. Here, we report that the cytokine IL-1β, which is abundantly produced during multiple sclerosis (MS), arthritis (RA), and osteoarthritis (OA) both in humans and in animal models, drives pain associated with these diseases. We found that the type 1 IL-1 receptor (IL-1R1) is highly expressed in the mouse and human by a subpopulation of TRPV1+ dorsal root ganglion neurons specialized in detecting painful stimuli, termed nociceptors. Strikingly, deletion of the Il1r1 gene specifically in TRPV1+ nociceptors prevented the development of mechanical allodynia without affecting clinical signs and disease progression in mice with experimental autoimmune encephalomyelitis and K/BxN serum transfer-induced RA. Conditional restoration of IL-1R1 expression in nociceptors of IL-1R1-knockout mice induced pain behavior but did not affect joint damage in monosodium iodoacetate-induced OA. Collectively, these data reveal that neuronal IL-1R1 signaling mediates pain, uncovering the potential benefit of anti-IL-1 therapies for pain management in patients with chronic inflammatory diseases.
Learn More >The transient receptor potential cation channel subfamily V member 3 (TRPV3) channel plays a critical role in skin physiology, and mutations in TRPV3 result in the development of a congenital skin disorder, Olmsted syndrome. Here we describe multiple cryo-electron microscopy structures of human TRPV3 reconstituted into lipid nanodiscs, representing distinct functional states during the gating cycle. The ligand-free, closed conformation reveals well-ordered lipids interacting with the channel and two physical constrictions along the ion-conduction pore involving both the extracellular selectivity filter and intracellular helix bundle crossing. Both the selectivity filter and bundle crossing expand upon activation, accompanied by substantial structural rearrangements at the cytoplasmic intersubunit interface. Transition to the inactivated state involves a secondary structure change of the pore-lining helix, which contains a π-helical segment in the closed and open conformations, but becomes entirely α-helical upon inactivation. Together with electrophysiological characterization, structures of TRPV3 in a lipid membrane environment provide unique insights into channel activation and inactivation mechanisms.
Learn More >The rostral agranular insular cortex (RAIC) is a relevant structure in nociception. Indeed, recruitment of GABAergic activity in RAIC promotes the disinhibition of the locus coeruleus (LC), which in turn inhibits (by noradrenergic action) the peripheral nociceptive input at the spinal cord level. In this regard, at the cortical level, oxytocin can modulate the GABAergic transmission; consequently, an interaction modulating nociception could exist between oxytocin and GABA at RAIC. Here, we tested in male Wistar rats the effect of oxytocin microinjection into RAIC during an inflammatory (by subcutaneous peripheral injection of formalin) nociceptive input. Oxytocin microinjection produces a diminution of (i) flinches induced by formalin and (ii) spontaneous firing of spinal wide dynamic range cells. The above antinociceptive effect was abolished by microinjection (at RAIC) of (i) L-368,899 (an oxytocin receptor -OTR- antagonist) or by (ii) bicuculline (a preferent GABA receptor blocker), suggesting a GABAergic activation induced by OTR. Since intrathecal injection of an α-adrenoceptor antagonist (BRL 44408) partially reversed the oxytocin effect, a descending noradrenergic antinociception is suggested. Besides, injection of L-368,899 induces a pronociceptive behavioral effect, suggesting a tonic endogenous oxytocin release during inflammatory nociceptive input. Accordingly, we found bilateral projections from the paraventricular nucleus of the hypothalamus (PVN) to RAIC. Some of the PVN-projecting cells are oxytocinergic and destinate GABAergic and OTR-expressing cells inside RAIC. Aside from the direct anatomical link between PVN and RAIC, our findings provide evidence about the role of oxytocinergic mechanisms modulating the pain process at the RAIC level.Oxytocin is a neuropeptide involved in several functions ranging from lactation to social attachment. Over the years, the role of this molecule in pain processing has emerged, showing that at the spinal level, oxytocin blocks pain transmission. The present work suggests that oxytocin also modulates pain at the cortical insular level by favoring cortical GABAergic transmission and activating descending spinal noradrenergic mechanisms. Indeed, we show that the paraventricular hypothalamic nucleus sends direct oxytocinergic projections to the rostral agranular insular cortex on GABAergic and oxytocin receptor expressing neurons. Together, our data support the notion that the oxytocinergic system could act as an orchestrator of pain modulation.
Learn More >Transient receptor potential vanilloid subfamily member 3 (TRPV3) is a temperature-sensitive cation channel. Previous cryo-EM analyses of TRPV3 in detergent micelles or amphipol proposed that the lower gate opens by α-to-π helical transitions of the nearby S6 helix. However, it remains unclear how physiological lipids are involved in the TRPV3 activation. Here we determined the apo state structure of mouse (Mus musculus) TRPV3 in a lipid nanodisc at 3.3 Å resolution. The structure revealed that lipids bound to the pore domain stabilize the selectivity filter in the narrow state, suggesting that the selectivity filter of TRPV3 affects cation permeation. When the lower gate is closed in nanodisc-reconstituted TRPV3, the S6 helix adopts the π-helical conformation without agonist- or heat-sensitization, potentially stabilized by putative intra-subunit hydrogen bonds and lipid binding. Our findings provide insights into the lipid-associated gating mechanism of TRPV3.
Learn More >PTSD symptoms and other negative psychosocial factors have been implicated in the transition from acute to persistent pain. Women (N = 375) who presented to an inner-city Emergency Department (ED) with complaints of acute pain were followed for 3 months. They completed a comprehensive battery of questionnaires at an initial visit, and provided ratings of pain intensity at the site of pain presented in the ED during 3 monthly phone calls. Latent class growth analyses were used to detect possible trajectories of change in pain intensity from initial visit to 3 months later. A 3-trajectory solution was found which identified three groups of participants. One group (early recovery; n = 93) had recovered to virtually no pain by the initial visit, whereas a second group (delayed recovery; n = 120) recovered to no pain only after one month. A third group (no recovery; n = 162) still reported elevated pain at 3-months post ED visit. The no recovery group reported significantly greater PTSD symptoms, anger and sleep disturbance, as well as lower social support, at initial visit than both the early recovery and delayed recovery groups. Results suggest that women with high levels of PTSD symptoms, anger, sleep disturbance and low social support who experience an acute pain episode serious enough to prompt an ED visit may maintain elevated pain at this pain site for at least three months. Such an array of factors may place women at increased risk of developing persistent pain following acute pain.
Learn More >Besides neuraxial analgesia, non-pharmacological methods are also proposed to help women coping with pain during labor. We aimed to identify the individual and organizational factors associated with the use of non-pharmacological analgesia for labor pain management. Women who attempted vaginal delivery with labor analgesia were selected among participants included in the 2016 National Perinatal Survey, a population-based cross-sectional study. Labor analgesia was studied as neuraxial analgesia alone, non-pharmacological analgesia alone, and neuraxial and non-pharmacological analgesia combined. The associations were studied by multilevel multinomial logistic regression. Among the 9,231 women included, 62.4% had neuraxial analgesia alone, 6.4% had non-pharmacological analgesia alone and 31.2% had both. Non-pharmacological analgesia alone or combined with neuraxial analgesia were both associated with high educational level (adjusted odds ratio 1.55; 95%CI, 1.08 to 2.23 and 1.39; 95%CI, 1.18 to 1.63), antenatal preference to deliver without neuraxial analgesia, and public maternity unit status. Non-pharmacological analgesia alone was more frequent among multiparous women, and in maternity units with an anesthesiologist not dedicated to delivery unit (1.57; 95%CI, 1.16 to 2.12) and with the lowest midwife workload (2.15; 95%CI, 1.43 to 3.22). Neuraxial and non-pharmacological analgesia combined was negatively associated with inadequate prenatal care (0.70; 95%CI, 0.53 to 0.94). In France, most women who had non-pharmacological analgesia during labor used it as a complementary method to neuraxial analgesia. The use of non-pharmacological analgesia combined with neuraxial analgesia mainly depends on the woman's preference, but also on socioeconomic factors, quality of prenatal care and care organization.
Learn More >Increased descending pain facilitation accounts for opioid-induced hyperalgesia, but the underlying mechanisms remain elusive. Given the role of µ-opioid receptors in opioid-induced hyperalgesia in animals, the authors hypothesized that the dorsal reticular nucleus, a medullary pain facilitatory area, is involved in opioid-induced hyperalgesia through altered µ-opioid receptor signaling.
Learn More >Musculoskeletal disorders such as knee osteoarthritis (OA) are the primary cause of chronic pain in older adults. Recommended self-management strategies for knee OA include staying physically active in the face of pain, but many patients avoid activities they are capable of doing. The overall purpose of this study was to examine the extent to which daily pain catastrophizing, a maladaptive coping strategy, could influence OA patients' physical activity and sedentary behavior. The current study utilized data from 143 older knee OA patients who completed electronic daily diaries for 22 days and wore an accelerometer to capture physical activity and sedentary behavior. At the beginning of each day, patients reported their pain catastrophizing regarding the day ahead. Results from multilevel models demonstrated that on mornings when patients catastrophized more than usual about their pain in the day ahead, they spent more time in sedentary behavior and engaged in fewer minutes of moderate to vigorous physical activity that day. Cross-day lagged analyses further showed that the effect of morning pain catastrophizing on subsequent sedentary behavior extended to the next day. More time spent in sedentary behavior, in turn, contributed to greater pain catastrophizing the next morning. These findings support the mechanistic role of daily pain catastrophizing in the avoidance of physical activity for older OA patients, and suggest that effective interventions for pain catastrophizing may also reduce sedentary behavior and enhance physical activity, with longer-term benefits for pain management, physical function, and overall health.
Learn More >Children diagnosed with Christianson Syndrome (CS), a rare X-linked neurodevelopmental disorder characterized by intellectual disability, epilepsy, ataxia and mutism, also suffer from hyposensitivity to pain. This places them at risk of sustaining serious injuries that often go unattended. CS is caused by mutations in the alkali cation/proton exchanger SLC9A6/NHE6 that regulates recycling endosomal pH homeostasis and trafficking. Yet it remains unclear how defects in this transporter lead to altered somatosensory functions. In this study, we validated a Nhe6 knockout (KO) mouse as a model of CS and used it to identify the cellular mechanisms underlying the elevated pain tolerance observed in CS patients. Within the central nervous system, NHE6 immunolabelling is detected in a small percentage of cortical neurons involved in pain processing, including those within the primary somatosensory and the anterior cingulate cortices as well as the periaqueductal grey. Interestingly, it is expressed in a larger percentage of nociceptors. Behaviourally, Nhe6 KO mice have decreased nocifensive responses to acute noxious thermal, mechanical and chemical (i.e., capsaicin) stimuli. The reduced capsaicin-sensitivity in the KO mice correlates with a decreased expression of the transient receptor potential channel TRPV1 at the plasma membrane and capsaicin-induced Ca influx in primary cultures of nociceptors. These data indicate that NHE6 is a significant determinant of nociceptor function and pain behaviours, vital sensory processes that are impaired in CS.
