Browse by Audience
Gastrin-releasing peptide (GRP) functions as a neurotransmitter for non-histaminergic itch, but its site of action (sensory neurons vs spinal cord) remains controversial. To determine the role of GRP in sensory neurons, we generated a floxed Grp mouse line. We found that conditional knockout of Grp in sensory neurons results in attenuated non-histaminergic itch, without impairing histamine-induced itch. Using a Grp-Cre knock-in mouse line, we show that the upper epidermis of the skin is exclusively innervated by GRP fibers, whose activation via optogeneics and chemogenetics in the skin evokes itch- but not pain-related scratching or wiping behaviors. In contrast, intersectional genetic ablation of spinal Grp neurons does not affect itch nor pain transmission, demonstrating that spinal Grp neurons are dispensable for itch transmission. These data indicate that GRP is a neuropeptide in sensory neurons for non-histaminergic itch, and GRP sensory neurons are dedicated to itch transmission.
Learn More >Acid-sensing ion channels (ASICs) are proton-gated cation channels that contribute to neurotransmission, as well as initiation of pain and neuronal death following ischemic stroke. As such, there is a great interest in understanding the in vivo regulation of ASICs, especially by endogenous neuropeptides that potently modulate ASICs. The most potent endogenous ASIC modulator known to date is the opioid neuropeptide big dynorphin (BigDyn). BigDyn is up-regulated in chronic pain and increases ASIC-mediated neuronal death during acidosis. Understanding the mechanism and site of action of BigDyn on ASICs could thus enable the rational design of compounds potentially useful in the treatment of pain and ischemic stroke. To this end, we employ a combination of electrophysiology, voltage-clamp fluorometry, synthetic BigDyn analogs, and noncanonical amino acid-mediated photocrosslinking. We demonstrate that BigDyn binding results in an ASIC1a closed resting conformation that is distinct from open and desensitized states induced by protons. Using alanine-substituted BigDyn analogs, we find that the BigDyn modulation of ASIC1a is primarily mediated through electrostatic interactions of basic amino acids in the BigDyn N terminus. Furthermore, neutralizing acidic amino acids in the ASIC1a extracellular domain reduces BigDyn effects, suggesting a binding site at the acidic pocket. This is confirmed by photocrosslinking using the noncanonical amino acid azidophenylalanine. Overall, our data define the mechanism of how BigDyn modulates ASIC1a, identify the acidic pocket as the binding site for BigDyn, and thus highlight this cavity as an important site for the development of ASIC-targeting therapeutics.
Learn More >Neuropeptides play important modulatory roles throughout the nervous system, functioning as direct effectors or as interacting partners with other neuropeptide and neurotransmitter systems. Limbic brain areas involved in learning, memory and emotions are particularly rich in neuropeptides. This review will focus on the amygdala, a limbic region that plays a key role in emotional-affective behaviors and pain modulation. The amygdala is comprised of different nuclei; the basolateral (BLA) and central (CeA) nuclei and in between, the intercalated cells (ITC), have been linked to pain-related functions. A wide range of neuropeptides are found in the amygdala, particularly in the CeA, but this review will discuss those neuropeptides that have been explored for their role in pain modulation. Calcitonin gene-related peptide (CGRP) is a key peptide in the afferent nociceptive pathway from the parabrachial area and mediates excitatory drive of CeA neurons. CeA neurons containing corticotropin releasing factor (CRF) and/or somatostatin (SOM) are a source of long-range projections and serve major output functions, but CRF also acts locally to excite neurons in the CeA and BLA. Neuropeptide S (NPS) is associated with inhibitory ITC neurons that gate amygdala output. Oxytocin and vasopressin exert opposite (inhibitory and excitatory, respectively) effects on amygdala output. The opioid system of mu, delta and kappa receptors (MOR, DOR, KOR) and their peptide ligands (β-endorphin, enkephalin, dynorphin) have complex and partially opposing effects on amygdala function. Neuropeptides therefore serve as valuable targets to regulate amygdala function in pain conditions.
Learn More >Extracellular nucleosides and nucleotides have widespread functions in responding to physiological stress. The "purinome" encompasses four G protein-coupled receptors (GPCRs) for adenosine, eight GPCRs activated by nucleotides (P2YRs), seven adenosine 5'-triphosphate(ATP)-gated P2X ion channels, as well as the associated enzymes and transporters that regulate native agonist levels. Purinergic signaling modulators, such as receptor agonists and antagonists, have potential for treating chronic pain. Adenosine and its analogues potently suppress nociception in preclinical models by activating A1 and/or A3 adenosine receptors(ARs), but safely harnessing this pathway to clinically treat pain has not been achieved. Both A2AAR agonists and antagonists are efficacious in pain models. Highly selective A3AR agonists offer a novel approach to treat chronic pain. We have explored the structure activity relationship of nucleoside derivatives at this subtype using a computational structure-based approach. Novel A3AR agonists for pain control containing a bicyclic ring system (bicyclo[3.1.0]hexane) in place of ribose were designed and screened using an in vivo phenotypic model, which reflected both pharmacokinetic and pharmacodynamic parameters. High specificity (>10,000-fold selective for A3AR) was achieved with the aid of receptor homology models based on related GPCR structures. These A3AR agonists are well tolerated in vivo and highly efficacious in models of chronic neuropathic pain. Furthermore, signaling molecules acting at P2X3, P2X4, P2X7 and P2Y12Rs play critical roles in maladaptive pain neuroplasticity, and their antagonists reduce chronic or inflammatory pain, and, therefore, purine receptor modulation is a promising approach for future pain therapeutics. Structurally novel antagonists for these nucleotide receptors were discovered recently.
Learn More >We aimed to evaluate the efficacy of an enhanced mindfulness based stress reduction (MBSR+) versus stress management for headache (SMH). We performed a randomized, assessor-blind, clinical trial of 98 adults with episodic migraine recruited at a single academic center comparing MBSR+ (n=50) to SMH (n=48). MBSR+ and SMH were delivered weekly by group for 8 weeks, then bi-weekly for another 8 weeks. The primary clinical outcome was reduction in headache days from baseline to 20 weeks. MRI outcomes included activity of left dorsolateral prefrontal cortex (DLPFC) and cognitive task network during cognitive challenge, resting state connectivity of right dorsal anterior insula (daINS) to DLPFC and cognitive task network, and gray matter volume of DLPFC, daINS, and anterior midcingulate. Secondary outcomes were headache-related disability, pain severity, response to treatment, migraine days, and MRI whole-brain analyses. Reduction in headache days from baseline to 20 weeks was greater for MBSR+ (7.8 [95%CI, 6.9-8.8] to 4.6 [95%CI, 3.7-5.6]) than for SMH (7.7 [95%CI 6.7-8.7] to 6.0 [95%CI, 4.9-7.0]) (P=0.04). 52% of the MBSR+ group showed a response to treatment (50% reduction in headache days) compared with 23% in the SMH group (P=0.004). Reduction in headache-related disability was greater for MBSR+ (59.6 [95%CI, 57.9-61.3] to 54.6 [95%CI, 52.9-56.4]) than SMH (59.6 [95%CI, 57.7-61.5] to 57.5 [95%CI, 55.5-59.4]) (P=0.02). There were no differences in clinical outcomes at 52 weeks or MRI outcomes at 20 weeks, although changes related to cognitive networks with MBSR+ were observed. MBSR+ is an effective treatment option for episodic migraine.
Learn More >Transcribed ultraconserved regions (T-UCRs) are a novel class of long noncoding RNAs (lncRNAs) and are completely conserved in humans, rats, and mice. T-UCRs have been implicated in diverse biological processes; however, very little is currently known about their role in pain modulation. Here, we found that the level of the spinal T-UCR uc.153 was significantly increased in a mouse model of sciatic nerve chronic constriction injury (CCI)-induced chronic neuropathic pain. The knockdown of spinal uc.153 prevented and reversed CCI-induced pain behaviours and spinal neuronal sensitization. In contrast, the overexpression of spinal uc.153 produced pain behaviours and neuronal sensitization in naive mice. Moreover, we found that uc.153 participates in the regulation of neuropathic pain by negatively modulating the processing of pre-miR-182-5p. Collectively, our findings reveal an important role for uc.153 in pain modulation and provide a novel drug target for neuropathic pain therapy.
