Browse by Audience
Astrocytes are essential contributors to neuronal function. As a consequence, disturbed astrocyte-neuron interactions are involved in the pathophysiology of several neurological disorders, with a strong impact on brain circuits and behavior. Here, we describe altered cortical physiology in a genetic mouse model of familial hemiplegic migraine type 2 (FHM2), with reduced expression of astrocytic Na,K-ATPases. We used whole-cell electrophysiology, two-photon microscopy, and astrocyte gene rescue to demonstrate that an impairment in astrocytic glutamate uptake promotes NMDA spike generation in dendrites of cingulate cortex pyramidal neurons and enhances output firing of these neurons. Astrocyte compensation of the defective ATPase in the cingulate cortex rescued glutamate uptake, prevented abnormal NMDA spikes, and reduced sensitivity to cranial pain triggers. Together, our results demonstrate that impaired astrocyte function alters neuronal activity in the cingulate cortex and facilitates migraine-like cranial pain states in a mouse model of migraine.
Learn More >Itch, in particular chronic forms, has been widely recognized as an important clinical problem, but much less is known about the mechanisms of itch in comparison with other sensory modalities such as pain. Recently, considerable progress has been made in dissecting the circuit mechanisms of itch at both the spinal and supraspinal levels. Major components of the spinal neural circuit underlying both chemical and mechanical itch have now been identified, along with the circuits relaying ascending transmission and the descending modulation of itch. In this review, we summarize the progress in elucidating the neural circuit mechanism of itch at spinal and supraspinal levels.
Learn More >Whether G protein-coupled receptors signal from endosomes to control important pathophysiological processes and are therapeutic targets is uncertain. We report that opioids from the inflamed colon activate δ-opioid receptors (DOPr) in endosomes of nociceptors. Biopsy samples of inflamed colonic mucosa from patients and mice with colitis released opioids that activated DOPr on nociceptors to cause a sustained decrease in excitability. DOPr agonists inhibited mechanically sensitive colonic nociceptors. DOPr endocytosis and endosomal signaling by protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) pathways mediated the sustained inhibitory actions of endogenous opioids and DOPr agonists. DOPr agonists stimulated the recruitment of Gα and β-arrestin1/2 to endosomes. Analysis of compartmentalized signaling revealed a requirement of DOPr endocytosis for activation of PKC at the plasma membrane and in the cytosol and ERK in the nucleus. We explored a nanoparticle delivery strategy to evaluate whether endosomal DOPr might be a therapeutic target for pain. The DOPr agonist DADLE was coupled to a liposome shell for targeting DOPr-positive nociceptors and incorporated into a mesoporous silica core for release in the acidic and reducing endosomal environment. Nanoparticles activated DOPr at the plasma membrane, were preferentially endocytosed by DOPr-expressing cells, and were delivered to DOPr-positive early endosomes. Nanoparticles caused a long-lasting activation of DOPr in endosomes, which provided sustained inhibition of nociceptor excitability and relief from inflammatory pain. Conversely, nanoparticles containing a DOPr antagonist abolished the sustained inhibitory effects of DADLE. Thus, DOPr in endosomes is an endogenous mechanism and a therapeutic target for relief from chronic inflammatory pain.
Learn More >Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.
Learn More >Though sex differences in chronic pain have been consistently described in the literature, their underlying neural mechanisms are poorly understood. Previous work in humans has demonstrated that men and women differentially invoke distinct brain regions and circuits in coping with subjective pain unpleasantness. The goal of the present work was to elucidate the molecular mechanisms in the basolateral nucleus of the amygdala (BLA) that modulate hyperalgesic priming, a pain plasticity model, in males and females. We used plantar incision as the first, priming stimulus and prostaglandin E (PGE) as the second stimulus. We sought to assess whether hyperalgesic priming can be prevented or reversed by pharmacologically manipulating molecular targets in the BLA of male or female mice. We found that administering ZIP, a cell-permeable inhibitor of aPKC, into the BLA attenuated aspects of hyperalgesic priming induced by plantar incision in males and females. However, incision only upregulated PKCζ/PKMζ immunoreactivity in the BLA of male mice, and deficits in hyperalgesic priming were seen only when we restricted our analysis to male mice. On the other hand, intra-BLA microinjections of pep2m, a peptide that interferes with the trafficking and function of GluA2-containing AMPA receptors, a downstream target of aPKC, reduced mechanical hypersensitivity after plantar incision and disrupted the development of hyperalgesic priming in both male and female mice. In addition, pep2m treatment reduced facial grimacing and restored aberrant behavioral responses in the sucrose splash test in male and female primed mice. Immunofluorescence results demonstrated upregulation of GluA2 expression in the BLA of male and female primed mice, consistent with pep2m findings. We conclude that, in a model of incision-induced hyperalgesic priming, PKCζ/PKMζ in the BLA is critical for the development of hyperalgesic priming in males, while GluA2 in the BLA is crucial for the expression of both reflexive and affective pain-related behaviors in both male and female mice in this model. Our findings add to a growing body of evidence of sex differences in molecular pain mechanisms in the brain.