Learn More >Musculoskeletal pain is the greatest cause of disability worldwide. Due to its increasing prevalence and burden, the importance of affordable treatments has been highlighted. Text messages interventions are accessible, low-cost and effective in promoting healthy behaviour and managing chronic diseases. However, little is known about their role in musculoskeletal pain. This systematic review was conducted to appraise the literature on the effects of text messages (as an intervention or a component of an intervention) compared to any control on pain and function in people with musculoskeletal pain (PROSPERO: CRD42018117371). MEDLINE, EMBASE, CINAHL, Cochrane and PEDro databases were searched from inception to April 2020. Keywords relating to musculoskeletal pain, text messages and randomised controlled trials were combined. Methodological quality was assessed using the PEDro score. Of the 12,022 studies identified, 11 were included, with a mean PEDro score of 5.4/10 points (SD 1.3). Pooled analyses were not performed due to heterogeneity of interventions and clinical characteristics. When text messages were added to and compared with usual care, some positive effects were found only on treatment adherence. Although small and inconsistent, some positive effects were reported for pain intensity, function, care seeking behaviour, adherence and quality of life when text messages were added to multicomponent interventions. Moreover, text message and telephone counselling interventions had similar effects on function. Overall included studies were of limited methodological quality and heterogeneous. However, our results indicate potential benefits of text messages in the treatment of musculoskeletal pain which need to be confirmed in future trials.
Learn More >The presence and magnitude of placebo responses is important for the outcome in clinical trials of analgesics. This explorative study aimed at identifying patients and trial specific factors with impact on this response in randomized, controlled, cross-over trials in peripheral neuropathic pain. Data were derived from 7 trials and included observations on pin-prick hyperalgesia, allodynia, and pain on repetitive stimulation. The studies were all performed by the same collaboration group in Denmark. Pain was rated daily using numeric 0-10 point rating scales (NRS) and placebo response was calculated as the difference in weekly average or median NRS from baseline to the last week of treatment. A clinically meaningful placebo response was defined as more than 30% reduction of pain on placebo. In 318 individual observations the response was on average small (0.17 points, range -4.5 to 6). There was no significant impact on size of placebo response of trial specific factors such as treatment sequence and chance of having placebo treatment in each period or of the patient specific factors age, sensory signs and pain symptoms. The findings were similar in patients having placebo in the first treatment period. There was no marked difference between patients with and without a clinically meaningful placebo response with respect to the patient specific factors including frequency of sensory signs and symptoms. In conclusion, this study on cross-over trials in peripheral neuropathic pain found no robust impact of trial and patient specific factors on the placebo response.
Learn More >Recent meta-analyses have shown MBIs to be effective for chronic pain, but no pooled estimates of the effect of MBIs on acute pain are available. This meta-analysis was conducted to fill that gap. A literature search was conducted in four databases. Articles were eligible if they reported on randomized controlled trials of MBIs for people with acute pain and included one of the following outcomes: pain severity, pain threshold, pain tolerance or pain-related distress. Two authors independently extracted the data, assessed risk of bias and provided GRADE ratings. Twenty-two studies were included. There was no evidence of an effect of MBIs on the primary outcome of pain severity in clinical (Hedge's g=0.52; [95%CI -0.241, 1.280]) or experimental settings (Hedge's g= 0.043; 95%CI [-0.161, 0.247]). There was a beneficial effect of MBIs on pain tolerance (Hedge's g=0.68; 95%CI [0.157, 1.282]) and pain threshold (Hedge's g=0.72; 95%CI [0.210, 1.154]) in experimental studies. There was no evidence of an effect of MBIs compared to control for pain-related distress in clinical (Hedge's g=0.159; 95%CI [-0.018, 0.419]) or experimental settings (Hedge's g=0.439; 95%CI [-0.164, 0.419]). GRADE assessment indicated that except for pain tolerance, the data were of low or very low quality. There is moderate evidence that MBIs are efficacious in increasing pain tolerance and weak evidence for pain threshold. However, there is an absence of good quality evidence for the efficacy of MBIs for reducing the pain severity or pain-related distress in either clinical or experimental settings.
Learn More >Luminal distention and abdominal pain are major clinical hallmarks of obstructive bowel disorders and functional bowel disorders linked to gut dysbiosis. Our recent studies found that chronic lumen distention increased visceral sensitivity and decreased abundance of gut commensal Lactobacillus reuteri in a rodent model of partial colon obstruction (OB). To establish causation, we performed precision microbial therapy to assess whether recolonization of L. reuteri prevents visceral hypersensitivity in lumen distention, and if so, to identify the gut-microbiota mechanism. Lumen distention was induced in Sprague-Dawley rats by implanting an obstruction band in the distal colon for up to 7 days. L. reuteri strains or vehicle were gavage ingested 1X10 CFU/g daily starting 2 days prior to obstruction. L. reuteri rat strains that were able to recolonize obstructed colon significantly improved food intake and body weight in OB rats, and attenuated referred visceral hyperalgesia measured by the withdrawal response to von Frey filament applications to the abdomen. Mechanistically, L. reuteri treatment attenuated hyper-excitability of the dorsal root ganglia neurons projecting to the distended colon by promoting opioid receptor function in affected tissues. The expression of µ, δ, and κ opioid receptors was significantly downregulated in colonic muscularis externae and sensory neurons in OB rats. However, L. reuteri treatment prevented the loss of opioid receptors. Further, administration of peripheral opioid receptor antagonist naloxone methiodide abolished the analgesic effect of L. reuteri in OB. In conclusion, precision L. reuteri therapy prevents lumen distention-associated visceral hypersensitivity by local bacterial induction of opioid receptors.
Learn More >Acute pain that persists for a few days is associated with a reduction in patients' quality of life. Orofacial persistent pain promotes psychological disorders such as anxiety, impairs daily essential activities such as eating, and results in decreased social interaction. Here, we investigated whether rats subjected to orofacial formalin injection or intraoral incision surgery display persistent facial heat hyperalgesia, ongoing pain, anxiety-like behavior and changes in ultrasonic vocalization. Orofacial formalin injection or intraoral incision caused facial heat hyperalgesia for 3 days compared to saline-injected and sham animals. Additionally, both experimental groups showed a reduction in the number of entries and in the time spent in the open arms in the elevated plus maze test on day 3, suggesting that anxiety-like behavior developed as a consequence of persistent pain. At this time point, both groups also displayed a reduction in the number of 50-kHz calls, specifically in the flat subtype, which suggests a decrease in social communication. Moreover, on day 3 after surgery, systemic morphine produced robust conditioned place preference in rats subjected to intraoral incision compared to sham, and the former group also presented increased spontaneous facial grooming, revealing the presence of ongoing pain. Finally, western blot and immunohistochemistry analysis showed a reduction in tyrosine hydroxylase expression in the nucleus accumbens (NAc), which may reflect a decrease in mesolimbic dopaminergic activity. Altogether, the results demonstrate that acute orofacial pain causes prolonged changes in behavioral and affective pain components, which may be related to dopaminergic changes in the NAc.
Learn More >Aerobic exercise is believed to be an effective chronic low back pain (CLBP) intervention, although its mechanisms remain largely untested. This study evaluated whether endogenous opioid (EO) mechanisms contributed to the analgesic effects of an aerobic exercise intervention for CLBP. Individuals with CLBP were randomized to a 6-week, 18-session aerobic exercise intervention (n = 38) or usual activity control (n = 44). Before and after the intervention, participants underwent separate laboratory sessions to assess responses to evoked heat pain after receiving saline placebo or i.v. naloxone (opioid antagonist) in double-blinded, crossover fashion. Chronic pain intensity and interference were assessed before and after the intervention. EO analgesia was indexed by naloxone-placebo condition differences in evoked pain responses (blockade effects). Relative to controls, exercise participants reported significantly greater pre-post intervention decreases in chronic pain intensity and interference (p's < .04) and larger reductions in placebo condition evoked pain responsiveness (McGill Pain Questionnaire-Short Form [MPQ]-Total). At the group level, EO analgesia (MPQ-Total blockade effects) increased significantly pre-post intervention only among female exercisers (p = .03). Dose-response effects were suggested by a significant positive association in the exercise group between exercise intensity (based on meeting heart rate targets) and EO increases (MPQ-Present Pain Intensity; p = .04). Enhanced EO analgesia (MPQ-Total) was associated with significantly greater improvement in average chronic pain intensity (p = .009). Aerobic exercise training in the absence of other interventions appears effective for CLBP management. Aerobic exercise-related enhancements in endogenous pain inhibition, in part EO-related, likely contribute to these benefits.
Learn More >PIEZO2 is the essential transduction channel for touch discrimination, vibration, and proprioception. Mice and humans lacking Piezo2 experience severe mechanosensory and proprioceptive deficits and fail to develop tactile allodynia. Bradykinin, a proalgesic agent released during inflammation, potentiates PIEZO2 activity. Molecules that decrease PIEZO2 function could reduce heightened touch responses during inflammation. Here, we find that the dietary fatty acid margaric acid (MA) decreases PIEZO2 function in a dose-dependent manner. Chimera analyses demonstrate that the PIEZO2 beam is a key region tuning MA-mediated channel inhibition. MA reduces neuronal action potential firing elicited by mechanical stimuli in mice and rat neurons and counteracts PIEZO2 sensitization by bradykinin. Finally, we demonstrate that this saturated fatty acid decreases PIEZO2 currents in touch neurons derived from human induced pluripotent stem cells. Our findings report on a natural product that inhibits PIEZO2 function and counteracts neuronal mechanical sensitization and reveal a key region for channel inhibition.
Learn More >A challenge in understanding chronic musculoskeletal pain is that research is often siloed between neuroscience, physical therapy/rehabilitation, orthopedics and rheumatology which focus respectively on 1) neurally-mediated effects on pain processes, 2) behavior and muscle activity, 3) tissue structure and 4) inflammatory processes. Although these disciplines individually study important aspects of pain, there is a need for more cross-disciplinary research that can bridge between them. Identifying the gaps in knowledge is important to understand the whole body, especially at the interfaces between the silos-between brain function and behavior, between behavior and tissue structure, between musculoskeletal and immune systems, and between peripheral tissues and the nervous system. Research on "mind and body" practices can bridge across these silos and encourage a "whole person" approach to better understand musculoskeletal pain by bringing together the brain and the rest of the body. Perspective: Research on chronic musculoskeletal pain is limited by significant knowledge gaps. To be fully integrated, musculoskeletal pain research will need to bridge across tissues, anatomical areas, and body systems. Research on mind and body approaches encourages a "whole person" approach to better understand musculoskeletal pain.
Learn More >In exposure for chronic pain, avoidance is often forbidden (extinction with response prevention; RPE) to prevent misattributions of safety. Although exposure is an effective treatment, relapse is common. Little is known about the underlying mechanisms of return of pain-related avoidance. We hypothesized that pain-related avoidance would recover when becoming available again after RPE and after unexpected pain episodes ("reinstatement"), especially when restricting avoidance during RPE (compared to instructing not to use it). In an operant pain-related avoidance conditioning paradigm, healthy volunteers used a robotic arm to perform various arm reaching movements differing in pain-effort trade-off. During acquisition, participants learned to avoid pain by performing more effortful movements. During RPE they only performed the formerly pain-associated movement under extinction, and were either forbidden (Restricted group) or merely instructed (Instructed group) not to perform other movements. One day later, we tested spontaneous recovery and reinstatement of pain-related fear and avoidance with availability of all movements. Results showed that pain-related fear and avoidance re-emerge after RPE, though not to pre-treatment levels. The reinstatement manipulation had no additional effect. No group differences were observed. We discuss findings in the context of learning processes in (chronic) pain disability and relapse prevention in chronic pain treatment. Perspective: Using experimental models of relapse, we investigated the return of pain-related avoidance behaviour after extinction with response prevention. Findings are potentially informative for clinicians performing exposure treatment with chronic pain patients.