Learn More >Physical disuse could lead to a state of chronic pain typified by complex regional pain syndrome type I due to fear of pain through movement (kinesiophobia) or inappropriate resting procedures. However, the mechanisms by which physical disuse is associated with acute/chronic pain and other pathological signs remain unresolved. We have previously reported that inflammatory signs, contractures, disuse muscle atrophy, spontaneous pain-like behaviors, and chronic widespread mechanical hyperalgesia based on central plasticity occurred after 2-weeks of cast immobilization in chronic post-cast pain (CPCP) rat model. In the present study, we also demonstrated dystrophy-like changes, both peripheral nociceptive signals and activation of the central pain pathway in CPCP rats. This was done by the following methods: (1) vascular permeability (Evans blue dye) and inflammatory- and oxidative stress-related messenger RNA (mRNA) changes (real-time quantitative polymerase chain reaction); (2) immunofluorescence of pERK and/or c-Fos expression in the spino-parabrachio-amygdaloid pathway; and (3) blockade of nociceptive-related signals using sciatic nerve block (SNB). Furthermore, we demonstrated tactile allodynia using an optogenetic method in a transgenic rat line (W-TChR2V4), cold allodynia using the acetone test, and activation of dorsal horn neurons in the chronic phase associated with chronic mechanical hyperalgesia using c-Fos immunofluorescence. In addition, we showed that nociceptive signals in the acute phase are involved in chronic pathological pain-like behaviors by studying the effects of SNB. Thus, we conclude that physical disuse contributes to dystrophy-like changes, spontaneous pain-like behavior, and chronic widespread pathological pain-like behaviors in CPCP rats after 2 weeks of cast immobilization.
Learn More >Although a fluctuating pattern of orofacial pain across the life span has been proposed, data on its natural course is lacking. The longitudinal course of orofacial pain in the general population was evaluated using data from routine dental check-ups at all Public Dental Health services in Västerbotten, Sweden. In a large population sample, two screening questions were used to identify individuals with pain once a week or more in the orofacial area. Incidence and longitudinal course of orofacial pain were evaluated using annual data for 2010-2017. To evaluate predictors for orofacial pain remaining over time, individuals who reported pain on at least two consecutive dental check-ups were considered persistent. A generalized estimating equation model was used to analyze the prevalence, accounting for repeated observations on the same individuals. In total, 180,308 individuals (equal gender distribution) were examined in 525,707 dental check-ups. More women than men reported orofacial pain (OR 2.58, 95% CI 2.48-2.68), and there was a significant increase in the prevalence of reported pain from 2010 to 2017 in both women and men. Longitudinal data for 135,800 individuals were available for incidence analysis. Women were at higher risk of both developing orofacial pain (IRR 2.37; 95% CI 2.25-2.50) and reporting pain in consecutive check-ups (IRR 2.56, 95% CI 2.29-2.87). In the northern Swedish population studied, the prevalence of orofacial pain increases over time and more so in women, thus indicating increasing differences in gender for orofacial pain.
Learn More >Some forms of chronic pain are thought to be driven and maintained by nociceptive input, which can drive plasticity within nociceptive pathways. We have previously identified abnormalities along the entire nociceptive pathway in chronic myalgic temporomandibular disorders (mTMD), including the trigeminal nerves, brainstem pathways, and in the thalamus and somatosensory cortex. These data suggest that there is a peripheral nociceptive drive in mTMD, but the source of this nociceptive activity remains unknown. Here, our aim was to determine whether structural abnormalities exist in the muscles of mastication of patients with chronic mTMD. Specifically, we tested whether the volume of the temporalis muscle and its tendon-aponeurosis-complex (TAC, a structure that dissipates forces in a muscle) in mTMD patients differ compared to age- and sex-matched controls. To do so, we segmented these structures on T1-weighted structural MR images. We found that muscle volumes in mTMD were not different to controls. However, the mTMD group had significantly smaller volumes of the bilateral temporalis TAC, and thus a smaller TAC-to-muscle volume ratio. These findings were consistent across 2 independent cohorts of 17 mTMD patients, compared to 17 age- and sex-matched controls. We propose a model where reduced TAC-to-muscle ratio could result in a predisposition to muscle tissue injury. In sum, abnormalities of the temporalis muscles in mTMD supports our hypothesis that chronic mTMD pathophysiology may be related to peripheral nociceptive barrage originating from the muscles of mastication.
Learn More >Women who develop bladder pain syndrome (BPS), irritable bowel syndrome, or dyspareunia frequently have an antecedent history of dysmenorrhea. Despite the high prevalence of menstrual pain, its role in chronic pelvic pain emergence remains understudied. We systematically characterized bladder, body, and vaginal mechanical sensitivity with quantitative sensory testing in women with dysmenorrhea (DYS, n = 147), healthy controls (HCs) (n = 37), and women with BPS (n = 25). Previously, we have shown that a noninvasive, bladder-filling task identified a subset of women with both dysmenorrhea and silent bladder pain hypersensitivity, and we repeated this to subtype dysmenorrhea sufferers in this study (DYSB; n = 49). DYS, DYSB, and BPS participants had lower vaginal mechanical thresholds and reported more pain to a cold stimulus during a conditioned pain modulation task and greater pelvic examination after-pain than HCs (P's < 0.05). DYSB participants also had reduced body mechanical thresholds and less conditioned pain modulation compared to HCs and DYS participants (P's < 0.05). Comparing quantitative sensory testing results among the DYS and HC groups only, provoked bladder pain was the only significant predictor of self-reported menstrual pain (r = 0.26), bladder pain (r = 0.57), dyspareunia (r = 0.39), and bowel pain (r = 0.45). Our findings of widespread sensory sensitivity in women with dysmenorrhea and provoked bladder pain, much like that observed in chronic pain, suggest a need to study the trajectory of altered mechanisms of pain processing in preclinical silent visceral pain phenotypes to understand which features convey inexorable vs modifiable risk.
Learn More >Peer relationship problems are associated with pain complaints; however, experimental data linking the two are lacking. The purpose of this study was to determine whether brief social exclusion influences pain processing in healthy adolescents.
Learn More >Chronic pain is the most common reason reported for using medical cannabis. The goal of this research was to determine if the two primary phytocannabinoids, THC and CBD, are effective treatments for persistent inflammatory pain. In Experiment 1, inflammation was induced in male and female rats by intraplantar injection of complete Freund's adjuvant (CFA). Then THC (0.0-4.0 mg/kg i.p.) or CBD (0.0-10 mg/kg i.p.) was administered twice-daily for 3 days. On day 4, vehicle, THC, or CBD was administered and allodynia, hyperalgesia, weight-bearing, locomotor activity, and hindpaw edema were assessed 0.5-4 h post-injection. In Experiment 2, CFA- or mineral oil (control)-treated rats were given vehicle, THC (2.0 mg/kg), or CBD (10 mg/kg) in the same manner as in Experiment 1. Four h post-injection on day 4, serum samples were taken for analysis of cytokines known to influence inflammatory pain: interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α. THC dose-dependently reduced pain-related behaviors but did not reduce hindpaw edema, and little tolerance developed to THC's effects. In contrast, CBD effects on inflammatory pain were minimal. THC produced little-to-no change in serum cytokines, whereas CBD decreased IL-1β, IL-10, and IFN-γ, and increased IL-6. Few sex differences in antinociception or immune modulation were observed with either drug, but adjuvant-induced immune activation was greater in males than females. These results suggest that THC may be more beneficial than CBD for reducing inflammatory pain, in that THC maintains its efficacy with short-term treatment in both sexes, and does not induce immune activation. SIGNIFICANCE STATEMENT: CBDs and THCs pain-relieving effects are examined in male and female rats with persistent inflammatory pain to determine if individual phytocannabinoids could be a viable treatment for men and women with chronic inflammatory pain. Additionally, sex differences in the immune response to an adjuvant and to THC and CBD are characterized to provided preliminary insight into immune-related effects of cannabinoid-based therapy for pain.
Learn More >Studying a spontaneous migraine attack is challenging, particularly the earliest components. Nitroglycerin is a potent, reliable and reproducible migraine trigger of the entirety of the migraine attack, making its use experimentally attractive.
Learn More >There is evidence of altered resting hypothalamic activity patterns and connectivity prior to a migraine, however it remains unknown if these changes are driven by changes in overall hypothalamic activity levels. If they are, it would corroborate the idea that changes in hypothalamic function result in alteration in brainstem pain processing sensitivity, which either triggers a migraine headache itself or allows an external trigger to initiate a migraine headache. We hypothesise that hypothalamic activity increases immediately prior to a migraine headache and this is accompanied by altered functional connectivity to pain processing sites in the brainstem.