Learn More >To determine the prevalence of and risk factors associated with opioid use in the treatment of migraine, we examined demographics and clinical characteristics of 867 individuals who reported using opioids for the treatment of migraine.
Learn More >In the lumbar spinal cord dorsal horn, release of afferent nerve glutamate activates the neurons that relay information about injury pain. Here, we examined the effects of protein tyrosine kinase (PTK) inhibition on NMDA receptor NR1 subunit protein expression and subcellular localization in an acute experimental arthritis model. PTK inhibitors genistein and lavendustin A reduced cellular histological translocation of NMDA NR1 in the spinal cord occurring after the inflammatory insult and the nociceptive behavioral responses to heat. The PTK inhibitors were administered into lumbar spinal cord by microdialysis, and secondary heat hyperalgesia was determined using the Hargreaves test. NMDA NR1 cellular protein expression and nuclear translocation were determined by immunocytochemical localization with light and electron microscopy, as well as with Western blot analysis utilizing both C- and N-terminal antibodies. Genistein and lavendustin A (but not inactive lavendustin B or diadzein) effectively reduced (i) pain related behavior, (ii) NMDA NR1 subunit expression increases in spinal cord, and (iii) the shift of NR1 from a cell membrane to a nuclear localization. Genistein pre-treatment reduced these events that occur within 4 h after inflammatory insult to the knee joint with kaolin and carrageenan (k/c). Cycloheximide reduced glutamate activated upregulation of NR1 content confirming synthesis of new protein in response to the inflammatory insult. In addition to this data, genistein or staurosporin inhibited upregulation of NMDA NR1 protein and nuclear translocation after treatment of human neuroblastoma clonal cell cultures (SH-SY5Y) with glutamate or NMDA (4 h). These studies provide evidence that inflammatory activation of peripheral nerves initiates increase in NMDA NR1 in the spinal cord coincident with development of pain related behaviors through glutamate non-receptor, PTK dependent cascades.
Learn More >No externally validated presurgical risk score for chronic postsurgical pain (CPSP) is currently available. We tested the generalizability of a six-factor risk model for CPSP developed from a prospective cohort of 2929 patients in four surgical settings. Seventeen centers enrolled 1225 patients scheduled for inguinal hernia repair, hysterectomy (vaginal or abdominal), or thoracotomy. The six clinical predictors were surgical procedure, younger age, physical health (Short Form Health Survey-12), mental health (Short Form Health Survey-12), preoperative pain in the surgical field, and preoperative pain in another area. CPSP was confirmed by physical examination at 4 months. The model's discrimination (c-statistic), calibration, and diagnostic accuracy (sensitivity, specificity and positive and negative likelihood ratios) were calculated to assess geographic and temporal transportability in the full cohort and two subsamples (historical and new centers). The full dataset after exclusions and losses included 1088 patients; 20.6% had developed CPSP at 4 months. The c-statistics (95% CI) were similar in the full validation sample and the two subsamples: 0.69 (0.65-0.73), 0.69 (0.63-0.74) and 0.68 (0.63-0.74), respectively. Calibration was good (slope b and intercept close to 1 and 0, respectively and nonsignificance in the Hosmer-Lemeshow goodness-of-fit test). The validated model based on six clinical factors reliably identifies risk for CPSP risk in about 70% of patients undergoing the surgeries studied, allowing surgeons and anesthesiologists to plan and initiate risk reduction strategies in routine practice and researchers to screen for risk when randomizing patients in trials.