Learn More >Metabotropic γ-aminobutyric acid receptors (GABA) are involved in the modulation of synaptic responses in the central nervous system and have been implicated in neuropsychological conditions that range from addiction to psychosis. GABA belongs to class C of the G-protein-coupled receptors, and its functional entity comprises an obligate heterodimer that is composed of the GB1 and GB2 subunits. Each subunit possesses an extracellular Venus flytrap domain, which is connected to a canonical seven-transmembrane domain. Here we present four cryo-electron microscopy structures of the human full-length GB1-GB2 heterodimer: one structure of its inactive apo state, two intermediate agonist-bound forms and an active form in which the heterodimer is bound to an agonist and a positive allosteric modulator. The structures reveal substantial differences, which shed light on the complex motions that underlie the unique activation mechanism of GABA. Our results show that agonist binding leads to the closure of the Venus flytrap domain of GB1, triggering a series of transitions, first rearranging and bringing the two transmembrane domains into close contact along transmembrane helix 6 and ultimately inducing conformational rearrangements in the GB2 transmembrane domain via a lever-like mechanism to initiate downstream signalling. This active state is stabilized by a positive allosteric modulator binding at the transmembrane dimerization interface.
Learn More >Pain neuroscience education (PNE) is an approach used in the management of chronic musculoskeletal pain (CMP). Previous reviews on PNE and other pain interventions, have focussed on mean treatment effects, but in the context of "precision medicine", any inter-individual differences in treatment response are also important to quantify. If inter-individual differences are present, and predictors identified, PNE could be tailored to certain people for optimising effectiveness. Such heterogeneity can be quantified using recently-formulated approaches for comparing the response variance between the treatment and control groups. Therefore, we conducted a systematic review and meta-analysis on the extracted standard deviations of baseline-to-follow up change to quantify the inter-individual variation in pain, disability and psychosocial outcomes in response to PNE. Electronic databases were searched between 01/01/2002 and 14/06/2018. The review included five randomised controlled trials (n=428) in which disability outcomes were reported. Using a random effects meta-analysis, the pooled SD (95% CI) for control group-adjusted response heterogeneity to PNE was 7.36 units /100 (95% CI: -3.93 to 11.12). The 95% prediction interval for this response heterogeneity SD was wide (-10.20 to 14.57 units /100). The control group-adjusted proportion of "responders" in the population who would be estimated to exceed a clinically important change of 10/100 ranged from 18-45%. Therefore, when baseline-to-follow up random variability in disability is taken into account (informed by the control arm), there is currently insufficient evidence for the notion of clinically important inter-individual differences in disability responses to PNE in people with CMP. The protocol was published on PROSPERO (CRD42017068436). PERSPECTIVE: We bring a novel method to pain science for calculating inter-individual differences in response to a treatment. This is conducted within the context of a systematic review and meta-analysis on PNE. We highlight how using erroneous methods for calculating inter-individual differences can drastically change conclusions when compared to appropriate methods.
Learn More >Prolonged opioid use after surgery may be associated with opioid dependency and increased health care use. However, published studies have reported varying estimates of the magnitude of prolonged opioid use and risk factors associated with the transition of patients to long-term opioid use.
Learn More >Medication overuse is a significant issue that complicates the treatment of headache disorders. The most effective medications for the acute treatment of migraine all have the capacity to induce medication overuse headache (MOH). Novel acute migraine-specific treatments are being developed. However, because the mechanism(s) underlying medication overuse headache are not well understood, it is difficult to predict whether any particular acute medication will induce MOH in susceptible individuals. LY573144 (lasmiditan), a 5-HT receptor agonist, has recently been shown to be effective in the acute treatment of migraine in phase 3 trials. The aim of this study is to determine whether frequent administration of lasmiditan induces behaviors consistent with MOH in a pre-clinical rat model.
Learn More >The goal of the current study was to enhance the measurement of the pediatric chronic pain experience through a methodologically rigorous approach. This paper outlines the development and initial validation of a pain intensity measure for pediatric patients with chronic pain using PROMIS® methodology. Measure development incorporated feedback from children with painful conditions. Based on input from pediatric participants and content experts, four candidate items assessing pain intensity were included for large scale testing. Children completed self-report items pertaining to their pain experience that were developed as part of a larger pool of new candidate PROMIS® pediatric pain domain items as well as measures of pain interference, depressive symptoms, fatigue, pain behavior, pain intensity, and pain catastrophizing. The final sample for the large scale testing included N = 442 pediatric patients between the ages 8 to 18 years (Mean age = 13.54, SD = 2.78; 71.27% female) experiencing chronic pain. Psychometric analysis resulted in a final measure that included three items with evidence of reliability (Cronbach alpha = 0.82) and convergent validity. The Likert format of the response options may be preferable to the traditional numeric rating scale for use in pediatric populations who experience chronic pain based on patients' feedback, which was directly utilized in designing the scale. Further, the inclusion of fewer and clinically meaningful response options should reduce ambiguity for young respondents. Perspective: We have developed and evaluated a clinically sensitive and psychometrically precise 3-item pain intensity measure with Likert-type responses for self-report use among children and adolescents ages 8-18 with chronic pain. Development of the item content and response options included input from children and adolescents with chronic pain. The development of pain intensity items with pediatric appropriate language, and labeled, fewer response options to yield maximal clinically meaningful information improves the precision of pain intensity measurement in children.
Learn More >The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network initiated a second observational cohort study-the Symptom Patterns Study (SPS)-to further investigate the underlying pathophysiology of Urologic Chronic Pelvic Pain Syndrome (UCPPS) and to discover factors associated with longitudinal symptom changes and responses to treatments.
Learn More >Exercise is a core treatment for persistent non-specific low back pain (NSLBP), but results from randomised controlled trials (RCTs) of exercise typically show only small to moderate standardised mean differences (SMDs) compared to non-exercise controls. The choice of primary outcome, and relationship to the specific targets of exercise may influence this. This systematic review aimed to explore whether primary outcomes match the exercise treatment targets used in NSLBP RCTs and the potential impact of matching on SMDs. Included RCTs were conducted with patients with persistent NSLBP, compared exercise to no exercise, with sample sizes >60 per arm. Screening, data extraction and risk of bias assessment were independently undertaken by paired reviewers. Of 19272 initial titles, 27 RCTs were included with 31 treatment targets and 6 primary outcome domains identified. Only 25% of included RCTs had primary outcomes that matched the treatment targets. SMDs of exercise versus comparison arms were observed to be larger in the matched (SMD 0.54 (95% CI 0.23 to 0.85), p=0.0006) compared to the unmatched category (SMD 0.22 (95% CI 0.01, 0.44) p=0.04) but this difference was not statistically significant (p=0.10). These exploratory findings may have implications for future teams developing RCTs of exercise for NSLBP and warrant further investigation in larger datasets. Perspective This review was an exploratory study that investigated the primary outcome and treatment targets used in RCTs of exercise for NSLBP. The SMDs of the matched group were descriptively larger than those of the unmatched group, but further analysis with larger sample sizes is required to have confidence in these results.
Learn More >This systematic review and meta-analysis examined the evidence for altered central pain processing in people with non-traumatic neck pain and the relationship between central pain processing, demographics and pain-related characteristics. Case-control studies reporting measures of altered central pain processing using quantitative sensory testing were reviewed. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) between people with non-traumatic neck pain and controls were calculated. Meta-analysis was performed using random-effects models when appropriate. Associations between SMDs with demographics and pain-related characteristics were explored on a study level using meta-regression. Twenty-six studies were eligible with 25 included for meta-analysis. Meta-analysis demonstrated mechanical hyperalgesia at remote non-painful sites in the full sample [sample size (n)=1305, SMD=-0.68] and in the subgroup with moderate/severe disability [n=165, SMD=-0.86] (moderate-quality evidence). Meta-regression indicated that remote mechanical hyperalgesia was negatively associated with age (R=25.4%, P=0.031). Very-low- to low-quality evidence of remote cold and heat hyperalgesia and dysfunctional conditioned pain modulation were identified. This review suggests that altered central pain processing is present in people with non-traumatic neck pain and may be associated with disability levels and age. Perspective: This review found moderate-quality evidence of mechanical hyperalgesia at remote non-painful sites in patients with non-traumatic neck pain compared to controls, indicating altered central pain processing. However, more studies are needed to confirm findings from dynamic quantitative sensory testing.
Learn More >N-methyl-D-aspartate (NMDA) receptor activation is known to be critical in remifentanil-induced hyperalgesia. Evidence indicates that iron accumulation participates in NMDA neurotoxicity. This study aims to investigate the role of iron accumulation in remifentanil-induced hyperalgesia. Remifentanil was delivered intravenously in rats to induce hyperalgesia. The NMDA receptor antagonist MK-801 was intrathecally administrated. The levels of divalent metal transporter 1 without iron-responsive element [DMT1(-)IRE] and iron were detected. Behavior testing was performed in DMT1(-)IRE knockdown rats and rats treated with iron chelator DFO. Meanwhile, the spinal dorsal horn neurons were cultured and transfected with DMT1(-)IRE siRNA, and then respectively incubated with remifentanil and MK-801. The levels of intracellular Ca and iron were assessed by fluorescence imaging. Our data revealed that spinal DMT1(-)IRE and iron content significantly increased in remifentanil-treated rats, and MK-801 inhibited the enhancements. DMT1(-)IRE knockdown and DFO prevented against remifentanil-induced hyperalgesia. Notably, the levels of Ca and iron increased in remifentanil-incubated neurons, and these growths can be blocked by MK-801. DMT1(-)IRE knockdown attenuated iron accumulation but did not influence Ca influx. This study suggests that DMT1(-)IRE-mediated iron accumulation is likely to be the downstream event following NMDA receptor activation and Ca influx, contributing to remifentanil-induced hyperalgesia. PERSPECTIVE: Remifentanil-induced hyperalgesia is common even when used within clinical accepted doses. This study presents that aberrant iron accumulation is involved in the development of remifentanil-induced hyperalgesia in vivo and in vitro. Iron chelation may be a potential therapeutic strategy for the prevention of hyperalgesia in populations at high risk.
Learn More >Pain is a major health problem among US adults. Surprisingly little, however, is known about educational disparities in pain, especially among the nonelderly. In this study, we analyze disparities in pain across levels of educational attainment. Using data from the 2010-2017 National Health Interview Survey among adults aged 30-49 (N=74,051), we estimate logistic regression models of pain prevalence using a dichotomous summary pain index and its five constituent pain sites (low back, joint, neck, headache/migraine, and facial/jaw). We find a significant and steep pain gradient: greater levels of educational attainment are associated with less pain, with two important exceptions. First, adults with a high-school equivalency diploma (GED) and those with 'some college' have significantly higher pain levels than high school graduates despite having an equivalent or higher attainment, respectively. Second, the education-pain gradient is absent for Hispanic adults. After taking into account important covariates including employment, economic resources, health behaviors, physical health conditions, and psychological wellbeing, educational disparities in pain are no longer statistically significant except for the GED and 'some college' categories, which still show significantly higher pain levels than high school graduates. We thus document the overall education-pain gradient in most younger US adult populations, and identify groups where pain is higher than expected (certain educational categories) or lower than expected (e.g., less-educated Hispanics). Understanding the causes of these anomalous findings could clarify factors shaping pain prevalence and disparities therein. PERSPECTIVE Over 50% of US adults age 30-49 report pain. Overall, more educated Americans report substantially less pain than the less educated. However, adults with a GED and 'some college' report more pain than other groups. Understanding the causes could help illuminate the mechanisms through which social factors influence pain.