Learn More >Background and aims A sizable body of research has elucidated the significant role of psychological reactions to trauma on pain coping and outcomes. In order to best inform intervention development and clinical care for patients with both trauma and pain at the tertiary care level, greater clarity is needed regarding the magnitude of these effects and the specific pathways through which they may or may not function at the time of first presentation to such a treatment setting. To achieve this, the current study examined the cross-sectional relationships between traumatic etiology of pain, psychological distress (anger, depressive symptoms, and PTSD symptoms), and pain outcomes (pain catastrophizing, physical function, disability status). Methods Using a structural path modeling approach, analyses were conducted using a large sample of individuals with chronic pain (n = 637) seeking new medical evaluation at a tertiary pain management center, using the Collaborative Health Outcomes Information Registry (CHOIR). We hypothesized that the relationships between traumatic etiology of pain and poorer pain outcomes would be mediated by higher levels of psychological distress. Results Our analyses revealed modest relationships between self-reported traumatic etiology of pain and pain catastrophizing, physical function, and disability status. In comparison, there were stronger relationships between indices of psychological distress and pain catastrophizing, but a weaker pattern of associations between psychological distress and physical function and disability measures. Conclusions To the relatively small extent that self-reported traumatic etiology of pain correlates with pain-related outcomes, these relationships appear to be due primarily to the presence of psychiatric symptoms and manifest most notably in the context of psychological responses to pain (i.e. catastrophizing about pain). Implications Findings from this study highlight the need for early intervention for patients with traumatic onset of pain and for clinicians at tertiary pain centers to include more detailed assessments of psychological distress and trauma as a component of comprehensive chronic pain treatment.
Learn More >Normally, opioids function in a receptor-dependent manner. They bind to opioid receptors, activate or inhibit receptor activation, and subsequently modulate downstream signal transduction. However, the complex functions of opioids and the low expression of opioid receptors and their endogenous peptide agonists in neural stem cells (NSCs) suggest that some opioids may also modulate NSCs via a receptor-independent pathway. In the current study, two opioids, morphine and naloxone, are demonstrated to facilitate NSC proliferation via a receptor-independent and ten-eleven translocation methylcytosine dioxygenase 1 (TET1)-dependent pathway. Morphine and naloxone penetrate cell membrane, bind to TET1 protein via three key residues (1,880-1,882), and subsequently result in facilitated proliferation of NSCs. In addition, the two opioids also inhibit the DNA demethylation ability of TET1. In summary, the current results connect opioids and DNA demethylation directly at least in NSCs and extend our understanding on both opioids and NSCs.
Learn More >Studies of the relation of fibromyalgia (FM) and widespread pain (WSP) to mortality have differed as to the presence or absence of an association and the extent of cause-specific mortality. However, no studies have investigated which definitions of FM and WSP associate with mortality, nor of FM mortality in other diseases. We investigated these issues and the meaning of mortality in patients with FM.
Learn More >Even with optimized medical management, pain remains an inevitable part of pediatric cancer care. The most effective interventions for nonpharmacologic pain management within pediatric psychology include parent skills training. This review specifically explored the role of parents in cancer-related pain management with the goal of defining a set of evidence-based skills that could translate to improved pediatric cancer pain management.
Learn More >Migraine is a highly disabling neurovascular disorder characterized by a severe headache (associated with nausea, photophobia and/or phonophobia), and trigeminovascular system activation involving the release of calcitonin-gene related peptide (CGRP). Novel anti-migraine drugs target CGRP signaling through either stimulation of 5-HT receptors on trigeminovascular nerves (resulting in inhibition of CGRP release) or direct blockade of CGRP or its receptor. Lasmiditan is a highly selective 5-HT receptor agonist and, unlike the triptans, is devoid of vasoconstrictive properties, allowing its use in patients with cardiovascular risk. Since lasmiditan can actively penetrate the blood-brain barrier, central therapeutic as well as side effects mediated by 5-HT receptor activation should be further investigated. Other novel anti-migraine drugs target CGRP signaling directly. This neuropeptide can be targeted by the monoclonal antibodies eptinezumab, fremanezumab and galcanezumab, or by CGRP-neutralizing L-aptamers called Spiegelmers. The CGRP receptor can be targeted by the monoclonal antibody erenumab, or by small-molecule antagonists called gepants. Currently, rimegepant and ubrogepant have been developed for acute migraine treatment, while atogepant is studied for migraine prophylaxis. Of these drugs targeting CGRP signaling directly, eptinezumab, erenumab, fremanezumab, galcanezumab, rimegepant and ubrogepant have been approved for clinical use, while atogepant is in the last stage before approval. Although all of these drugs seem highly promising for migraine treatment, their safety should be investigated in the long-term. Moreover, the exact mechanism(s) of action of these drugs need to be elucidated further, to increase both safety and efficacy and to increase the number of responders to the different treatments, so that all migraine patients can satisfactorily be treated.
Learn More >Sex differences in certain types of pain sensitivity and emotional responses have been previously reported. Synaptic plasticity is a key cellular mechanism for pain perception and emotional regulation, including long-term potentiation (LTP) and long-term depression (LTD). However, it is unclear whether there is a sex difference at synaptic level. Recent studies indicate that excitatory transmission and plasticity in the anterior cingulate cortex (ACC) are critical in chronic pain and pain related emotional responses. In the present study, we used 64-channel multielectrode (MED64) system to record synaptic plasticity in the ACC of male and female adult mice. We found that there was no significant difference in theta-burst stimulation (TBS)-induced LTP between female and male mice. Furthermore, the recruitment of inactive channels was also not different. For LTD, we found that LTD was greater in slices of ACC in male mice than female mice. Our results demonstrate that LTP in the ACC does not show any sex-related difference.
Learn More >Hyperalgesia is a heightened pain response to a noxious stimulus and is a hallmark of many common neuropathic and chronic pain conditions. In a double-blind placebo-controlled drug-crossover trial the effects of concomitant and delayed minocycline treatment on the initiation and resolution of muscle hyperalgesia were tested.
Learn More >Anodal transcranial direct current stimulation over the primary cortex has been shown to activate regions of the brain involved in the descending modulation of pain sensitivity. However, more research is required in order to dissect the spinal cord analgesic mechanisms associated with the development of central sensitisation.
Learn More >Glycine receptors (GlyRs) are anion-permeable pentameric ligand-gated ion channels (pLGICs). The GlyR activation is critical for the control of key neurophysiological functions, such as motor coordination, respiratory control, muscle tone and pain processing. The relevance of the GlyR function is further highlighted by the presence of abnormal glycinergic inhibition in many pathophysiological states, such as hyperekplexia, epilepsy, autism and chronic pain. In this context, previous studies have shown that the functional inhibition of GlyRs containing the α3 subunit is a pivotal mechanism of pain hypersensitivity. This pathway involves the activation of EP2 receptors and the subsequent PKA-dependent phosphorylation of α3GlyRs within the intracellular domain (ICD), which decrease the GlyR-associated currents and enhance neuronal excitability. Despite the importance of this mechanism of glycinergic dis-inhibition associated with dysfunctional α3GlyRs, our current understanding of the molecular events involved is limited. Here, we report that the activation of PKA signaling pathway decreases the unitary conductance of α3GlyRs. We show in addition that the substitution of the PKA-targeted serine with a negatively charged residue within the ICD of α3GlyRs and of chimeric receptors combining bacterial GLIC and α3GlyR was sufficient to generate receptors with reduced conductance. Thus, our findings reveal a potential biophysical mechanism of glycinergic dis-inhibition and suggest that post-translational modifications of the ICD, such as phosphorylation, may shape the conductance of other pLGICs.
Learn More >Impaired performance on tasks assessing executive function has been linked to chronic pain. We hypothesised that poor performance on tests assessing the ability to adjust thinking in response to changing environmental stimuli (cognitive flexibility) would be associated with persistent post-surgical pain.
Learn More >A 6-month opioid use educational program consisting of webinars on pain assessment, postoperative and multimodal pain opioid management, safer opioid use, and preventing addiction coupled with on-site coaching and monthly assessments reports was implemented in 31 hospitals. The authors hypothesized the intervention would measurably reduce and/or prevent opioid-related harm among adult hospitalized patients compared to 33 nonintervention hospitals.
Learn More >The antihyperalgesic and sedative effects of the α2-subunit preferring GABA positive allosteric modulator (GAM), N-Desmethyl-Clobazam (NDMC), 20 and 60 mg, were assessed in a randomized, placebo and active-controlled (clonazepam 1,5 mg), 4-way crossover study, in healthy volunteers, using the UVB-induced experimental pain model. Single (20, 40, 60 mg) and repeated doses (20mg over 15 days) NDMC pharmacokinetic were evaluated. Thirty-two subjects participated to the study. Primary outcome parameter was maximal change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH). ASH decreased under all treatments. Mean (SD) relative change was 79 (22) %, 83 (24) %, 77 (30) % and 92 (16) % for placebo, NDMC20, NDMC60 and clonazepam, respectively. Neither absolute change nor relative change in ASH was significantly different between NDMC60 and placebo (mean difference= 2.3 cm [95%CI 4.0 to 8.5], p=0.462 and 0.4% [-11.9 to 12.6], p=0.952, respectively). An overall treatment effect was found on level of sedation. Compared to placebo, sedation was higher under clonazepam (mean difference= 39 mm [30 to 49] on a visual analog scale, p<0.001) while NDMC was free of sedative effect. NDMC pharmacokinetic after single doses showed poor absorption, but was linear. Steady-state plasma concentrations of NDMC20 were attained within 14 days, with low between-subjects variability. Mean steady-state concentration (C , SD) reached 209 (22) ng/mL. NDMC absence of sedative effect and its overall well characterized safety coming from years of utilization as a metabolite from clobazam, raise the prospect of dose escalating trials in patients to quantify its clinical utility.