Learn More >As treatment for postsurgical pain (PSP) remains a major unmet medical need, the emergence of safe and innovative non-opioid drugs has been strongly coveted. Tetrahydrobiopterin (BH4) is an interesting molecule for gaining a better understanding the pathological mechanism of neuropathic pain. However, whether BH4 and its pathway are involved in the pathogenesis of PSP remains unclear. In this study, we found that early in a rat paw incision model, the gene expression of GTP cyclohydrolase 1 (GTPCH) and sepiapterin reductase (SPR), BH4-producing enzymes in the de novo pathway, were significantly increased in incised compared with naïve paw skin. Although a significant increase in GTPCH protein levels was observed in incised paw skin until only 1 day after incision, a significant increase in BH4 levels was observed until 7 days after incision. In vivo, Spr-knockout mice showed an antinociceptive phenotype in the hind paw incision compared with the wild-type and Spr heterozygote groups. Furthermore, QM385, the SPR inhibitor, showed a significant dose-dependent, antinociceptive effect, which was supported by a reduction in BH4 levels in incised skin tissues, with no apparent adverse effects. Immunohistochemical analysis demonstrated that macrophages expressing GTPCH protein were increased around the injury site in the rat paw incision model. These results indicate that BH4 is involved in the pathogenesis of PSP, and that inhibition of the BH4 pathway could provide a new strategy for the treatment of acute PSP.
Learn More >Chronic pelvic pain syndrome (CPPS), is a multi-symptom syndrome with unknown etiology. The experimental autoimmune prostatitis (EAP) mouse model of CPPS is associated with immune cell infiltration into the prostate, expression of C-C Chemokine ligand 2 (CCL2) and neuroinflammation in the spinal cord. Here, we studied CCL2 expression in tissues along the nociceptive pathway and its association with neuroimmune cells during pain development. Examination of prostate tissues at days 14 and 28 after EAP induction revealed CCL2 expression was increased in epithelial cells and was associated with increased numbers of macrophages lying in close apposition to PGP9.5-positive afferent neuronal fibers. CCL2 immunoreactivity was elevated to a similar degree in the DRG at day 14 and day 28. D14 of EAP was associated with elevated IBA1 cells in the DRG that were not evident at D28. Adoptive transfer of GFP+ leukocytes into EAP mice demonstrated monocytes are capable of infiltrating the spinal cord from peripheral blood with what appeared to be a proinflammatory phenotype. In the lower dorsal spinal cord, CCL2 expression localized to NeuN expressing neurons and GFAP-expressing astrocytes. Myeloid derived cell infiltration into the spinal cord in EAP was observed in the L6-S2 dorsal horn. Myeloid derived CD45+ IBA1+ cells were localized with IBA1+ TMEM199+ microglia in the dorsal horn of the spinal cord in EAP, with intimate association of the two cell types suggesting cell-cell interactions. Lastly, intrathecal administration of liposomal clodronate ameliorated pelvic pain symptoms, suggesting a mechanistic role for macrophages and microglia in chronic pelvic pain.
Learn More >The voltage-gated calcium channels CaV3.1-3.3 constitute the T-type subfamily, whose dysfunctions are associated with epilepsy, psychiatric disorders, and chronic pain. The unique properties of low voltage-activation, faster inactivation, and slower deactivation of these channels support their role in modulation of cellular excitability and low-threshold firing. Thus, selective T-type calcium channel antagonists are highly sought after. Here, we explored Ugi-azide multicomponent reaction (MCR) products to identify compounds targeting T-type calcium channel. Of the 46 compounds tested, an analog of benzimidazolonepiperidine – 5bk (1-{1-[(R)-{1-[(1S)-1-phenylethyl]-1H-1,2,3,4-tetrazol-5-yl}(thiophen-3-yl)methyl]piperidin-4-yl}-2,3-dihydro-1H-1,3-benzodiazol-2-one) modulated depolarization-induced calcium influx in rat sensory neurons. Modulation of T-type calcium channels by 5bk was further confirmed in whole-cell patch clamp assays in dorsal root ganglion (DRG) neurons, where pharmacological isolation of T-type currents led to a time- and concentration-dependent regulation with a low micromolar IC50. Lack of an acute effect of 5bk argues against a direct action on of T-type channels. Genetic knockdown revealed CaV3.2 to be the isoform preferentially modulated by 5bk. High voltage-gated calcium, as well as tetrodotoxin-sensitive and -resistant sodium, channels were unaffected by 5bk. 5bk inhibited spontaneous excitatory post synaptic currents and depolarization-evoked release of calcitonin gene-related peptide (CGRP) from lumbar spinal cord slices. Notably, 5bk did not bind human mu, delta, or kappa opioid receptors. 5bk reversed mechanical allodynia in rat models of HIV-associated neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), and spinal nerve ligation (SNL)-induced neuropathy, without effects on locomotion or anxiety. Thus, 5bk represents a novel T-type modulator that could be used to develop non-addictive pain therapeutics.