Learn More >Effective treatment of high-impact pain patients is one of the major stated goals of the National Pain Strategy in the United States. Identification of new targets and mechanisms underlying neuropathic pain will be critical in developing new target-specific medications for better neuropathic pain management. We recently discovered that peripheral nerve injury-induced upregulation of an axonal guidance phosphoprotein collapsin response mediator protein 2 (CRMP2) and the N-type voltage-gated calcium (CaV2.2) as well as the NaV1.7 voltage-gated sodium channel, correlates with the development of neuropathic pain. In our previous studies, we found that interfering with the phosphorylation status of CRMP2 is sufficient to confer protection from chronic pain. Here we examined the expression of CRMP2 and CRMP2 phosphorylated by cyclin-dependent kinase 5 (Cdk5, on serine residue 522 (S522)) in sciatic nerve, nerve terminals of the glabrous skin, and in select subpopulations of DRG neurons in the SNI model of neuropathic pain. By enhancing our understanding of the phosphoregulatory status of CRMP2 within DRG subpopulations, we may be in a better position to design novel pharmacological interventions for chronic pain.
Learn More >Placebo effects influence symptom perceptions and treatment outcomes. Placebo effects can be explored in laboratory settings controlling for natural history and expectations. Such a mechanistic approach to neurological disorders has been implemented in the domain of chronic clinical pain and other neurological disorders. This article therefore focuses on definitions and historical notes related to placebo effects and mechanisms of placebo effects in chronic pain. Knowledge on mechanisms of placebo effects could inform current clinical practice for the treatment of neurological disorders by focusing on patients (and providers) expectations for outcome optimization.
Learn More >Compelling human genetic studies have identified the voltage-gated sodium channel Na1.7 as a promising therapeutic target for the treatment of pain. The analgesic spider-venom-derived peptide μ-theraphotoxin-Pn3a is an exceptionally potent and selective inhibitor of Na1.7; however, little is known about the structure-activity relationships or channel interactions that define this activity. We rationally designed 17 Pn3a analogues and determined their activity at hNa1.7 using patch-clamp electrophysiology. The positively charged amino acids K22 and K24 were identified as crucial for Pn3a activity, with molecular modeling identifying interactions of these residues with the S3-S4 loop of domain II of hNa1.7. Removal of hydrophobic residues Y4, Y27, and W30 led to a loss of potency (>250-fold), while replacement of negatively charged D1 and D8 residues with a positively charged lysine led to increased potencies (>13-fold), likely through alterations in membrane lipid interactions. Mutating D8 to an asparagine led to the greatest improvement in Pn3a potency at Na1.7 (20-fold), while maintaining >100-fold selectivity over the major off-targets Na1.4, Na1.5, and Na1.6. The Pn3a[D8N] mutant retained analgesic activity , significantly attenuating mechanical allodynia in a clinically relevant mouse model of postsurgical pain at doses 3-fold lower than those with wild-type Pn3a, without causing motor-adverse effects. Results from this study will facilitate future rational design of potent and selective peptidic Na1.7 inhibitors for the development of more efficacious and safer analgesics as well as to further investigate the involvement of Na1.7 in pain.
Learn More >Activation of kappa opioid receptor (KOR) produces analgesia, antipruritic effect, sedation and dysphoria. To characterize neuroanatomy of KOR at high resolutions and circumvent issues of specificity of KOR antibodies, we generated a knock-in mouse line expressing KOR fused at the C-terminus with the fluorescent protein tdTomato (KtdT). The selective KOR agonist U50,488H caused anti-scratch effect and hypolocomotion, indicating intact KOR neuronal circuitries. Clearing of brains with CLARITY revealed 3-dimensional (3-D) images of distribution of KOR, and any G protein-coupled receptors, for the first time. 3-D brain images of KtdT and immunohistochemistry (IHC) on brain sections with antibodies against tdTomato show similar distribution to that of autoradiography of [H]U69,593 binding to KOR in wildtype mice. KtdT was observed in regions involved in reward and aversion, pain modulation and neuroendocrine regulation. KOR is present in several areas with unknown roles, including the claustrum, dorsal endopiriform nucleus, paraventricular nucleus of the thalamus, lateral habenula and substantia nigra pars reticulata (SNr), which are discussed. Prominent KtdT-containing fibers were observed to project from caudate putamen (CP) and nucleus accumbens (ACB) to substantia innominata (SI) and SNr. Double IHC revealed co-localization of KtdT with tyrosine hydroxylase (TH) in brain regions, including CP, ACB and ventral tegmental area (VTA). KOR was visualized at the cellular level, such as co-localization with TH and agonist-induced KOR translocation into intracellular space in some VTA neurons. These mice thus represent a powerful and heretofore unparalleled tool for neuroanatomy of KOR at both the 3-D and cellular levels. A combination of tagging KOR with tdTomato and tissue clearing with CLARITY enables 3-D mouse brain imaging of KOR, or any G protein-coupled receptors, for the first time. This approach reveals prominent KOR-expressing fiber bundles from caudate putamen and nucleus accumbens to substantia nigra pars reticulata and allows visualization of the KOR at the cellular level, including co-localization with TH and agonist-induced KOR translocation in some neurons. Regions expressing moderate to high KOR, but with no known functions, are highlighted and discussed, including claustrum, dorsal endopiriform nucleus, paraventricular nucleus of the thalamus and lateral habenula. The mouse line will be a valuable tool for investigation of KOR neurobiology. This approach paves ways for future similar studies.
Learn More >The main cause of trigeminal neuralgia (TN) is compression of a blood vessel at the root entry zone of the trigeminal nerve. However, a neurovascular conflict does not seem to be the only etiology and other mechanisms are implicated in the development of the disease. We hypothesized that TN patients may have distinct protein expression in the CSF. In this study, lumbar CSF from TN patients (n=17), scheduled to undergo microvascular decompression (MVD), and from controls (n=20) was analyzed and compared with mass spectrometry-based shotgun proteomics. 2552 unique proteins were identified of which 46 were significantly altered (26 increased, and 20 decreased, q-value < 0.05) in TN patients compared with controls. An over-representation analysis showed proteins involved in high-density lipoprotein (HDL), such as APOA-4, APOM and APOA-1, and the extracellular region, including proteins involved in the complement cascade to be over-represented. We conclude that TN patients have distinct protein expression in the CSF compared to controls. The pathophysiological background of the protein alterations found in this study warrants further investigation in future studies. Perspective: In this article, cerebrospinal fluid from patients with trigeminal neuralgia was analyzed using in depth shotgun proteomics, revealing 46 differentially expressed proteins compared to controls. Among these, apolipoproteins and proteins involved in the complement system were elevated and significantly over-represented, implying an inflammatory component in the pathophysiology of the disease.
Learn More >Eight P2YR antagonists, including three newly synthesized analogues, containing a naphthalene or phenyl-triazolyl scaffold were compared in a mouse model of chronic neuropathic pain (sciatic constriction). P2YR antagonists rapidly (≤30 min) reversed mechano-allodynia, with maximal effects typically within 1 h after injection. Two analogues (4-[4-(4-piperidinyl)phenyl]-7-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxylic acid and -acetyl analogue , 10 μmol/kg, i.p.) achieved complete pain reversal (100%) at 1 to 2 h, with relief evident up to 5 h for (41%). A reversed triazole analogue reached 87% maximal protection. Receptor affinity was determined using a fluorescent antagonist binding assay, indicating similar mouse and human P2YR affinity. The mP2YR affinity was only partially predictive of efficacy, suggesting the influence of pharmacokinetic factors. Thus P2YR is a potential therapeutic target for treating chronic pain.
Learn More >Acute and chronic pain delay recovery and impair outcomes after major pediatric surgery. Understanding unique risk factors for acute and chronic pain is critical to developing effective treatments for youth at risk. We aimed to identify adolescent and family psychosocial predictors of acute and chronic postsurgical pain following major surgery in adolescents. Participants included 119 youth age 10-18 years (M=14.9;78.2% white) undergoing major musculoskeletal surgery and their parents. Participants completed pre-surgery baseline questionnaires, with youth reporting on baseline pain, anxiety, depression, insomnia and sleep quality, and parents reporting on parental catastrophizing and family functioning. At baseline, 2-weeks, and 4-months post-surgery, youth completed 7-days of daily pain diaries and reported on health-related quality of life. Sequential logistic regression models examined pre-surgery predictors of acute and chronic postsurgical pain, defined as significant pain with impairment in health-related quality of life. Acute pain was experienced by 27.2% of youth at 2-weeks, while 19.8% of youth met criteria for chronic pain at 4-months. Baseline pain predicted acute pain (OR=1.96; 95%CI=1.32-2.90), while depressive symptoms (OR=1.22; 95%CI=1.01-1.47) and sleep quality (OR=0.26; 95%CI=0.08-0.83) predicted chronic pain. Tailored interventions need to be developed and incorporated into perioperative care to address risk factors for acute and chronic pain. Perspective: Longitudinal results demonstrate adolescents' pre-surgery pain severity predicts acute postsurgical pain, while depressive symptoms and poor sleep quality predict chronic postsurgical pain. Tailored interventions should address separate risk factors for acute and chronic pain after adolescent surgery.
Learn More >Avoidance behavior is protective, yet in the absence of genuine bodily threat, it may become disabling. Therefore, we investigated whether avoidance generalizes to novel safe contexts based on the similarity with the acquisition context. Healthy participants performed arm movements using a robotic arm to reach a target. Three trajectories (T1-3) led to the target. During acquisition, a painful stimulus could be partly/completely prevented by performing more effortful trajectories (i.e. longer and more force needed), T2/T3, in the pain-avoidance context (e.g. black background); in the yoked context (e.g. white background), the same reinforcement schedule was applied irrespective of the chosen trajectories. Generalization of avoidance was tested in two novel contexts (e.g. shades of grey backgrounds). We assessed self-reported pain-expectancy and pain-related fear for all trajectories, and avoidance behavior (i.e. maximal deviation from T1). Results confirm that fear and expectancy ratings reflect the response-outcome contingencies and differential learning selectively generalized to the novel context resembling the original pain-avoidance context. Furthermore, a linear trend in avoidance behavior across contexts emerged, which is indicative of a generalization gradient. Participants avoided more in the context resembling the original pain-avoidance context than in the one resembling the yoked context, but this effect was not statistically significant. PERSPECTIVE: We demonstrated acquisition of pain-related avoidance behavior in a within-subjects design, showing modulation of pain-related fear and pain-expectancy by context and providing limited evidence that avoidance selectively generalizes to novel, similar contexts. These results provide insight regarding the underlying mechanisms of the spreading of protective behavior in chronic pain patients.