Learn More >Social environment influences the trajectory of developing opioid use disorder (OUD). Thus, the present study tested the hypothesis that sociability levels will affect the responses to opioids. Mice were tested for their baseline sociability, anxiety levels, pain sensitivities, and their acute locomotor response to 5 mg/kg opioids. Then, they were administered repeatedly with saline, hydrocodone, or morphine (20 mg/kg for 5 days, and then 40 mg/kg for 5 days). Subsequently, they were examined for the expression of locomotor sensitization and retested for the effects of opioids on their sociability, anxiety levels, and pain sensitivity. On the basis of their baseline sociability level, mice were divided into socially avoiding and socially exploring. Socially avoiding and socially exploring mice did not differ in their baseline weight and anxiety sensitivities. Socially avoiding mice had slightly higher baseline heat sensitivity than those in socially exploring mice. Repeated administration of opioids had differential effects in socially avoiding and socially exploring mice. In both social groups, repeated morphine administration had overall stronger effects compared with hydrocodone. Morphine-treated socially exploring mice developed greater locomotor sensitization than those in morphine-treated socially avoiding mice. Morphine-treated socially avoiding mice, but not socially exploring mice, spent more time in the center zone of the open-field test and in the light zone of light/dark boxes, and developed heat hyperalgesia. This study suggests that socially exploring animals are more sensitive to the sensitizing effects of opioids. In contrast, opioids have greater effects on the stress and pain systems of socially avoiding animals. Thus, the underlying mechanisms for developing OUD might differ in individuals with various sociability levels.
Learn More >The scarcity and limited risk/benefit ratio of painkillers available on the market, in addition to the opioid crisis, warrant reflection on new innovation strategies. The pharmacopoeia of analgesics is based on products that are often old and derived from clinical empiricism, with limited efficacy or spectrum of action, or resulting in an unsatisfactory tolerability profile. Although they are reference analgesics for nociceptive pain, opioids are subject to the same criticism. The use of opium as an analgesic is historical. Morphine was synthesized at the beginning of the 19th century. The efficacy of opioids is limited in certain painful contexts and these drugs can induce potentially serious and fatal adverse effects. The current North American opioid crisis, with an ever-rising number of deaths by opioid overdose, is a tragic illustration of this. It is therefore legitimate to develop research into molecules likely to maintain or increase opioid efficacy while improving their tolerability. Several avenues are being explored including targeting of the mu opioid receptor (MOR) splice variants, developing biased agonists or targeting of other receptors such as heteromers with MOR. Ion channels acting as MOR effectors, are also targeted in order to offer compounds without MOR-dependent adverse effects. Another route is to develop opioid analgesics with peripheral action or limited central nervous system (CNS) access. Finally, endogenous opioids used as drugs or compounds that modify the metabolism of endogenous opioids (Dual ENKephalinase Inhibitors) are being developed. The aim of the present review is to present these various targets/strategies with reference to current indications for opioids, concerns about their widespread use, particularly in chronic non-cancer pains, and ways of limiting the risk of opioid abuse and misuse.
Learn More >The aim of this study was to validate the English version of the Itch Cognition Questionnaire in a sample of patients with chronic itch due to psoriasis or atopic dermatitis. An English-language version of an instrument assessing itch-related cognitions is needed since cognitions can contribute to a worsening of itch, and chronic itch is prevalent in English-speaking counties and internationally.
Learn More >There are various approaches to the psychological management of chronic pain and it is difficult to know which components of psychological therapies are necessary or desirable for the effective management of chronic pain.
Learn More >Developing potent non-opioid pain medications is an integral part of the battle to conquer both chronic pain and the current opioid crisis. Although most screening approaches use in vitro surrogate targets, in vivo screening of analgesic candidates is a necessary pre-clinical step in drug discovery. Here, we report the design of a new automated behavioral testing apparatus based on the principle of a thermal place preference test (TPPT). This new design can detect, quantify, and differentiate behavioral responses to cold stimuli between sham and chronic constriction injury (CCI) rodents with up to 12 animals tested simultaneously. At an optimized temperature pair of 12.5°C vs 30.0°C (± 0.5℃), the TPPT design has captured the antinociceptive effects of morphine and pregabalin on CCI rats in individual 10-min tests. Moreover, it can differentiate analgesic effects by morphine or pregabalin from anxiolytic effects by diazepam. The results, along with the relatively low cost to construct the apparatus and moderately high throughput, make our TPPT design applicable for behavioral studies of chronic pain in rodents and for high-throughput in vivo screening of the next generation of pain medications.
Learn More >Glycine neurotransmission in the dorsal horn of the spinal cord plays a key role in regulating nociceptive signaling, but in chronic pain states reduced glycine neurotransmission is associated with the development of allodynia and hypersensitivity to painful stimuli. This suggests that restoration of glycine neurotransmission may be therapeutic for the treatment of chronic pain. Glycine Transporter 2 inhibitors have been demonstrated to enhance glycine neurotransmission and provide relief from allodynia in rodent models of chronic pain. In recent years, photoswitchable compounds have been developed to provide the possibility of controlling the activity of target proteins using light. In this study we have developed a photoswitchable non-competitive inhibitor of Glycine Transporter 2 that has different affinities for the transporter at 365 nm compared to 470 nm light.
Learn More >The use of opioids for the relief of pain and headache disorders has been studied for years. Nowadays, particularly because of its ability to produce analgesia in various pain models, delta opioid receptor (DOPr) emerges as a promising target for the development of new pain therapies. Indeed, their potential to avoid the unwanted effects commonly observed with clinically used opioids acting at the mu opioid receptor (MOPr) suggests that DOPr agonists could be a therapeutic option. In this review, we discuss the use of opioids in the management of pain in addition to describing the evidence of the analgesic potency of DOPr agonists in animal models.
Learn More >Spinal cord stimulation (SCS) is an established treatment for chronic neuropathic, neuropathic-like and ischaemic pain. However, the heterogeneity of patients in daily clinical practice makes it often challenging to determine which patients are eligible for this treatment, resulting in undesirable practice variations. This study aimed to establish patient-specific recommendations for referral and selection of SCS in chronic pain.
Learn More >To evaluate the efficacy and safety of duloxetine in the treatment of patients with osteoarthritis (OA) or chronic low back pain (CLBP).
Learn More >To evaluate the feasibility of a randomised trial of a modified, pre-existing, mindfulness meditation smartphone app for women with chronic pelvic pain.
Learn More >Migraine carries a high global burden, disproportionately affects women, and has been implicated as a risk factor for cardiovascular disease. Migraine with aura has been consistently associated with increased risk of cardiovascular mortality. However, published evidence on relationships between migraine or non-migraine headache and all-cause mortality is inconclusive. Therefore, we aimed to estimate the effect of non-migraine headache and migraine as well as migraine subtypes on all-cause and cause-specific mortality in women.
Learn More >Migraine is the most common acute primary headache in children and adolescents. In 2014, topiramate became the first preventive drug for migraine, approved by the Food and Drug Administration (FDA) for adolescents. This meta-analysis was aimed to evaluate the efficacy and safety of topiramate in the prevention of pediatric migraine. We searched the PubMed, EMBASE, Cochrane Library, and Chinese National Knowledge Infrastructure (CNKI) databases up to June 2019 for eligible randomized controlled trials (RCTs). The primary outcomes were mean migraine days per month, ≥50% reduction rate, and Pediatric Migraine Disability Assessment Scale (PedMIDAS) scores. RevMan5.3 software was performed for statistical analysis. Overall, 5 RCTs recruiting 531 patients (6-17 years of age) were included in the meta-analysis. The target dose of topiramate was 2 mg/kg (the maintenance phase was 12 weeks), 2-3 mg/kg, 50 mg/day, and 100 mg/day (maintaining for 16 weeks), respectively, in the included studies. Our results demonstrate that participants receiving topiramate had a significant advantage in remitting the monthly migraine days than those receiving placebo, with a mean difference (MD) of -0.78 ( = 531; 95% CI, -1.23 to -0.32; = 3.37; = 0.0008). Topiramate could also reduce the mean PedMIDAS scores ( = 238; 95% CI, -16.53 to -0.49; = 2.43; = 0.04). However, there was no significant difference in the percentage of patients experiencing a ≥50% reduction in monthly headache days between topiramate and placebo groups ( = 531; 95% CI, 0.94-1.77; = 1.58; = 0.11). Topiramate was associated with higher rates of side effects such as weight decrease ( = 395; 95% CI, 2.73-22.98; = 3.81; < 0.01) and paresthesia ( = 531; 95% CI, 3.05-13.18; = 4.94; < 0.01). Topiramate can significantly decrease monthly headache days and migraine-related burden in migraine patients <18 years old. However, it failed to increase 50% response rate. Adverse events seem to be more frequent in topiramate-treated children.