Learn More >Migraine is one of the most disabling disorders worldwide but the underlying mechanisms are poorly understood. Stress is consistently reported as a common trigger of migraine attacks. Here we show that repeated stress in mice causes migraine-like behaviors that are responsive to a migraine therapeutic. Adult female and male mice were exposed to 2 hours of restraint stress for 3 consecutive days, after which they demonstrated facial mechanical hypersensitivity and facial grimace responses that were resolved by 14 days post-stress. Hypersensitivity or grimace was not observed in either control animals or those stressed for only 1 day. Following return to baseline, the NO-donor sodium nitroprusside (SNP; 0.1 mg/kg) elicited mechanical hypersensitivity in stressed but not in control animals, demonstrating the presence of hyperalgesic priming. This suggests the presence of a migraine-like state, since NO-donors are reliable triggers of attacks in migraine patients but not controls. The stress paradigm also caused priming responses to dural pH 7.0 treatment. The presence of this primed state after stress is not permanent as it was no longer present at 35 days post-stress. Finally, mice received either the CGRP monoclonal antibody ALD405 (10 mg/kg) 24 hours prior to SNP or a co-injection of sumatriptan (0.6 mg/kg). ALD405, but not sumatriptan, blocked the facial hypersensitivity due to SNP. This stress paradigm in mice and the subsequent primed state caused by stress, allow further preclinical investigation of mechanisms contributing to migraine, particularly those caused by common triggers of attacks.
Learn More >An epileptic seizure can trigger a headache during (ictal) or after (postictal) the termination of the event. Little is known about the pathophysiology of seizure-induced headaches. In the current study, we determined whether a seizure can activate nociceptive pathways that carry pain signals from the meninges to the spinal cord, and if so, to what extent and through which classes of peripheral and central neurons. To achieve these goals, we used single-unit recording techniques and an established animal model of seizure (picrotoxin) to determine the effects of epileptic seizure on the activity of trigeminovascular Aδ-, C-, wide-dynamic range, and high-threshold neurons in male and female rats. Occurrence of seizure activated 54%, 50%, 68%, and 39% of the Aδ-, C-, wide-dynamic range, and high-threshold neurons, respectively. Regardless of their class, activated neurons exhibited a twofold to fourfold increase in their firing, which started immediately (1 min) or up to 90 min after seizure initiation, and lasted as short as 10 min or as long as 120 min. Administration of lidocaine to the dura prevented activation of all neuronal classes but not the initiation or maintenance of the seizure. These findings suggest that all neuronal classes may be involved in the initiation and maintenance of seizure-induced headache, and that their activation patterns can provide a neural substrate for explaining the timing and duration of ictal and possibly postictal headaches. By using seizure, which is evident in humans, this study bypasses controversies associated with cortical spreading depression, which is less readily observed in humans.This preclinical study provides a neural substrate for ictal and postictal headache. By studying seizure effects on the activity of peripheral (C and Aδ) and central (wide dynamic range and high-threshold) trigeminovascular neurons in intact and anesthetized dura, the findings help resolve two outstanding questions about the pathophysiology of headaches of intracranial origin. The first is that abnormal brain activity (i.e., seizure) that is evident in human (unlike cortical spreading depression) gives rise to specific and selective activation of the different components of the trigeminovascular system, and the second is that the activation of all components of the trigeminovascular pathway (i.e., peripheral and central neurons) depends on activation of the meningeal nociceptors from their receptors in the dura.