Learn More >The main objective of this study was to assess painful memory as well as long-term episodic memory, both in patients with chronic pain (CP) and in asymptomatic participants (AP).
Learn More >To understand the changes in functional connectivity between brain areas of potential importance in migraine during different phases of the attack.
Learn More >Glycine receptor α1 subunit is located at inhibitory synapses in the superficial dorsal horn of adult spinal cord and is engaged in the glycinergic inhibition of nociceptive neuronal excitability and transmission. The α1 phosphorylation at Ser380 by extracellular signal-regulated kinase (ERK) has been shown to decrease glycinergic synaptic currents and contribute to spinal disinhibition. Here we found that peripheral inflammation induced by Complete Freund's Adjuvant increased Ser380 phosphorylation in spinal cord dorsal horn of mice, which was repressed by specific activation of adenosine A1 receptor (A1R). Protein phosphatase-1 (PP1), a ubiquitously-distributed serine/threonine phosphatase, was required for A1R to reduce Ser380 phosphorylation. Our data showed that Gβγ dimer, when released after activation of Gi protein-coupled A1R, interacted with PP1 and directed this phosphatase to α1, allowing for the full dephosphorylation of Ser380 residue. Sequestration of Gβγ dimer by viral expression of the C-terminal tail of β-adrenergic receptor kinase (βARKct) dissociated PP1 from α1 complex, leading to robust Ser380 phosphorylation. Meanwhile, Gβγ inhibition compromised the ability of A1R to alleviate inflammatory pain. The inhibitory effect of A1R on Ser380 phosphorylation was also attributed to the inactivation of ERK in CFA mice. Our data thus identified glycine receptor α1 subunit as an important target for adenosinergic suppression of inflammatory pain.
Learn More >Glutamate and metabotropic glutamate receptors on primary sensory neurons play a pivotal role in modulating pain sensitivity. However, it is unclear how inflammation affects mGluR-mediated nociceptive responses. We therefore investigated the effects of mGluR1/5 agonists on pain-related behavior under persistent inflammation and explored the underlying mechanisms.
Learn More >Gabapentinoid drugs (gabapentin and pregabalin) are effective in neuropathic pain, which has a prevalence of ∼7%. Concerns about increased prescribing have implications for patient safety, misuse, and diversion. Drug-related deaths (DRDs) have increased and toxicology often implicates gabapentinoids. We studied national and regional prescribing rates (2006-2016) and identified associated sociodemographic factors, co-prescriptions and mortality, including DRDs.
Learn More >Post-traumatic headache (PTH) is a condition that frequently affects individuals after traumatic brain injury (TBI). Inflammation is one of the major causes of this disability. However, little is known about the trigger for, and endurance of, this painful process. Thus, the involvement of fibers containing the transient receptor potential vanilloid 1 (TRPV1) channels on the PTH and inflammation after TBI through neonatal treatment with capsaicin are investigated. Fluid percussion injury (FPI) in adult male Wistar rats caused periorbital allodynia in one, three and seven days after injury, and the neonatal treatment reversed the painful sensation in seven days. The lack of TRPV1 channels reduced the activation of macrophages and glial cells induced by TBI in the trigeminal system, which were characterized by glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule-1 (IBA-1) immune content in the ipsilateral trigeminal ganglion, brainstem, and perilesional cortex. Immunofluorescence analyses of the ipsilateral Sp5C nucleus demonstrated a hypertrophic astrocytes profile after TBI which was reduced with treatment. Moreover, effects of succinate sumatriptan (SUMA – 1 mg/kg), TRPV1 selective antagonist capsazepine (CPZ – 2 mg/kg), and TRP non-selective antagonist ruthenium red (RR – 3 mg/kg) were evaluated. Although all mentioned drugs reduced the painful sensation, SUMA and CPZ demonstrated a stronger effect compared to the RR treatment, reinforcing the involvement of TRPV1 channels in periorbital allodynia after TBI. Hence, this report suggests that TRPV1-containing fibers and TRPV1 channels are able to induce inflammation of the trigeminal system and maintain the painful sensation after TBI.
Learn More >Tissue injury and inflammation may result in chronic pain, a severe debilitating disease that is associated with great impairment of quality of life. An increasing body of evidence indicates that members of the Rab family of small GTPases contribute to pain processing; however, their specific functions remain poorly understood. Here, we found using immunofluorescence staining and in situ hybridization that the small GTPase Rab27a is highly expressed in sensory neurons and in the superficial dorsal horn of the spinal cord of mice. Rab27a mutant mice, which carry a single-nucleotide missense mutation of Rab27a leading to the expression of a nonfunctional protein, show reduced mechanical hyperalgesia and spontaneous pain behavior in inflammatory pain models, while their responses to acute noxious mechanical and thermal stimuli is not affected. Our study uncovers a previously unrecognized function of Rab27a in the processing of persistent inflammatory pain in mice.
Learn More >Current deficiency in our understanding of acute-to-chronic pain transition remains a hurdle for developing effective treatments against chronic pain. Whereas neurocentric mechanisms alone are insufficient to provide satisfactory explanation for such transition, neuro-immune crosstalk has attracted attention in recent pain research. In contrast to brain microglia, spinal microglia are activated immediately in various pain states. The fast-responsive enrichment and activation of spinal microglia among different pain conditions have highlighted the crucial role of neuroinflammation caused by microglia-neuron crosstalk in pain initiation. Recent studies have revealed spinal microglia-neuron interactions are also involved in chronic pain maintenance, albeit, with different anatomic distribution, cellular and molecular mechanisms, and biologic functions. Delineating the exact temporal discrepancies of spinal microglia distribution and functions along acute-to-chronic pain transition may provide additional mechanistic insights for drug development to prevent deterioration of acute pain into the chronic state. This narrative review summerizes the longitudinal alterations of spinal microglia-neuron interactions in the initiation of pain hypersensitivity, acute-to-chronic pain progression, and chronic pain maintenance, followed by an overview of current clinical translation of preclinical studies on spinal microglia. This review highlights the crucial role of the interaction between spinal microglia and neighboring neurons in the initiation and maintenance of pain hypersensitivity, in relation to the release of cytokines, chemokines, and neuroactive substances, as well as the modulation of synaptic plasticity. Further exploration of the uncharted functions of spinal microglia-neuron crosstalk may lead to the design of novel drugs for preventing acute-to-chronic pain transition.
Learn More >Epigenetics of neurotrophic factors holds the potential to unravel the mechanisms underlying the pathophysiology of complex conditions such as chronic fatigue syndrome (CFS). This study explored the role of brain-derived neurotrophic factor (BDNF) genetics, epigenetics, and protein expression in patients with both CFS and comorbid fibromyalgia (CFS/FM).
Learn More >While dipyrone is a widely used analgesic, its mechanism of action is not completely understood. Recently we have reported that the dipyrone metabolite 4-aminoantipirine (4-AA) reduces prostaglandin E (PGE )-induced pain-related behaviour through the cannabinoid type 1 (CB1) receptor. Here, we ascertained, in naive and PGE -induced "inflamed" conditions, both in vivo and in vitro, the molecular mechanisms involved in the 4-AA-induced analgesic effects.
Learn More >Numerous factors are considered in the academic promotion of pain medicine physicians. In this study, we investigated the importance of research productivity, career duration, leadership, and gender on attaining professorship in chronic pain medicine fellowship programs in the USA.
Learn More >The power of placebos is commonly associated with the placebo effect. In contrast, detrimental effects related to the use of a placebo are little studied and less well recognized. This chapter covers the nocebo and lessebo effects defined, respectively, as expectation of harm in the form of adverse events in a placebo arm and reduction of therapeutic benefit due to the uncertainty of being allocated to placebo. The lessebo effect is a more recent concept and has been described only in depression, schizophrenia and Parkinson's disease. The nocebo response was evaluated in many neurological diseases, including epilepsy, multiple sclerosis, Parkinson's disease, Alzheimer's disease, restless leg syndrome, among others. Meta-analyses of randomized controlled trials in these conditions reveal a significant variability of the magnitude of the nocebo response and that factors related to study design, study participants or neurological disease can be associated with a nocebo response, although with the opposing findings across conditions. The knowledge about neurobiological mechanisms of the nocebo effect is poor for neurological diseases, and most of the information has been generated in pain. Functional neuroimaging suggests the existence of a distinct network for the anticipation and the experience of a hyperalgesia nocebo response. Different types of neurotransmitters have been involved, including cholecystokinin, dopamine and opioids. Recognizing the potential impact of nocebo and lessebo effects, mitigating strategies are in development with application to clinical research and clinical practice, such as a contextualized informed consent process, alternative study designs and enhancement of patient-physician communication.
Learn More >The development of antinociceptive morphine tolerance is a clinically intractable problem. Previous studies clarified the pivotal roles of platelet-derived growth factor (PDGF) and its receptor PDGFRβ in morphine tolerance. Herein, we investigated the role of spinal heat shock protein 27 (HSP27) in morphine tolerance and its relationship with PDGFRβ activation.
Learn More >The management of acute and chronic pain for individuals living with sickle cell disease (SCD) is a clinical challenge. This reflects the paucity of clinical SCD pain research and limited understanding of the complex biological differences between acute and chronic pain. These issues collectively create barriers to effective, targeted interventions. Optimal pain management requires interdisciplinary care.
Learn More >Pain is evolutionarily hardwired to signal potential danger and threat. It has been proposed that altered pain-related associative learning processes, i.e., emotional or fear conditioning, might contribute to the development and maintenance of chronic pain. Pain in or near the face plays a special role in pain perception and processing, especially with regard to increased pain-related fear and unpleasantness. However, differences in pain-related learning mechanisms between the face and other body parts have not yet been investigated. Here, we examined body-site specific differences in associative emotional conditioning using electrical stimuli applied to the face and the hand. Acquisition, extinction, and reinstatement of cue-pain associations were assessed in a 2-day emotional conditioning paradigm using a within-subject design. Data of 34 healthy subjects revealed higher fear of face pain as compared to hand pain. During acquisition, face pain (as compared to hand pain) led to a steeper increase in pain-related negative emotions in response to conditioned stimuli (CS) as assessed using valence ratings. While no significant differences between both conditions were observed during the extinction phase, a reinstatement effect for face but not for hand pain was revealed on the descriptive level and contingency awareness was higher for face pain compared to hand pain. Our results indicate a stronger propensity to acquire cue-pain-associations for face compared to hand pain, which might also be reinstated more easily. These differences in learning and resultant pain-related emotions might play an important role in the chronification and high prevalence of chronic facial pain and stress the evolutionary significance of pain in the head and face.