Learn More >Dezocine is an opioid analgesic widely used in China, occupying over 45% of the domestic market of opioid analgesics. We have recently demonstrated that dezocine produced mechanical antiallodynia and thermal antihyperalgesia through spinal μ-opioid receptor activation and norepinephrine reuptake inhibition in neuropathic pain. This study further explored the dual μ-opioid receptor and norepinephrine reuptake mechanisms underlying dezocine-induced mechanical antiallodynia in bone cancer pain, compared with tapentadol, the first recognized analgesic in this class. Dezocine and tapentadol, given subcutaneously, exerted profound mechanical antiallodynia in bone cancer pain rats in a dose-dependent manner, yielding similar maximal effects but different potencies: EDs of 0.6 mg/kg for dezocine and 7.5 mg/kg for tapentadol, respectively. Furthermore, their mechanical antiallodynia was partially blocked by intrathecal injection of the specific μ-opioid receptor antagonist CTAP, but not κ-opioid receptor antagonists GNTI and nor-BNI or δ-opioid receptor antagonist naltrindole. Intrathecal administrations of the specific norepinephrine depletor 6-OHDA (but not the serotonin depletor PCPA) for three consecutive days and single injection of the α-adrenoceptor antagonist phentolamine/α2-adrenoceptor antagonist yohimbine partially blocked dezocine- and tapentadol-induced mechanical antiallodynia. Strikingly, the combination of CTAP and yohimbine nearly completely blocked dezocine- and tapentadol-induced mechanical antiallodynia. Our results illustrate that both dezocine and tapentadol exert mechanical antiallodynia in bone cancer pain through dual mechanisms of μ-opioid receptor activation and norepinephrine reuptake inhibition, and suggest that the μ-opioid receptor and norepinephrine reuptake dual-targeting opioids are effective analgesics in cancer pain.
Learn More >A growing body of studies have indicated that bone marrow mesenchymal stem cells (BMSCs) have powerful analgesic effects in animal models of bone cancer pain. Here, we explored the molecular mechanisms underlying how BMSCs alleviate pain sensation in a mouse model of bone cancer pain.
Learn More >Peripheral neurostimulation within the trigeminal nerve territory has been used for pain alleviation during migraine attacks, but the mechanistic basis of this non-invasive intervention is still poorly understood. In this study, we investigated the therapeutic role of peripheral stimulation of the trigeminal nerve, which provides homosegmental innervation to intracranial structures, by assessing analgesic effects in a nitroglycerin-induced rat model of migraine. As a result of neurogenic inflammatory responses in the trigeminal nervous system, plasma protein extravasation was induced in facial skin by applying noxious stimulation to the dura mater. Noxious chemical stimulation of the dura mater led to protein extravasation in facial cutaneous tissues and caused mechanical sensitivity. Trigeminal ganglion neurons were double-labeled via retrograde tracing to detect bifurcated axons. Extracellular recordings of wide dynamic range neurons in the spinal trigeminal nucleus caudalis demonstrated the convergence and interaction of inputs from facial tissues and the dura mater. Peripheral neurostimulation of homotopic facial tissues represented segmental pain inhibition on cephalic cutaneous allodynia in the migraine model. The results indicated that facial territories and intracranial structures were directly connected with each other through bifurcated double-labeled neurons in the trigeminal ganglion and through second-order wide dynamic range neurons. Homotopic stimulation at the C-fiber intensity threshold resulted in much stronger inhibition of analgesia than the same intensity of heterotopic stimulation. These results provide novel evidence for the neurological bases through which peripheral neurostimulation may be effective in treating migraine in clinical practice.
Learn More >Veterans experience chronic pain more frequently than civilians. Identification of neurobiological mechanisms underlying the pathophysiology of chronic pain in a veteran population may aid in the development of novel treatment targets. In this pilot proof-of-concept study, veterans with chronic pain (N = 61) and no chronic pain (N = 19) completed clinical interviews, self-report questionnaires inquiring about pain history, interference of pain with daily life, and pain catastrophizing, as well as measures of depressive and anxious symptoms. Veterans also underwent single-voxel proton (H) magnetic resonance spectroscopy (MRS) at 3 Tesla in the anterior cingulate cortex (ACC) using a two-dimensional (2D) J-resolved point spectroscopy sequence. We found no group difference in neurometabolites between veterans with and without chronic pain; however, pain intensity, negative thinking about pain, and description of pain in affective terms were associated with lower GABA/Cre in the ACC. In addition, the Glu/GABA ratio in the ACC was positively associated with anxiety and depressive symptoms in veterans with chronic pain. Reductions in GABA in the ACC may contribute to increased pain intensity and greater pain catastrophizing in veterans with chronic pain. Furthermore, a disturbance in the excitatory-inhibitory balance may contribute to the anxious and depressive symptoms related to chronic pain. Given the pilot nature of the study, these findings must be considered preliminary.
Learn More >Opioids are the only class of drug with the proven ability to control severe pain. The introduction of stringent opioid prescribing restrictions has inevitably impacted upon the ability of those prescribing opioids for advanced life-limited disease to practice as previously and could limit the supply of adequate pain relief to patients with cancer. This review considers the evidence that symptom management of patients with advanced cancer contributes to the "opioid problem" and whether there is adequate recognition of the risks involved.
Learn More >Despite the high incidence of acute and chronic pain in the general population, the efficacy of currently available medications is unsatisfactory. Insufficient management of pain has a profound impact on the quality of life and can have serious physical, psychological, social, and economic consequences. This unmet need reflects a failure to develop novel classes of analgesic drugs with superior clinical properties and lower risk of abuse. Nevertheless, recent advances in our understanding of the neurobiology of pain are offering new opportunities for developing different therapeutic approaches. Among those, the activation of M2 muscarinic acetylcholine receptors, which play a key role in the cholinergic regulation of the nociceptive transmission, constitutes one of the most promising strategies. We have recently developed a small library of novel pharmacological agents by merging the structures of known orthosteric and allosteric muscarinic ligands through their molecular hybridization, an emerging approach in medicinal chemistry based on the combination of pharmacophoric moieties of different bioactive substances to produce a new compound with improved pharmacological properties. Herein we report the functional characterization of the new ligands in vitro and the assessment of their efficacy as analgesic agents and tolerability in mice. This work provides new insights for the development and optimization of novel muscarinic hybrid compounds for the management of pain.
Learn More >Pain management is a challenging and unmet medical need. Despite their demonstrated efficacy, currently used opioid drugs and nonsteroidal anti-inflammatory drugs are frequently associated with several adverse events. The identification of new and safe analgesics is therefore needed. MP1104, an analogue of 3'-iodobenzoyl naltrexamine, is a potent nonselective full agonist at mu (MOR), kappa (KOR), and delta (DOR) opioid receptors, respectively. It was shown to possess potent antinociceptive effects in acute thermal pain assays without aversion in mice. In this study, we investigated MP1104 in the formalin test, a model of tonic pain. MP1104 (0.05, 0.1, and 1.0 mg/kg) reduced pain-like behaviors in phases I and II of the formalin test in male and female ICR mice. Pretreatment with KOR antagonist (norbinaltorphimine 10 mg/kg) and DOR antagonist (naltrindole 10 mg/kg) abolished the antinociceptive effects of MP1104 in the formalin test. These findings support the development of MP1104 for further testing in other pain models.
Learn More >Severe pain often accompanies major spine surgery. Opioids are the cornerstone of postoperative pain management but their use can be limited by numerous side effects. Several studies claim that adjuvant treatment with intravenous (IV) ketamine reduces opioid consumption and pain after back surgery. However, the exact role of ketamine for this indication is yet to be elucidated. We compared 2 different doses of S-ketamine with placebo on postoperative analgesic consumption, pain, and adverse events in adult, opioid-naïve patients after lumbar fusion surgery.