Learn More >Unpleasant somatosensory stimuli such as pain and itch can interrupt normal behavior. But survival can depend on resuming normal behavior before these challenges are fully resolved. The neural mechanisms that prioritize behavior when individuals are challenged with unpleasant somatosensory sensations, however, are not fully understood. Recently, we identified a neural circuit activated by hunger that can inhibit pain, prioritizing food seeking over tending to an injury. Here, we examine the ability of hunger, and neurons activated by hunger, to inhibit behavioral responses to another unpleasant somatosensory sensation – itch. We demonstrate that food deprivation inhibits scratching induced by 3 different pruritogenic stimuli: histamine, serotonin, and chloroquine. The inhibition of scratching correlates with the level of food deprivation, suggesting a cross-competition of alarm systems in the brain whereby more energy need more efficiently inhibits competing drives. Finally, we show that activity in hunger-sensitive, hypothalamic agouti-related protein (AgRP)-expressing neurons is sufficient to inhibit itch. Taken together, we showed that hunger or AgRP neuron activity inhibits itch, demonstrating that organisms have neural systems to filter and process ascending spinal signals activated by unpleasant somatosensory stimuli to prioritize salient needs.
Learn More >Naltrexone reversibly blocks the effects of opioids and has been shown to decrease placebo analgesia. However, it is not clear (1) to what extent naltrexone affects pain modulation in a nontreatment context, for example, in response to pain cues or (2) how naltrexone given prior to pain-cue learning shapes pain responses. In a double-blind procedure prior to pain-cue conditioning, 30 healthy participants were randomized to receive an oral dose of naltrexone (50 mg) or inert pill. During functional magnetic resonance imaging, high and low pain pressures were paired with two different visual cues: a high pain cue and a low pain cue (learning sequence). During a test sequence, medium levels of pressure were used for both cues and the difference in subjective pain ratings following high and low pain cues was calculated. Results showed significant conditioned pain responses across groups (<.001); however, no significant difference between participants receiving naltrexone or inert pill (=.193). There was a significant correlation between the difference in high and low pain ratings during the learning sequence and the effect of high and low pain cues during the test sequence (r = .575, =.002). Functional magnetic resonance imaging analyses revealed no significant difference in brain activation between groups. Here, we demonstrate comparable learning of pain responses in participants treated with naltrexone or inert pill. The results point to the possibility that associative learning, and conditional responding to pain cues, is not dependent on endogenous opioids. Our results, using pain-cue conditioning to create reduced pain responses, contrast previous studies where opioid antagonists significantly reduced the placebo effect in treatment of pain.
Learn More >Pain catastrophizing (PC) has been recognized as an important and consistent psychosocial predictor of nearly every key pain-related outcome. The purpose of this study was to develop a new measure of PC using modern psychometric methodology. People with chronic pain (N=795) responded to thirty items. Data were analyzed using Item Response Theory (IRT), including assessment of differential item functioning (DIF) and reliability. Sensitivity to change and validity were examined using data collected from patients undergoing spinal fusion surgery (n=184) and participating in an ongoing longitudinal aging with a disability survey study (n=1388). The final 24-item bank had no items with significant local dependence, misfit, or DIF. Results provided strong evidence of reliability and validity. Six- and 2-item short forms were developed for use when computer adaptive testing (CAT) is not feasible or desirable. The item bank was named the University of Washington Concerns About Pain (CAP) scale because the term "catastrophizing" was considered stigmatizing by people with chronic pain. Guidance for score interpretation was developed with extensive feedback from individuals with chronic pain. The CAP item bank, short forms, and user manuals are free and publicly available to all users and can be accessed online at https://uwcorr.washington.edu/measures/. PERSPECTIVE: This article presents the development of the University of Washington Concerns About Pain scale, the first IRT-based item bank of pain catastrophizing. The measure is intended for clinicians interested in improving outcomes of patients with chronic pain and for researchers who study impact of and treatment interventions aimed at reducing pain catastrophizing.