Learn More >Individuals with spinal cord injury (SCI) often develop debilitating neuropathic pain, which may be driven by neuronal damage and neuroinflammation. We have previously demonstrated that treatment using 670 nm (red) light irradiation alters microglia/macrophage responses and alleviates mechanical hypersensitivity at 7-days post-injury. Here, we investigated the effect of red-light on the development of mechanical hypersensitivity, neuronal markers, and glial response in the subacute stage (days 1-7) following SCI. Wistar rats were subjected to a mild T10 hemi-contusion SCI or sham surgery followed by daily red-light treatment (30 min/day; 670 nm LED; 35 mW/cm2) or sham treatment. Mechanical sensitivity of the rat dorsum was assessed from 1-day post-injury and repeated every second day. Spinal cords were collected at 1, 3, 5 and 7-days post injury for analysis of myelination, neurofilament protein NF200 expression, neuronal cell death, reactive astrocytes (GFAP+ cells), interleukin1β (IL1β) expression, and inducible nitric oxide synthase (iNOS) production in IBA1+ microglia/macrophages. Red-light treatment significantly reduced the cumulative mechanical sensitivity and the hypersensitivity incidence following SCI. This effect was accompanied by significantly reduced neuronal cell death, reduced astrocyte activation and reduced iNOS expression in IBA1+ cells at the level of the injury. However, myelin and NF200 immunoreactivity and IL1β expression in GFAP+ and IBA1+ cells were not altered by red-light treatment. Thus, red-light therapy may represent a useful non-pharmacological approach for treating pain during the subacute period after SCI by decreasing neuronal loss and modulating the inflammatory glial response.
Learn More >Knee pain from osteoarthritis is frequent in the adult population. Prior trials have had conflicting results concerning vitamin D's therapeutic effects on knee pain and few trials have investigated marine omega-3 fatty acids (n-3 FA).
Learn More >Activation of glial cells has been shown to play an important role in chronic itch. However, whether glial cells play an important role in the development of psoriasis-induced chronic itch has not been fully elucidated. This study investigated the role of spinal glial cells in psoriasis-induced chronic itch. To develop a mouse model of psoriasis-induce chronic itch, we used 5% imiquimod cream to receive a daily topical application on the shaved back skin for seven consecutive days. The results showed that the expression of microglial marker ionized calcium binding adaptor molecule-1 was significantly increased after 5% imiquimod treatment in cervical spinal cord dorsal horn (C3-C4), and the intrathecal microglial inhibitor minocycline or PLX5622 diet suppressed both spontaneous itch and microglial activation. Furthermore, we found that the number of scratches and alloknesis score in female mice was significantly greater than in male mice after 5% imiquimod treatment. Our results indicate that microglia mediate chronic psoriatic itch induced by imiquimod.
Learn More >Glycine receptors (GlyRs) mediate inhibitory neurotransmission within the spinal cord and play a crucial role in nociceptive signalling. This makes them primary targets for the development of novel chronic pain therapies. Endogenous lipids have previously been shown to modulate glycine receptors and produce analgesia in pain models, however little is known about what chemical features mediate these effects. In this study, we characterised lipid modulation of GlyRs by screening a library of N-acyl amino acids across all receptor subtypes and determined chemical features crucial for their activity. Acyl-glycine's with a C18 carbon tail were found to produce the greatest potentiation, and require a cis double bond within the central region of the carbon tail (ω6 – ω9) to be active. At 1 µM, C18 ω6,9 glycine potentiated glycine induced currents in α and αβ receptors by over 50%, and α, α, αβ and αβ receptors by over 100%. C18 ω9 glycine (N-oleoyl glycine) significantly enhance glycine induced peak currents and cause a dose-dependent shift in the glycine concentration response. In the presence of 3 µM C18 ω9 glycine, the EC of glycine at the α receptor was reduced from 17 µM to 10 µM. This study has identified several acyl-amino acids which are positive allosteric modulators of GlyRs and make promising lead compounds for the development of novel chronic pain therapies.
Learn More >Migraine clinical profile may change with age, making it necessary to verify that migraine treatments are equally safe and effective in older patients. These analyses evaluated the effects of patient age on the pharmacokinetics (PK), efficacy, and safety of galcanezumab for prevention of migraine.
Learn More >Type 2 diabetes related polyneuropathy (DPN) is associated with increased vascular events and mortality, but determinants and outcomes of pain in DPN are poorly understood. We sought to examine the effect of neuropathic pain on vascular events and mortality in patients without DPN, DPN with pain (DPN+P), and DPN without pain (DPN-P).
Learn More >To evaluate the potential for pharmacokinetic interaction and the safety and tolerability when ubrogepant and sumatriptan are coadministered in a Phase 1 study in healthy participants, and to inform the safety and tolerability of ubrogepant alone and in combination with triptans in Phase 3 trials in participants with migraine.
Learn More >The impact of psychosocial vulnerability on pain in the year following breast cancer diagnosis has been little studied. To identify a score of psychosocial vulnerability (cognitive, emotional, quality of life and precariousness parameters) as a predictor of a pain trajectory, we conducted an observational prospective study and included women with newly diagnosed breast cancer. One year follow-up with 3 visits (day of breast cancer diagnosis; 6 and 12 months) aimed to identify distinct pain-time trajectories. Baseline psychosocial vulnerability was characterized by z-score transformation, a higher score representing a more vulnerable patient. A total of 89 patients were included (59.3 ± 10.7 years). Two trajectories of pain were identified-"Transient Pain trajectory" (TP) (39/89 patients) and "Persistent Pain trajectory" (PP) (50/89). A significant difference of pain over time between trajectories (PP vs. TP at 6 months: 2.23 ± 0.23 vs. 0.27 ± 0.09, < 0.001) was observed. Psychosocial vulnerability showed a large effect size (d, -0.82; 95% CI, -1.25 to -0.38; < 0.001) and a higher score in "Persistent pain trajectory" (PP vs. TP: 0.12 ± 0.36 vs. -0.14 ± 0.26, < 0.001). A predictive vulnerability marker of pain development is proposed and could be used at cancer diagnosis to orientate the care pathway of patients experiencing breast cancer.
Learn More >Painful peripheral neuropathy is a common adverse effect of paclitaxel (PTX) treatment. To analyze the contribution of transient receptor potential vanilloid 1 (TRPV1) in the development of PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia, TRPV1 expression in the rat spinal cord was analyzed after intraperitoneal administration of 2 and 4 mg/kg PTX. PTX treatment increased the expression of TRPV1 protein in the spinal cord. Immunohistochemistry showed that PTX (4 mg/kg) treatment increased TRPV1 protein expression in the superficial layers of the spinal dorsal horn 14 days after treatment. Behavioral assessment using the paw withdrawal response showed that PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia after 14 days was significantly inhibited by oral or intrathecal administration of the TRPV1 antagonist AMG9810. We found that intrathecal administration of small interfering RNA (siRNA) to knock down TRPV1 protein expression in the spinal cord significantly decreased PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia. Together, these results demonstrate that TRPV1 receptor expression in spinal cord contributes, at least in part, to the development of PTX-induced painful peripheral neuropathy. TRPV1 receptor antagonists may be useful in the prevention and treatment of PTX-induced peripheral neuropathic pain.
Learn More >Binaural Beats (BB) consist of two artificial acoustic stimuli with different frequency, presented simultaneously but independently to each ear. The human brain perceives and synchronizes to this frequency difference (entrainment).
Learn More >Tremendous progress has been made in the past decades for the treatment of headache disorders. Chronic migraine is the most disabling type of headache and requires the use of acute and preventive medications, many of which are associated with adverse events that limit patient adherence. Botulinum toxin (BoNT) serotype A, a neurotoxin derived from certain strains of Clostridium, disrupts neuropeptide secretion and receptor translocation related to trigeminal nociception, thereby preventing pain sensitization through peripheral and possibly central mechanisms. Ever since the first randomized controlled trial on onabotulinumtoxinA (onabotA) for migraine was published two decades ago, onabotA has been the only BoNT formulation approved for use in the prevention of chronic migraine. Superior tolerability and efficacy have been demonstrated on multiple migraine endpoints in many controlled trials and real-life studies. OnabotA is a safe and efficacious treatment for chronic migraine and possibly high-frequency episodic migraine. Further research is still needed to understand its mechanism of action to fully develop its therapeutic potential.
Learn More >Healthy peripheral nerves encounter, with increased frequency, numerous chemical, biological, and biomechanical forces. Over time and with increasing age, these forces collectively contribute to the pathophysiology of a spectrum of traumatic, metabolic, and/or immune-mediated peripheral nerve disorders. The blood-nerve barrier (BNB) serves as a critical first-line defense against chemical and biologic insults while biomechanical forces are continuously buffered by a dense array of longitudinally orientated epineural collagen fibers exhibiting high-tensile strength. As emphasized throughout this Experimental Neurology Special Issue, the BNB is best characterized as a functionally dynamic multicellular vascular unit comprised of not only highly specialized endoneurial endothelial cells, but also associated perineurial cells, pericytes, Schwann cells, basement membrane, and invested axons. The composition of the BNB, while anatomically distinct, is not functionally dissimilar to that of the well characterized neurovascular unit of the central nervous system. While the BNB lacks a glial limitans and an astrocytic endfoot layer, the primary function of both vascular units is to establish, maintain, and protect an optimal endoneurial (PNS) or interstitial (CNS) fluid microenvironment that is vital for proper neuronal function. Altered endoneurial homeostasis as a secondary consequence of BNB dysregulation is considered an early pathological event in the course of a variety of traumatic, immune-mediated, or metabolically acquired peripheral neuropathies. In this review, emerging experimental advancements targeting the endoneurial microvasculature for the therapeutic management of immune-mediated inflammatory peripheral neuropathies, including the AIDP variant of Guillain-Barré syndrome, are discussed.
Learn More >The present study explores the benefits of an 8-week mindfulness-based stress reduction (MBSR) program to white matter integrity among breast cancer survivors experiencing chronic neuropathic pain (CNP).
Learn More >Migraine is a complex neurovascular disorder characterized by attacks of moderate to severe unilateral headache, accompanied by photophobia or other neurological signs. Although an arsenal of antimigraine agents is currently available in the market, not all patients respond to them. As calcitonin gene-related peptide (CGRP) plays a key role in the pathophysiology of migraine, CGRP receptor antagonists (gepants) have been developed. Unfortunately, further pharmaceutical development (for olcegepant and telcagepant) was interrupted due to pharmacokinetic issues observed during the randomized clinical trials (RCT). On this basis, the use of monoclonal antibodies (mAbs; immunoglobulins) against CGRP or its receptor has recently emerged as a novel pharmacotherapy to treat migraine. RCT showed that these mAbs are effective against migraine producing fewer adverse events. Presently, the U.S. Food and Drug Administration approved four mAbs, namely: (i) erenumab; (ii) fremanezumab; (iii) galcanezumab; and (iv) eptinezumab. In general, specific antimigraine compounds exert their action in the trigeminovascular system, but the locus of action (peripheral vs. central) of the mAbs remains elusive. Since these mAbs have a molecular weight of 150 kDa, some studies rule out the relevance of their central actions as they seem unlikely to cross the blood-brain barrier (BBB). Considering the therapeutic relevance of this new class of antimigraine compounds, the present review has attempted to summarize and discuss the current evidence on the probable sites of action of these mAbs.