Learn More >Opioid-induced constipation (OIC), a typical side effect of opioids, is due to activation of the μ-opioid receptors in the enteric nervous system. Peripherally acting μ-opioid receptor antagonists (PAMORAs) can reverse OIC by inhibiting the peripheral action of opioids without affecting centrally mediated analgesia. Naldemedine is a PAMORA with potent antagonist activity against μ-, δ-, and κ-opioid receptors. In this study, the pharmacological profiles of naldemedine, compared to those of naloxone and naloxegol, were evaluated. In vitro, Schild plot analysis indicated that naldemedine was a non-competitive antagonist of μ-opioid receptors, while other compounds were competitive antagonists. Also, naldemedine showed slower association and dissociation kinetics than the other compounds. In vivo, naldemedine dose-dependently ameliorated morphine-induced inhibition of small intestinal transit (SIT). The dose response curve was not sifted at 1 and 3 mg/kg morphine. On the contrary, that of naloxegol was significantly shifted to the right from 1 to 3 mg/kg morphine. In morphine-dependent rats, naldemedine caused peripheral withdrawal symptoms (diarrhea) at doses higher than 1 mg/kg, while the dose that produced half the maximal preventive effect (ED50) against constipation was 0.03 mg/kg. Naldemedine showed slower onset and a lesser severity of diarrhea than the other compounds at close to the ED50 value in the SIT model. Our results reveal that naldemedine has different pharmacological profiles (type of antagonism and binding kinetics) to the other compounds. This might explain the differential inhibition of morphine-induced SIT and withdrawal symptoms among the three antagonist compounds. SIGNIFICANCE STATEMENT: Naldemedine is a novel PAMORA with potent antagonist activity against μ-, δ-, and κ-opioid receptors. Naldemedine showed a non-competitive antagonism and slower association and dissociation kinetics against μ opioid receptors than naloxone and naloxegol. Naldemedine showed insurmountable antagonism of morphine-induced SIT inhibition and lower and slower peripheral withdrawal symptoms (diarrhea) than the other compounds. Therefore, naldemedine has a different pharmacological profile (the type of antagonism and binding kinetics) to the other compounds.
Learn More >To determine whether a pre-existing smartphone app to teach mindfulness meditation is acceptable to women with chronic pelvic pain (CPP) and can be integrated into clinical practice within the National Health Service (NHS) CPP pathways, and to inform the design of a potential randomised clinical trial.
Learn More >Uncontrolled cancer pain is a significant problem in palliative medicine. Opioids are often first-line treatment that increase risks of analgesic tolerance and hyperalgesia. Topical ketamine with other adjuvant pain medications is an often-overlooked treatment, yet may be most effective in difficult-to-treat cancer pain. We report a case series of hospice patients with uncontrolled cancer pain who were suboptimally treated with opioids and nerve blocks, whose symptoms responded to topical ketamine with other adjuvants. We review the pronociceptive properties of opioids and how topical multimodal treatment of cancer pain can be more effective than standard opioids, other topical adjuvant medications, and nerve blocks. We discuss the shortcomings of the World Health Organization (WHO) stepladder for the treatment of cancer pain and suggest an adjuvant treatment algorithm, directing physicians to appropriate adjuvant pain agents based on pain type and distinct receptor actions. This is a retrospective case series of patients who responded to topical multimodal pain treatment with implementation of findings into an addendum to the WHO stepladder. Subjects were from a case series of community-based hospice patients with previously uncontrolled cancer pain. Measurement was made by self-report of pain levels using the 10-point numeric pain rating scale. Patients' pain was controlled with topical adjuvant medications with return to previously lost function and prevention of otherwise escalating opioid dosing. These patient cases reveal how ketamine-based topical treatment for cancer pain can be more effective than standard opioids, other topical adjuvant medications, and nerve blocks with no noted side effects and observed reduction in opioid consumption.
Learn More >Pannexin-1 (Panx1) is a large pore membrane channel with unique conduction properties ranging from non-selective ion permeability to the extracellular release of signalling molecules. The release of ATP by Panx1 has been particularly well-characterized with implications in purine signalling across a variety of biological contexts. Panx1 activity is also important in inflammasome formation and the secretion of pro-inflammatory molecules such as interleukin-1β. Within the central nervous system (CNS), Panx1 is expressed on both neurons and glia, and is thought to mediate crosstalk between these cells. A growing body of literature now supports the pathological activity of Panx1 in contributing to disease processes including seizure, stroke, migraine headache and chronic pain. Emerging evidence also reveals a physiological function of Panx1 in regulating neural stem cell survival, neuronal maturation and synaptic plasticity, with possible relevance to normal cognitive functioning. The aim of this review is to summarize the current evidence regarding the roles of Panx1 in the CNS, with emphasis on how putative signalling properties and activation mechanisms of this channel contribute to various physiological and pathophysiological processes.
Learn More >Our previous findings indicate that HCN2 contributes to oxaliplatin-induced neuropathic pain, but the mechanisms underlying the development of neuropathic pain are still unclear. Here, we found that the rat HCN2 levels significantly increased after high-frequency stimulation-induced long-term potentiation (LTP). Spinal local application of ZD7288 (a cyclic-nucleotide-gated-channel-specific inhibitor) prevented LTP induction after intraperitoneal injection of oxaliplatin. In addition, oxaliplatin administration induced spinal LTP via activation of the CaMKII-CREB cascade in the rat spinal dorsal horn. Moreover, we found that administration of oxaliplatin significantly increased the amplitude of excitatory postsynaptic currents and the number of action potentials, but these effects were attenuated by pretreatment with either CaMKII inhibitor KN-93 or NR2B antagonist Ro 25-6981. An increase in the phosphorylation of spinal N-methyl-d-aspartate (NMDA) receptor subunit 1 (NR1) after oxaliplatin administration was weakened by ZD7288 pretreatment. Administration of noncompetitive NMDA receptor antagonist MK-801 blocked oxaliplatin-evoked CaMKII-CREB cascade activation and prevented HCN2-mediated spinal-LTP induction in vitro and suppressed neuropathic-pain behaviors of rats. All these data suggest that HCN2 contributes to the development of neuropathic pain by inducing spinal LTP via activation of NMDA receptor-mediated CaMKII signaling.
Learn More >Transcranial direct current stimulation (tDCS) is used for various chronic pain conditions, but experience with tDCS for acute postoperative pain is limited. This study investigated the effect of tDCS vs. sham stimulation on postoperative morphine consumption and pain intensity after thoracotomy.
Learn More >Burning mouth syndrome (BMS) is one of the most frequently seen idiopathic pain conditions in a dental setting. Peri- and postmenopausal women are most frequently affected, and patients who experience BMS complain of persistent burning pain mainly at the tip and the bilateral border of the tongue. Recent studies have assessed whether BMS is a neuropathic pain condition, based on morphologic changes in biopsied tongue specimens, and whether there are abnormal pain responses in patients with this disease. Somatosensory studies have reported some abnormal findings in sensory and pain detection thresholds with inconsistency; however, the most distinct finding was exaggerated responses to painful stimuli. Imaging and electrophysiologic studies have suggested the possibility of dysregulation of the pain-modulating system in the central nervous system, which may explain the enhanced pain responses despite the lack of typical responses toward quantitative sensory tests. Basic studies have suggested the possible involvement of neuroprotective steroids, although the underlying mechanisms of this condition have not been elucidated. Experimental studies are looking for preferable supportive therapies for BMS patients despite the obscure pathogenesis.
Learn More >The lungs, the immune and nervous systems functionally interact to respond to respiratory environmental exposures and infections. The lungs are innervated by vagal sensory neurons of the jugular and nodose ganglia, fused together in smaller mammals as the jugular-nodose complex (JNC). While the JNC shares properties with the other sensory ganglia, the trigeminal (TG) and dorsal root ganglia (DRG), these sensory structures express differential sets of genes that reflect their unique functionalities. Here, we used RNAseq in mice to identify the differential transcriptomes of the three sensory ganglia types. Using a fluorescent retrograde tracer and fluorescence-activated cell sorting we isolated a defined population of airway-innervating JNC neurons and determined their differential transcriptional map after pulmonary exposure to lipopolysaccharide (LPS), a major mediator of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) after infection with Gram-negative bacteria or inhalation of organic dust. JNC neurons activated an injury response program leading to increased expression of gene products such as the G-protein coupled receptors, Cckbr, inducing functional changes in neuronal sensitivity to peptides, and Gpr151, also rapidly induced upon neuropathic nerve injury in pain models. Unique JNC-specific transcripts, present at only minimal levels in TG, DRG and other organs, were identified. These included TMC3, encoding for a putative mechanosensor, and Urotensin 2B, a hypertensive peptide. These findings highlight the unique properties of the JNC and reveal that ALI/ARDS rapidly induce a nerve-injury related state changing vagal excitability.
Learn More >The long-term incidence of chronic postsurgical pain (CPSP) after thoracic surgery has not yet been reported.