Learn More >Pain is an unfortunate consequence of many medical procedures, which in some patients becomes chronic and debilitating. Among the factors affecting medical pain, clinician-patient (C-P) similarity and nonverbal communication are particularly important for pain diagnosis and treatment. Participants (N=66) were randomly assigned to the clinician and patient roles and were grouped into C-P dyads. Clinicians administered painful stimuli to patients as an analogue of a painful medical procedure. We manipulated the perceived C-P similarity of each dyad using groups ostensibly based on shared beliefs and values, and each patient was tested twice: Once with a same group clinician (concordant, CC) and once with a clinician from the other group (discordant, DC). Movement synchrony was calculated as a marker of nonverbal communication. We tested whether movement synchrony mediated the effects of group concordance on patients' pain and trust in the clinician. Movement synchrony was higher in CC than DC dyads. Higher movement synchrony predicted reduced pain and increased trust in the clinician. Movement synchrony also formally mediated the group concordance effects on pain and trust. These findings increase our understanding of the role of nonverbal C-P communication on pain and related outcomes and suggest that interpersonal synchrony may be associated with better patient outcomes, independent of the specific treatment provided. Perspective This article demonstrates that movement synchrony in clinician-patient interactions is an unobtrusive measure related to their relationship quality, trust towards the clinician, and pain. These findings suggest that interpersonal synchrony may be associated with better patient outcomes, independent of the specific treatment provided.
Learn More >Although support provision by a partner is an important resource for individuals with chronic pain (ICPs), it poses a challenge for partners because it competes with other important personal goals of partners. The current study examined the impact of experimentally induced goal conflict in partners on their motives for helping, quality of provided help, and on partners' and ICPs' affect. Sixty-eight couples, with at least one person having chronic pain, performed two series of household activities, with partners either asked to be simply available for help (i.e., control condition) or to additionally work on a puzzle task (i.e., goal conflict condition). Couples reported on interpersonal (e.g., helping motives) and intrapersonal (e.g., affect) outcomes. In addition, quality of partners' helping behavior and ICPs' pain behavior were videotaped and coded afterwards. In the goal conflict condition, ICPs were less satisfied with the received help and they experienced more pain. Also, the quality of the provided help was lower and partners experienced less positive and more negative affect. Addressing partners' goal conflict in clinical practice may help to avoid its negative impact on both ICPs and partners. Perspective: This article provides a compelling argument to include partners in chronic pain treatment by demonstrating the detrimental effects of partners' experienced conflicts in goals upon the quality of help they provide, partners' affective functioning and ICPs' pain-related outcomes.
Learn More >Temporomandibular Disorder (TMD) patients report amplification of pain in the masticatory muscles after psychological trauma or stressful conditions. The mechanisms underlying this phenomenon are yet to be elucidated. This study combined immunohistochemistry with single cell in vivo electrophysiology recordings of masticatory muscle afferent fibers to investigate the role of α-adrenergic receptors in muscle nociception. It was found that a subset of trigeminal afferent fibers which innervate the masseter and temporal muscles expressed α, α and α receptors, including a smaller number of putative nociceptors which co-expressed TrpV receptors. Local injection of the selective α adrenergic receptor agonist phenylephrine into masticatory muscle decreased and increased the mechanical activation threshold of slow and fast conducting afferent fibers, respectively. This effect was reversed by co-administration of the α selective antagonist terazosin. To rule out the possibility that local ischemia was responsible for the observed effect of phenylephrine on masticatory muscle afferent fibers, additional experiments were conducted where blood flow to the masticatory muscle was reduced by common carotid artery occlusion. This investigation found that muscle blood flow occlusion increased the mechanical activation threshold of the majority of masticatory muscle afferent fibers unrelated to conduction velocity. These findings suggest that under conditions of increased sympathetic tone, such as those related to stress, noradrenaline may sensitize masticatory muscle nociceptors to increase pain and desensitize muscle proprioceptors to alter muscle tone, through activation of α receptors.
Learn More >Focused ultrasound (FUS) is a promising technology for facilitating treatment of brain diseases including chronic pain. Focused ultrasound is a unique modality for delivering therapeutic levels of energy into the body, including the central nervous system (CNS). It is non-invasive and can target spatially localized effects through the intact skull to cortical or subcortical regions of the brain. FUS can achieve three different mechanisms of action in the brain that are relevant for chronic pain treatment: (1) localized thermal ablation of neural tissue; (2) localized and transient disruption of the blood-brain barrier for targeted drug delivery to CNS structures; and (3) inhibition or stimulation of neuronal activity in targeted regions. This review provides an in-depth look at the technology of FUS with emphasis placed on applications to CNS-based treatments of chronic pain. While still in the early stages of clinical translation and with some technical challenges remaining, we suggest that FUS has great potential as a novel approach for manipulating CNS networks involved in pain treatment.