Learn More >Cortical spreading depression (CSD) is a pathological neural excitation that underlies migraine pathophysiology. Since glutamate receptor antagonists impair CSD propagation, susceptibility to CSD might be determined by any of the neuronal (excitatory amino acid carrier 1 [EAAC1]) and glial (GLutamate ASpartate Transporter [GLAST] and glial glutamate transporter 1 [GLT-1]) glutamate transporters, which are responsible for clearing extracellular glutamate. To investigate this hypothesis, we performed electrophysiological, hemodynamic, and electrochemical analyses using EAAC1- (EAAC1 KO), GLAST- (GLAST KO), and conditional GLT1-1-knockout mice (GLT-1 cKO) to assess altered susceptibility to CSD. Despite the incomplete deletion of the gene in the cerebral cortex, GLT-1 cKO mice exhibited significant reduction of GLT-1 protein in the brain without apparent alteration of the cytoarchitecture in the cerebral cortex. Physiological analysis revealed that GLT-1 cKO showed enhanced susceptibility to CSD elicited by chemical stimulation with increased CSD frequency and velocity compared to GLT-1 control. In contrast, the germ-line EAAC1 and GLAST KOs showed no such effect. Intriguingly, both field potential and cerebral blood flow showed faster dynamics with narrower CSD than the controls. An enzyme-based biosensor revealed more rapid accumulation of glutamate in the extracellular space in GLT-1 cKO mice during the early phase of CSD than in GLT-1 control, resulting in an increased susceptibility to CSD. These results provided the first evidence for a novel role of GLT-1 in determining susceptibility to CSD.
Learn More >Biases in the way that people direct their attention towards or away from pain-related information are hypothesised to contribute to the onset and severity of pain-related disorders. This systematic review summarised 24 eye-tracking studies (N = 1424) examining effects of chronic pain, stimulus valence, individual differences in pain-related constructs such as fear of pain and pain catastrophising, and experimentally-induced pain or pain-related threat on attentional processing of visual stimuli. The majority of studies suggest that people with and without chronic pain do not differ in their eye movements on pain-related stimuli, although there is preliminary evidence that gaze biases vary across subtypes of chronic pain and may be evident only for certain stimuli. In contrast, participants with and without chronic pain exhibit a general tendency to allocate more first fixations and total fixations upon pain-related compared to neutral stimuli. Fear of pain was found to have limited effects on eye movements, whereas the tendency to catastrophise about pain, the anticipation of pain, and actual experimental pain stimulation have had stronger associations with eye movements, although results have been mixed. Methodological limitations and future research directions are discussed.
Learn More >The COVID-19 health emergency has led many Headache providers to transition to virtual care overnight without preparation. We review our experience and discuss tips to bring humanity to the virtual visits.
Learn More >The aim was to quantify and to compare the associations between longitudinal changes in pain and depression in different chronic pain conditions.
Learn More >The prevalence of obesity skyrocketed over the past decades to become a significant public health problem. Obesity is recognized as a low-grade inflammatory disease and is linked with several comorbidities such as diabetes, circulatory disease, common neurodegenerative diseases, as well as chronic pain. Adipocytes are a major neuroendocrine organ that continually, and systemically, releases pro-inflammatory factors. While the exact mechanisms driving obesity-induced pain remain poorly defined, nociceptor hypersensitivity may result from the systemic state of inflammation characteristic of obesity as well as weight surplus-induced mechanical stress. Obesity and pain also share various genetic mutations, lifestyle risk factors, and metabolic pathways. For instance, fat pads are often found hyper-innervated and rich in immune cell types of multiple origins. These immunocytes release cytokines, amplifying nociceptor function, which, in turn, via locally released neuropeptides, sustain immunocytes' function. Here, we posit that along with mechanical stress stemming from extra weight, the local neuro-immune interplay occurring within the fat pads maintains the state of chronic low-grade inflammation and heightens sensory hypersensitivity. Overall, stopping such harmful neuro-immune crosstalk may constitute a novel pathway to prevent obesity-associated comorbidities, including neuronal hypersensitivity.
Learn More >The INTERMED instrument, which was developed to measure patient's biopsychosocial (BPS) complexity, represents a powerful diagnostic and therapeutic tool. Epigenetic changes are the interface between signals from the environment and genetic modifications, affecting gene expression, in particular, by DNA methylation of CpG dinucleotides in promotor regions of the corresponding genes. The brain-derived neurotrophic factor (BDNF) gene plays a crucial role in the central sensitization (CS) of pain. In this study, we hypothesized that chronic pain modifies the methylation levels of the BDNF gene in a manner that is interconnected with the BPS status.
Learn More >Latent sensitization is a long-term model of chronic pain in which hyperalgesia is continuously suppressed by opioid receptors, as demonstrated by the induction of mechanical allodynia by opioid antagonists. Different intracellular signals may mediate the initiation, maintenance and expression of latent sensitization. Our criterion for the involvement of a signal in the maintenance of latent sensitization is that inhibitors should permanently eliminate the allodynia produced by an opioid antagonist. We hypothesized that Src family kinases (SFKs) maintain latent sensitization and tested this hypothesis by inducing latent sensitization in rats with complete Freund's adjuvant (CFA) or spared nerve injury. After measures of mechanical allodynia returned to baseline, vehicle or the SFK inhibitor PP2 were injected intrathecally. The opioid antagonist naltrexone injected intrathecally 15 min later produced allodynia in control rats but not in rats injected with PP2. Vehicle or PP2 were injected daily for two more days and naltrexone was injected five days later. Again, naltrexone induced allodynia in the control rats but not in the rats injected with PP2. Results were similar when latent sensitization was induced with CFA or spared nerve injury. We concluded that an SFK, likely Fyn, maintains latent sensitization induced by inflammation or nerve injury.
Learn More >Although the prevalence of migraine tends to decrease in the fifth to sixth decades of life, there are still a significant number of patients > 65 years of age who experience migraine or have new-onset migraine. Because these older patients are often excluded from clinical trials, there are fewer evidence-based treatment guidelines for them. Migraine treatment in the older population requires careful consideration of changes in medication metabolism and increased medical comorbidities. Furthermore, older patients can present with an atypical migraine phenotype and have a higher rate of secondary headache, which may lead to a delay in diagnosis and subsequent treatment. Classic preventive treatments for migraine, including tricyclic antidepressants, antiepileptic drugs, and beta blockers, often have intolerable side effects. In addition, the presence of coronary artery disease, stroke, and peripheral arterial disease precludes the use of typical rescue medications such as triptans. As such, there has been a dire need for novel acute and preventive treatments for older adults. The purpose of this review is to provide an update on novel acute and preventive treatments for migraine in the older population. The advantages of these therapies include their efficacy, favorable side-effect profile, particularly in patients with atherosclerotic disease, as well as their tolerability.
Learn More >The pharmacological activation of A receptors has shown potential usefulness in the management of bowel inflammation. However, the role of these receptors in the control of visceral hypersensitivity in the presence of intestinal inflammation has not been investigated. The effects of AR170, a potent and selective A receptor agonist, and dexamethasone (DEX) were tested in rats with 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis to assess their tissue inflammatory parameters. The animals received AR170, DEX, or a vehicle intraperitoneally for 6 days, starting 1 day before the induction of colitis. Visceral pain was assessed by recording the abdominal responses to colorectal distension in animals with colitis. Colitis was associated with a decrease in body weight and an increase in spleen weight. The macroscopic damage score and tissue tumor necrosis factor (TNF), interleukin 1β (IL-1β), and myeloperoxidase (MPO) levels were also enhanced. AR170, but not DEX, improved body weight. Both drugs counteracted the increase in spleen weight, ameliorated macroscopic colonic damage, and decreased TNF, IL-1β, and MPO tissue levels. The enhanced visceromotor response (VMR) in rats with colitis was decreased via AR170 administration. In rats with colitis, AR170 counteracted colonic inflammatory cell infiltration and decreased pro-inflammatory cytokine levels, thereby relieving visceral hypersensitivity.
Learn More >Some chronic pain conditions and comorbidities suppress the hypothalamic-pituitary-adrenal (HPA) axis and response to dynamic testing. We measured HPA axis responses to corticotropin-releasing hormone (CRH) administration in relation to chronic pelvic pain and endometriosis. In a cross-sectional study of women (n = 54) with endometriosis-associated chronic pelvic pain (n = 22), chronic pelvic pain alone (n = 12), or healthy volunteers (n = 20), adrenocorticotropic-releasing hormone (ACTH) and cortisol levels were measured at 0, 15, 30, and 45 min after intravenous ovine CRH administration. ACTH and cortisol delta (peak-baseline) and area under the curve (AUC) were compared by study group and assessed for association with race and menstrual and non-menstrual pain severity. HPA axis responses did not differ among the racially diverse groups or in those with pain compared with healthy volunteers. However, when stratified by race, ACTH delta (129.9 ± 130.7 vs. 52.5 ± 66.0 pg/mL; p = 0.003), ACTH AUC (4813 ± 4707 vs. 2290 ± 2900 min*pg/mL; p = 0.013), and cortisol delta (26.3 ± 21.5 vs. 13.2 ± 9.7 μg/mL; p = 0.005) were significantly higher in black (n = 10) than predominately white (non-black) subjects (n = 44; 39/44 white). In analyses among primarily white (non-black) women, greater menstrual pain severity was associated with blunted ACTH delta (p = 0.015) and cortisol delta (p = 0.023), and greater non-menstrual pain severity with blunted cortisol delta (p = 0.017). Neuroendocrine abnormalities in women with chronic pelvic pain may differ by pain manifestations and may vary by race. The higher HPA axis response in black women merits investigation in pelvic pain studies stratified by race. In white (non-black) women experiencing pain, a blunted response was related to pain severity suggesting pain affects women independently of endometriosis lesions.
Learn More >Anti-cancer therapy based on the repeated administration of oxaliplatin is limited by the development of a disabling neuropathic syndrome with detrimental effects on the patient's quality of life. The lack of effective pharmacological approaches calls for the identification of innovative therapeutic strategies based on new targets. We focused our attention on the imidazoline I receptor (I-R) and in particular on the selective I-R agonist 2-(1-([1,1'-biphenyl]-2-yl)propan-2-yl)-4,5-dihydro-1H-imidazole) (carbophenyline). The purpose of this work was the preclinical evaluation of the efficacy of carbophenyline on oxaliplatin-induced neuropathic pain in mice. Carbophenyline, acutely per os administered (0.1-10 mg kg), induced a dose-dependent anti-hyperalgesic effect that was completely blocked by the pre-treatment with the I-R antagonist 3 or the I/α receptor antagonist efaroxan, confirming the I-R-dependent mechanism. Conversely, pre-treatment with the I-R antagonist BU224 did not block the anti-nociceptive effect evoked by carbophenyline. Repeated oral administrations of carbophenyline (1 mg kg) for 14 days, starting from the first day of oxaliplatin injection, counteracted the development of neuropathic pain in all behavioral tests (cold plate, Von Frey, and paw pressure tests) carried out 24 h after the last carbophenyline treatment on days 7 and 14. In the dorsal horn of the spinal cord, carbophenyline significantly decreased the oxaliplatin-induced astrocyte activation detected by immunofluorescence staining by the specific labelling with GFAP antibody. In conclusion, carbophenyline showed anti-neuropathic properties both after acute and chronic treatment with preventive effect against oxaliplatin-induced astrocyte activation in the spinal cord. Therefore, I-R agonists emerge as a new class of candidates for the management of oxaliplatin-induced neuropathic pain.