Learn More >Chronic pain in later life is a worldwide problem. In younger patients, chronic pain affects life satisfaction negatively; however, it is unknown whether this outcome will extend into old age.
Learn More >This study aimed at identifying characteristics of individuals who are most likely to benefit from long-term opioid therapy in terms of reduction in pain severity and improved mental health-related quality of life (mQoL) without considering potential risks.
Learn More >In the context of interventions aimed at reducing pain, disability and maladaptive pain cognitions in chronic neck pain, it is hypothesized that patients who have greater symptom reduction, possibly also demonstrate greater improvement in cervical motor output. Therefore, the aim of this study was to examine the effect of pain neuroscience education plus cognition-targeted motor control training on cervical motor output.
Learn More >The exact mechanisms underlying the development and maintenance of phantom limb pain are still unclear. This study aimed to identify the factors affecting pain intensity in chronic, lower limb, traumatic phantom limb pain patients.
Learn More >To examine the effectiveness of noninvasive brain stimulation (NIBS) on neuropathic pain (NP) in individuals with spinal cord injury (SCI).
Learn More >Given the changing political and social climate around opioids, we examined how clinicians in the outpatient setting made decisions about managing opioid prescriptions for new patients already on long-term opioid therapy.
Learn More >To examine the relationship between body mass index (BMI) and pain intensity among veterans with musculoskeletal disorder diagnoses (MSDs; nontraumatic joint disorder; osteoarthritis; low back, back, and neck pain).
Learn More >Acute pain trajectories are associated with long-term outcomes such as persistent pain and functional disability in adults. However, there are limited data on acute postoperative pain trajectories in the pediatric population. The aims of this study were to investigate acute postoperative pain trajectories, their predictors, and their impact on long- term outcomes in adolescents with idiopathic scoliosis.
Learn More >Chronic pain is prevalent, and approximately half of patients with chronic pain experience sleep disturbance. Exogenous melatonin is licensed to treat primary insomnia and there is some evidence for analgesic effects of melatonin.The aim of this study is to investigate the effects of oral melatonin (as Circadin) 2 mg at night in adults with severe non-malignant pain of at least 3 months' duration.
Learn More >Rural Nigeria has one of the greatest burdens of low back pain but there are no effective evidence-based interventions to manage it in this population. This paper presents the application of the intervention mapping (IM) approach in the development of a complex behavior change intervention – The Good Back program, aimed at reducing non-specific chronic low back pain (CLBP) disability in rural Nigeria.
Learn More >Dupilumab is an anti-interleukin-4 receptor monoclonal antibody that was recently approved for the treatment of atopic dermatitis (AD). In this single-center retrospective study, clinical baseline data of 117 severe AD patients treated with dupilumab were collected. At baseline and at weeks 4 and 16, disease severity was assessed through the Eczema Area and Severity Index (EASI) and quality of life through the Dermatology Life Quality Index (DLQI) questionnaire, Patient-Oriented Eczema Measure (POEM), Hospital Anxiety and Depression Scale (HADS), Peak Pruritus Numerical Rating Scale (NRS-itch), and VAS-sleep. Response to dupilumab was defined as an improvement of ≥75% in EASI from baseline (EASI75). At multivariate analysis, AD onset before 18 years [OR, 2.9; 95% CI, 1.2-7.2; = 0.0207] and absence of hypereosinophilia [OR, 2.24; 95% CI, 1.03-4.86; = 0.0412] were identified as significant predictive parameters for response to dupilumab in terms of EASI75 at week 4 but not at week 16. Significant reductions in EASI, DLQI, POEM, HADS, NRS-itch, and VAS-sleep were found between week 4 versus baseline ( < 0.0001 for all) and week 16 versus baseline ( < 0.0001 for all). Early AD onset and absence of hypereosinophilia may be suggested as predictive markers of early response to dupilumab. We confirmed the efficacy and safety of this agent along with the improvement of life quality in severe AD patients.
Learn More >Chronic pain affects over 100 million American adults. The prevalence of chronic pain is even higher among U.S. military personnel. Approximately 44% of active duty military experience pain upon returning from deployment compared with 26% of the general public who experience chronic pain. The high prevalence of chronic pain within the Military Health System is compounded by limited access to chronic pain specialists, specifically with regard to patients at remote military treatment facilities (MTFs). Thus, when compared to personnel at tertiary care MTFs, they often have decreased access to care and experience increased time away from their mission to receive care. Since 2009, Walter Reed National Military Medical Center (WRNMMC) has been using telemedicine to extend chronic pain consults to remote MTFs within the National Capital Region (NCR). The goal of this study was to determine if patients referred to the WRNMMC Telepain Program reported improvements in subjective measures associated with accessing care. To accomplish this, we surveyed a convenience sample of patients using the service to determine if participation: (1) improved pain, (2) improved quality of life, (3) decreased travel time, (4) improved access to care, and (5) decreased time away from work.
Learn More >Mirror image sensory dysfunction (MISD) after breast surgery has not yet been studied. This prospective observational study aimed to determine the incidence of MISD, persistent postoperative pain (PPP) and mirror image pain (MIP) during 6 months after total unilateral mastectomy.Visual analogue scale (VAS), Neuropathic Pain Symptom Inventory (NPSI), Pain Catastrophizing Scale (PCS), Hospital Anxiety and Depression Scale (HADS), Life orientation test (LOT) and Quantitative Sensory Testing (QST) (in ipsi and contralateral breast, axilla and thigh) were recorded. VAS > 3 at 1, 3, and 6 postoperative months was considered PPP. Contralateral changes of QST at any time was considered indicative of MISD and spontaneous contralateral VAS ≥ 1 as MIP.Sixty-four patients were included. PPP at 1, 3 and 6 months was 18.8%, 56.2%, and 21.3%, respectively Ten patients presented MIP. MISD was detected in 79.7% patients in contralateral breast and 62.5% in contralateral axilla. Furthermore, changes in QST were present in 39.1% of patients in thigh. Electronic Von Frey (EVF) changes in both contralateral breast and axilla, and in thigh significantly diminished at all postoperative times. Changes of postoperative EVF ≥ 20% in contralateral breast were associated to higher VAS values. NPSI scores were significantly higher at all postoperative times. At 1 month, PCS, depression HADS subscale and LOT scores were significantly worse than all the other periods.MISD incidence was almost 80%, and 15.6% of patients showed spontaneous contralateral VAS ≥ 1. At 6 months 21.3% of patients manifested PPP. The worst alteration of factors related to PPP occurred at 1 postoperative month. Most consistent QST was EVF.
Learn More >The Pain Assessment for Lower Back-Symptoms (PAL-S) and Impacts (PAL-I) were developed to incorporate patient perspective of treatment benefit in chronic low back pain (cLBP) trials. This study documents psychometric measurement properties of the PAL-S and PAL-I. In this multicenter, observational study, eligible participants clinically diagnosed with cLBP provided sociodemographic information and completed PAL measures and other patient-reported outcome measures of pain and/or disability. Confirmatory factor analyses (CFA), construct validity, and reliability were assessed. The 104 participants were 61% female, 89% white, and mean 55 years old; mean cLBP duration was 11.4 (range 0-47) years. Using painDETECT scores, 36.5% reported small likelihood of neuropathic pain, 30.8% reported unclear likelihood, and 32.7% reported definite likelihood. Persistent pain with pain attacks was reported by 38.5% of participants. CFA confirmed single components with adequate fit indices. Cronbach's alpha was 0.83 (PAL-S) and 0.87 (PAL-I), indicating reliable scales. Intraclass correlation coefficients (test-retest reproducibility, n = 44) were 0.81 (PAL-S) and 0.85 (PAL-I). PAL-S score correlation was 0.49 with Roland-Morris Disability Questionnaire (RMDQ) and 0.77 with Neuropathic Pain Symptom Inventory (NPSI). PAL-I correlated at 0.73 with RMDQ and -0.60 with Medical Outcomes Study (MOS)-36 Bodily Pain. Both measures significantly differentiated between pain intensity levels (based on numeric response scale) and painDETECT groups. The PAL-S and PAL-I generated highly reliable scores with substantial evidence of construct validity. Routine use of these measures in treatment trials will enhance comparability of LBP-related symptom and impact results, including patient perspective of treatment benefit.