Learn More >Burning mouth syndrome (BMS) is a chronic pain disorder affecting the oral cavity. Previous work has shown promising analgesic results of bodily illusions in other chronic pain conditions. The aim of this proof-of-concept, pilot study was to investigate whether bodily illusions reduce pain in BMS patients.
Learn More >At least one third of HIV-1-afflicted individuals experience peripheral neuropathy. Although the underlying mechanisms are not known, they may involve neurotoxic HIV-1 proteins. We assessed the influence of the neurotoxic HIV-1 regulatory protein, Tat, on inflammatory and neuropathic nociceptive behaviors using transgenic male and female transgenic mice that conditionally expressed (or did not express) HIV-1 Tat in glial fibrillary acidic protein-expressing glia in the central and peripheral nervous systems. Tat induction significantly attenuated the time spent paw-licking following formalin injection (2.5%, i.pl.) in both male and female mice. However, significant sex differences were observed in the onset and magnitude of inflammation and sensory sensitivity following complete Freund's adjuvant (CFA) injection (10%, i.pl.) after Tat activation. Unlike female mice, males showed a significant attenuation of paw swelling and an absence of mechanical/thermal hypersensitivity in response to CFA after Tat induction. Male Tat(+) mice also showed accelerated recovery from chronic constrictive nerve injury (CCI)-induced neuropathic mechanical and thermal hypersensitivity compared to female Tat(+) mice. Morphine (3.2 mg/kg) fully reversed CCI-induced mechanical hypersensitivity in female Tat(-) mice, but not in Tat(+) females. The ability of Tat to decrease edema, paw swelling, and limit allodynia suggest a sequela of events in which Tat-induced functional deficits precede the onset of mechanical hypersensitivity. Moreover, HIV-1 Tat attenuated responses to inflammatory and neuropathic insults in a sex-dependent manner. HIV-1 Tat appears to directly contribute to HIV sensory neuropathy and reveals sex differences in HIV responsiveness and/or the underlying peripheral neuroinflammatory and nociceptive mechanisms.
Learn More >The present series of studies examine the impact of systemically administered therapeutics on peripheral nerve injury (males; unilateral sciatic chronic constriction injury [CCI])-induced suppression of voluntary wheel running, across weeks after dosing cessation. Following CCI, active phase running distance and speed are suppressed throughout the 7-week observation period. A brief course of morphine, however, increased active phase running distance and speed throughout this same period, an effect apparent only in sham rats. For CCI rats, systemic co-administration of morphine with antagonists of either P2X7 (A438079) or TLR4 ((+)-naloxone) (receptors critical to the activation of NLRP3 inflammasomes and consequent inflammatory cascades) returned running behavior of CCI rats to that of shams through 5+ weeks after dosing ceased. This is a striking difference in effect compared to our prior CCI allodynia results using systemic morphine plus intrathecal delivery of these same antagonists, wherein a sustained albeit partial suppression of neuropathic pain was observed. This may point to actions of the systemic drugs at multiple sites along the neuraxis, modulating injury-induced, inflammasome-mediated effects at the injured sciatic nerve and/or dorsal root ganglia, spinal cord, and potentially higher levels. Given that our data to date point to morphine amplifying neuroinflammatory processes put into motion by nerve injury, it is intriguing to speculate that co-administration of TLR4 and/or P2X7 antagonists can intervene in these inflammatory processes in a beneficial way. That is, that systemic administration of such compounds may suppress inflammatory damage at multiple sites, rapidly and persistently returning neuropathic animals to sham levels of response.
Learn More >In the peripheral nerve, mechanosensitive axons are insulated by myelin, a multilamellar membrane formed by Schwann cells. Here, we offer first evidence that a myelin degradation product induces mechanical hypersensitivity and global transcriptomics changes in a sex-specific manner. Focusing on downstream signaling events of the functionally active 84-104 myelin basic protein (MBP84-104) fragment released after nerve injury, we demonstrate that exposing the sciatic nerve to MBP84-104 via endoneurial injection produces robust mechanical hypersensitivity in female, but not in male, mice. RNA-Seq and systems biology analyses revealed a striking sexual dimorphism in molecular signatures of the dorsal root ganglia (DRG) and spinal cord response, not observed at the nerve injection site. Mechanistically, intra-sciatic MBP84-104 induced phospholipase C (PLC)-driven (females) and phosphoinositide 3-kinase-driven (males) phospholipid metabolism (tier 1). PLC/inositol trisphosphate receptor (IP3R) and estrogen receptor co-regulation in spinal cord yielded Ca2+-dependent nociceptive signaling induction in females that was suppressed in males (tier 2). IP3R inactivation by intrathecal xestospongin C attenuated the female-specific hypersensitivity induced by MBP84-104. According to sustained sensitization in tiers 1-2, T cell-related signaling spreads to the DRG and spinal cord in females, but remains localized to the sciatic nerve in males (tier 3). These results are consistent with our previous finding that MBP84-104-induced pain is T cell-dependent. In summary, an autoantigenic peptide endogenously released in nerve injury triggers multi-site, sex-specific transcriptome changes, leading to neuropathic pain only in female mice. MBP84-104 acts through sustained co-activation of metabolic, estrogen receptor-mediated nociceptive and autoimmune signaling programs.