Learn More >Chronic pain is consistently associated with the presence of mental health disorders. Although previous research has shown relations between low levels of self-efficacy with chronic pain severity as well as comorbid mental health symptoms, the link between self-efficacy and mental health symptoms in chronic pain is not well understood. This study examined whether pain centrality, the extent to which pain is viewed as central to self-identity, may underlie these associations. Individuals with a diagnosis of chronic pain (N = 89) recruited through MTurkcompleted self-report measures including demographics, self-efficacy, pain centrality, pain severity, depression, and anxiety. Pain severity was associated with higher levels of pain centrality, depression, anxiety, and lower levels of self-efficacy. Path analysis demonstrated pain centrality significantly mediated the relationship between self-efficacy and pain severity, depression, and anxiety. Future studies would benefit from testing whether modifying pain centrality beliefs shift perceptions of control as well as pain and psychological outcomes.
Learn More >Better understanding of the episodic cancer pain (CP) spectrum, including pains that occur in addition to its conventionally defined breakthrough CP (BTcP) and incident CP (IcP) components, may inform CP assessment and management. This study aimed to determine the prevalence of episodic patient-reported CP and the prevalence and associations of study-defined BTcP (S-BTcP) and IcP (S-IcP) in patients with CP.
Learn More >Migraine is a complex and disabling neurological disorder, and the exact neurological mechanisms remain unclear. Thalamus is considered the hub of the central processing and integration of nociceptive information, as well as the modulation of these processes.
Learn More >Nonsteroidal anti-inflammatory drugs (NSAIDs) are, in general, the cornerstone of musculoskeletal pain management; however, systemic adverse events with oral formulations of NSAIDs are common. To address this problem and limit systemic exposure, topical formulations of some NSAIDs have been developed. The aim of this systematic review was to assess the available evidence on the efficacy and safety of the topical formulations of the NSAID etofenamate in patients with musculoskeletal disorders.
Learn More >An increasing number of patients with chronic persistent post-traumatic headache (PPTH) after mild traumatic brain injury (MTBI) are being referred to headache or pain specialists as conventional treatment options for primary headache disorders have not been able to adequately alleviate their debilitating headache symptoms. Evolving clinical and mechanistic evidences support the notation that chronic persistent MTBI related headaches (MTBI-HA) carry the hallmark characteristics of neuropathic pain. Thus, in addition to conventional treatment options applicable to non-traumatic primary headache disorders, other available treatment modalities for neuropathic pain should be considered. In this comprehensive review article, the author reveals the prevalence of MTBI-HA and its clinical manifestation, discusses existing clinical and mechanistic evidence supporting the classification of chronic persistent MTBI-HA as a neuropathic pain state, and explores current available treatment options and future directions of therapeutic research related to MTBI-HA.
Learn More >Methadone is increasingly being used for its analgesic properties. Despite the increasing popularity, many healthcare providers are not familiar with methadone's complex pharmacology and best practices surrounding its use. The purpose of this narrative review article is to discuss the pharmacology of methadone, the evidence surrounding methadone's use in acute pain management and both chronic cancer and non-cancer pain settings, as well as highlight pertinent safety, monitoring, and opioid rotation considerations. Methadone has a unique mechanism of action when compared with all other opioids and for this reason methadone has come to hold a niche role in the management of opioid-induced hyperalgesia and central sensitization. Understanding of the mechanisms of variability in methadone disposition and drug interactions has evolved over the years, with the latest evidence revealing that CYP 2B6 is the major determinant of methadone elimination and plays a key role in methadone-related drug interactions. From an acute pain perspective, most studies evaluating the use of intraoperative intravenous methadone have reported lower pain scores and post-operative opioid requirements. Oral methadone is predominantly used as a second-line opioid treatment for select chronic pain conditions. As a result, several oral morphine to oral methadone conversion ratios have been proposed, as have methods in which to rotate to methadone. From an efficacy standpoint, limited literature exists regarding the effectiveness of methadone in the chronic pain setting with most of the available efficacy data pertaining to methadone's use in the treatment of cancer pain. Many of the prospective studies that exist feature low participant numbers. Few clinical trials investigating the role of methadone as an analgesic treatment are currently underway. The complicated pharmacokinetic properties of methadone and risks of harm associated with this drug highlight how critically important it is that healthcare providers understand these features before prescribing/dispensing methadone. Particular caution is required when converting patients from other opioids to methadone and for this reason only experienced healthcare providers should undertake such a task. Further randomized trials with larger sample sizes are needed to better define the effective and safe use of methadone for pain management.
Learn More >To investigate the physiopathology of pain in chronic inflammatory rheumatic diseases (CIRDs), we assessed the prevalence of migraine and neuropathic pain in 499 patients with CIRDs. We studied 238 patients with rheumatoid arthritis, 188 with spondyloarthritis (SpA), 72 with psoriatic arthritis (PsA), and 1 unclassified. Migraine was diagnosed according to IHS migraine diagnostic criteria. Neuropathic pain was diagnosed when patients scored at least 3 on the DN4 questionnaire. Participants completed a validated self-assessment questionnaire. Migraine prevalence was 34% (165/484), and it was highest in PsA. Risk factors for migraine were a high level of anxiety, female sex, young age, and TNF-alpha inhibitor treatment (OR = 1.90 (1.13-3.25)). Besides, high disease activity was a risk factor in SpA. Blood CRP level was not significantly associated with migraine. Of 493 patients with CIRDs, 21.5% had chronic pain with neuropathic characteristics. Compared to the French general population, these patients had significantly higher prevalences of migraine (two-fold) and neuropathic pain (three-fold). This study showed that migraine and neuropathic pain frequently occurred in patients with rheumatic diseases. Therefore, upon reporting residual pain, these patients should be checked for the presence of migraine or neuropathic pain, despite adequate clinical control of rheumatic disease.
Learn More >Chronic pain surrounding the temporomandibular joints and masticatory muscles is often the primary chief complaint of patients with temporomandibular disorders (TMD) seeking treatment. Yet, the neuro-pathophysiological basis underlying it remains to be clarified. Neuroimaging techniques have provided a deeper understanding of what happens to brain structure and function in TMD patients with chronic pain. Therefore, we performed a systematic review of magnetic resonance imaging (MRI) studies investigating structural and functional brain alterations in TMD patients to further unravel the neurobiological underpinnings of TMD-related pain. Online databases (PubMed, EMBASE, and Web of Science) were searched up to August 3, 2019, as complemented by a hand search in reference lists. A total of 622 papers were initially identified after duplicates removed and 25 studies met inclusion criteria for this review. Notably, the variations of MRI techniques used and study design among included studies preclude a meta-analysis and we discussed the findings qualitatively according to the specific neural system or network the brain regions were involved in. Brain changes were found in pathways responsible for abnormal pain perception, including the classic trigemino-thalamo-cortical system and the lateral and medial pain systems. Dysfunction and maladaptive changes were also identified in the default mode network, the top-down antinociceptive periaqueductal gray-raphe magnus pathway, as well as the motor system. TMD patients displayed altered brain activations in response to both innocuous and painful stimuli compared with healthy controls. Additionally, evidence indicates that splint therapy can alleviate TMD-related symptoms by inducing functional brain changes. In summary, MRI research provides important novel insights into the altered neural manifestations underlying chronic pain in TMD.
Learn More >The International Association for the Study of Pain has released a new classification scheme for chronic pain. This classification scheme describes chronic pain as either a symptom of a disease (chronic secondary pain) or as the disease itself (chronic primary pain). Chronic temporomandibular disorders have many similarities to other proposed chronic overlapping pain disorders, but are classified and managed by dental practitioners as a localized pain condition of the orofacial region. We review the literature to describe the similarities between chronic temporomandibular disorders and chronic overlapping pain disorders, and discuss how this evolving concept may affect the way that dentists approach the diagnosis and management of chronic temporomandibular disorders.
Learn More >Painful traumatic trigeminal neuropathy (PTTN) may occur following major craniofacial or oral trauma, or may be subsequent to relatively minor dental interventions. Following injury, pain may originate from a peripheral nerve, a ganglion, or from the central nervous system. In this review, we focus on molecular mechanisms of pain resulting from injury to the peripheral branch of the trigeminal nerve. This syndrome has been termed painful traumatic trigeminal neuropathy (PTTN) by the International Headache Society and replaces previous terms including atypical odontalgia, deafferentation pain, traumatic neuropathy and phantom toothache. We emphasize the scientific evidence supporting the events purported to lead to PTTN by reviewing the pathophysiology of PTTN based on relevant animal models. Additionally, we briefly overview clinical correlates and pathophysiological manifestations of PTTN.
Learn More >Pruritus is a debilitating symptom of cholestatic diseases such as primary biliary cholangitis and primary sclerosing cholangitis and often results in major reduction in quality of life for afflicted patients. Classic treatment options for the treatment of cholestatic pruritus include antihistamines, bile acid resins, serotonin reuptake inhibitors, and mu-opioid antagonists. Unfortunately, these drugs are not always successful in treating pruritus of cholestasis and may be associated with adverse effects. Recent advances in our understanding of itch pathophysiology have led to the use of butorphanol, a kappa-opioid agonist and mu-opioid antagonist, for the treatment of various forms of pruritus. Reports of butorphanol to treat cholestatic itch specifically are rare.
Learn More >Rearranged during transfection (RET), in complex with glial cell line-derived (GDNF) family receptor alpha (GFRα), is the canonical signaling receptor for GDNF family ligands (GFLs) expressed in both central and peripheral parts of the nervous system and also in non-neuronal tissues. RET-dependent signaling elicited by GFLs has an important role in the development, maintenance and survival of dopamine and sensory neurons. Both Parkinson's disease and neuropathic pain are devastating disorders without an available cure, and at the moment are only treated symptomatically. GFLs have been studied extensively in animal models of Parkinson's disease and neuropathic pain with remarkable outcomes. However, clinical trials with recombinant or viral vector-encoded GFL proteins have produced inconclusive results. GFL proteins are not drug-like; they have poor pharmacokinetic properties and activate multiple receptors. Targeting RET and/or GFRα with small molecules may resolve the problems associated with using GFLs as drugs and can result in the development of therapeutics for disease-modifying treatments against Parkinson's disease and neuropathic pain.
Learn More >Sparse evidence has detailed the clinical phenotype of migraine presenting as isolated facial pain. This was a prospective audit, part of our multidisciplinary facial pain service evaluation, aiming to phenotype patients with migraine presenting as isolated facial pain who attended our service between 2013 and 2018.
Learn More >This study assessed the safety and efficacy of three different doses of BoNT-A for persistent myofascial pain (MFP). One hundred female subjects were randomly assigned into five groups ( = 20): oral appliance (OA), saline solution (SS) and three BoNT-A groups with different doses. Pain intensity and pressure pain threshold were evaluated up to 24 weeks after treatment. Adverse effects related to muscle contraction, masticatory performance, muscle thickness and mandibular bone volume were also assessed. Changes over time were compared within and between groups. The "nparLD" package and Wilcoxon signed-rank test were used to analyze the data. BoNT-A reduced pain intensity ( < 0.0001) and increased pressure pain threshold ( < 0.0001) for up to 24 weeks compared to the placebo. No differences were found between BoNT-A and OA at the last follow-up. A transient decline in masticatory performance ( < 0.05) and muscle contraction ( < 0.0001), and a decrease in muscle thickness ( < 0.05) and coronoid and condylar process bone volume ( < 0.05) were found as dose-related adverse effects of BoNT-A. Regardless of the dose, BoNT-A was as effective as OA on MFP. Notwithstanding, due to BoNT-A dose-related adverse effects, we suggest the use of low doses of BoNT-A in MFP patients that do not benefit from conservative treatments.
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