Learn More >Spinal cord injury-related pain is often a severe debilitating condition that adversely affects the patient's physical health, psychological wellbeing and quality of life. Opioid medications have historically been prescribed to this population with great frequency. As opioid abuse disorder becomes an ever-worsening public health issue, more attention must be placed upon non-opioid options. This paper reviews non-opioid medications to be considered when treating spinal cord injury-related pain. The pertinent literature is reviewed, and the advantages and pitfalls of various medication options are discussed in the complicated context of the individual with a spinal cord injury. Peer-reviewed journal articles and medication package insert data are reviewed.. The non-opioid medications with the greatest evidence for efficacy in the treatment of chronic spinal cord injury-related pain are drawn from the antiepileptic drug and antidepressant categories though the specific selection must be nuanced to the particular individual patient. More research is required to understand the role of calcitonin, lithium, and marijuana in treating spinal cord injury-related pain. The complex clinical situation of each individual patient must be weighed against the risks and benefits of each medication, as reviewed in this paper, to determine the ideal treatment strategy for chronic spinal cord injury-related pain.
Learn More >Neuromyelitis optica (NMO) is a disease characterised by severe relapses of optic neuritis and longitudinally extensive transverse myelitis and it has a strong female predilection. Pain is one of the most typical symptom in NMO. However, few studies have been conducted to examine the neuropathic pain mechanism of NMO patients or gender-specific effects using magnetic resonance imaging technique. A total of 38 female patients with NMO, 28 with pain (NMOWP) and 10 without pain (NMOWoP), were classified using the Brief Pain Inventory (BPI); 22 healthy females were also recruited. We used the FSL Image Registration and Segmentation Toolbox (FIRST) for subcortical region volumes quantifications, and voxel-based morphometry analysis for cortical gray matter (GM) volume, to examine the brain morphology in NMOWP patients. In addition, correlation test between structural measurements of NMO patients and clinical indexes was also performed. The results showed: 1) no significant differences in cortical GM density between the NMOWP and NMOWoP groups; 2) significantly smaller hippocampus and pallidum volumes in the NMOWP group compared with the NMOWoP group; 3) significant negative correlation between the average BPI and volumes of the accumbens nucleus and thalamus in NMO patients. These results revealed that structural abnormality exists in NMO female patients who have pain, with significant implications for our understanding of the brain morphology in NMO patients with pain.
Learn More >While the descending dopaminergic control system is not fully understood, it is reported that the hypothalamic A11 nucleus is its principle source. To better understand the impact of this system, particularly the A11 nucleus, on neuropathic pain, we created a chronic constriction injury model of the infraorbital nerve (ION-CCI) in rats. ION-CCI rats received intraperitoneal administrations of quinpirole (a dopamine D2 receptor agonist). ION-CCI rats received microinjections of quinpirole, muscimol [a gamma-aminobutyric acid type A (GABA) receptor agonist], or neurotoxin 6-hydroxydopamine (6-OHDA) into the A11 nucleus. A von Frey filament was used as a mechanical stimulus on the maxillary whisker pad skin; behavioral and immunohistochemical responses to the stimulation were assessed. After intraperitoneal administration of quinpirole and microinjection of quinpirole or muscimol, ION-CCI rats showed an increase in head-withdrawal thresholds and a decrease in the number of phosphorylated extracellular signal-regulated kinase (pERK) immunoreactive (pERK-IR) cells in the superficial layers of the trigeminal spinal subnucleus caudalis (Vc). Following 6-OHDA microinjection, ION-CCI rats showed a decrease in head-withdrawal thresholds and an increase in the number of pERK-IR cells in the Vc. Our findings suggest the descending dopaminergic control system is involved in the modulation of trigeminal neuropathic pain.
Learn More >There is growing interest in using cannabinoids for chronic pain. We performed a systematic review and meta-analysis of randomized controlled trials to evaluate the analgesic efficacy and adverse effects of cannabinoids for chronic non-cancer pain. PubMed, EMBASE, Web of Science, Cochrane CENTRAL and clinicaltrials.gov were searched up to December 2018. Information on the type, dosage, route of administration, pain conditions, pain scores, and adverse events were extracted for qualitative analysis. Meta-analysis of analgesic efficacy was performed. Meta-regression was performed to compare the analgesic efficacy for different pain conditions (neuropathic versus non-neuropathic pain). Risk of bias was assessed by The Cochrane Risk of Bias tool, and the strength of the evidence was assessed using the Grade of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Forty-three randomized controlled trials were included. Meta-analysis was performed for 33 studies that compared cannabinoids to placebo, and showed a mean pain score (scale 0-10) reduction of -0.70 (p < 0.001, random effect). Meta-regression showed that analgesic efficacy was similar for neuropathic and non-neuropathic pain (Difference = -0.14, p = 0.262). Inhaled, oral, and oromucosal administration all provided statistically significant, but small reduction in mean pain score (-0.97, -0.85, -0.45, all p < 0.001). Incidence of serious adverse events was rare, and non-serious adverse events were usually mild to moderate. Heterogeneity was moderate. The GRADE level of evidence was low to moderate. Pain intensity of chronic non-cancer patients was reduced by cannabinoids consumption, but effect sizes were small. Efficacy for neuropathic and non-neuropathic pain was similar.
Learn More >Somatic symptom disorder (SSD) is characterized by a persistent and distressing psychological reaction to somatic symptoms. In pain disorders, the preoccupation with physical symptoms is associated with poor long-term outcomes. SSD may therefore be of use to identify and help chronic pain patients with particular needs.
Learn More >Fentanyl and morphine are agonists of the Mu opioid receptor (MOR), which is a member of the GPCR family. Their analgesic effects are associated with unwanted side effects. On a signaling level downstream from MOR, it has been hypothesized that analgesia may be mediated through the G protein pathway, whereas the undesirable effects of opioids have been linked to the β-arrestin (βarr) pathway. Despite being an increasingly debated subject, little is known about a potential 'bias' (i.e. the preferential activation of one pathway over the other) of the novel synthetic opioids (NSO) -including fentanyl analogs- that have emerged on the illegal drug market. We have therefore developed and applied a novel, robust bio-assay platform to study the activity of 21 NSO, to evaluate to what extent these MOR agonists show biased agonism and to investigate the potential correlation with their structure. In addition, we evaluated the functional selectivity of TRV130, a purported G protein-biased agonist. We applied newly established stable bio-assays in HEK293T cells, based on the principle of functional complementation of a split nanoluciferase, to assess MOR activation via recruitment of a mini-Gi protein (GTPase domain of Gαi subunit) or βarr2. All but two of the tested NSO demonstrated a concentration-dependent response at MOR in both bio-assays. The developed bio-assays allow to gain insight into the βarr2 or G protein recruitment potential of NSO, which may eventually help to better understand why certain opioids are associated with higher toxicity. Adding to the recent discussion about the relevance of the biased agonism concept for opioids, we did not observe a significant bias for any of the evaluated compounds, including TRV130.
Learn More >The aim of this study was to investigate the changes of calcitonin gene-related peptide (CGRP) plasma levels in patients with classical trigeminal neuralgia (TN) and if plasma CGRP concentrations could be used to predict the response to botulinum toxin type A (BTX-A).
Learn More >Noninvasive vagus nerve stimulation (nVNS) has been proposed as a new neuromodulation therapy to treat primary headache disorders. The purpose of this study was to analyze the effectiveness and safety of peripheral nerve stimulation of the cervical branch of the vagal nerve for primary headache disorders.
Learn More >In this prospective, multicenter, double-blinded, randomized, crossover study, we compared the therapeutic efficacy of burst SCS delivered using a lead implanted with the paresthesia mapping approach to a lead implanted with an anatomic placement approach.
Learn More >Complex regional pain syndrome (CRPS) can be effectively treated with spinal cord stimulation (t-SCS). There is also evidence that dorsal root ganglion (DRG) stimulation may be superior to t-SCS in CRPS. However, there has been no published data, to our knowledge, that looked at the concurrent use of t-SCS and DRG stimulation for treatment of CRPS.
Learn More >Migraine and sleep disorders in children exhibit a bidirectional relationship. This relationship is based on shared pathophysiology. Migraine involves activation of the trigeminal vascular system. Nociceptive neurons that innervate the dura release various vasoactive peptides. Calcitonin gene-related peptide is the most active of these peptides. Neural pathways that are involved in sleep generation are divided into those responsible for circadian rhythm, wake promotion, non-rapid eye movement, and rapid eye movement sleep activation. Sleep state switches are a critical component of these systems. The cerebral structures, networks, and neurochemical systems that are involved in migraine align closely with those responsible for the regulation of sleep. Neurochemical systems that are involved with both the pathogenesis of migraine and regulation of sleep include adenosine, melatonin, orexin, and calcitonin gene-related peptide. Sleep disorders represent the most common comorbidity with migraine in childhood. The prevalence of parasomnias, obstructive sleep apnea, and sleep-related movement disorders is significantly greater in children migraineurs. Infantile colic is a precursor of childhood migraine. Treatment of comorbid sleep disorders is important for the appropriate management of children with migraine. Sleep-based behavioral interventions can be of substantial benefit. These interventions are particularly important in children due to limited evidence for effective migraine pharmacotherapy.
Learn More >