Learn More >Exposure treatments are shown to be effective in reducing pain-related fear and the perceived harmfulness of physical activities. However, due to the fragility of extinction its stability is questionable. We investigated the generalizability of exposure effects in chronic low back pain (CLBP) patients by integrating a behavioral test in the context of an intervention study.
Learn More >Transcranial direct current stimulation was suggested to provide beneficial effects in chronic migraine, a condition often associated with medication overuse for which no long-term therapy is available.
Learn More >Informal caregiving by spouses has become frequent in chronic pain settings. However, the impact of pain on occupational, functional, and health outcomes in spouses has not been systematically investigated.
Learn More >Dorsal root ganglion (DRG) stimulation is a novel treatment of chronic neuropathic pain and has been shown to be efficacious across several case reports and randomized trials. However, long-term follow-up is limited, as are reports of complication rates. This study presents efficacy and complications for patients treated with DRG stimulation.
Learn More >Serotonin (5-hydroxytryptamine, 5-HT) released by platelets, mast cells, and immunocytes is a potent inflammatory mediator which modulates pain and itch sensing in the peripheral nervous system. The serotonergic receptors expressed by primary afferent neurons involved in these sensory functions are not fully identified and appear to be to a large extent species dependent. Moreover, the mechanisms through which 5-HT receptor activation is coupled to changes in neuronal excitability have not been completely revealed. Using a combination of in vitro (calcium and voltage imaging and patch-clamp) and in vivo behavioral methods, we used both male and female Wistar rats to provide evidence for the involvement of two 5-HT receptor subtypes, 5-HT1A and 5-HT3, in mediating the sustained and transient effects, respectively, of 5-HT on rat primary afferent neurons involved in pain and itch processing. In addition, our results are consistent with a model in which sustained serotonergic responses triggered via the 5-HT1A receptor are due to closure of background potassium channels, followed by membrane depolarization and action potentials, during which the activation of voltage-gated calcium channels leads to calcium entry. Our results may provide a better understanding of mammalian serotonergic itch signaling.
Learn More >Reduced pain tolerance may be one of the possible explanations for high prevalence of chronic pain among older people. We hypothesized that age-related alterations in pain tolerance are associated with functioning deterioration of the frontal cortex during normal aging. Twenty-one young and 41 elderly healthy participants underwent a tonic heat pain test, during which cerebral activity was recorded using electroencephalography (EEG). Elderly participants were divided into two subgroups according to their scores on executive tests, high performers (HPs; = 21) and low performers (LPs; = 20). Pain measures [exposure times (ETs) and perceived pain ratings] and cerebral activity were compared among the three groups. ETs were significantly lower in elderly LPs than in young participants and elderly HPs. Electroencephalographic analyses showed that gamma-band oscillations (GBOs) were significantly increased in pain state for all subjects, especially in the frontal sites. Source analysis showed that GBO increase in elderly LPs was contributed not only by frontal but also by central, parietal, and occipital regions. These findings suggest that better preservation of frontal functions may result in better pain tolerance by elderly subjects.
Learn More >Pharmacological evidence indicated a functional interaction between neuropeptide FF (NPFF) and cannabinoid systems, and the cannabinoids combined with the NPFF receptor agonist neuropeptide VF (NPVF) produced antinociception without tolerance. In the present study, VF-13, a chimeric peptide containing the pharmacophores of the endogenous cannabinoid peptide VD-hemopressin(α) (VD-Hpα) and NPVF, was synthesized and pharmacologically evaluated. In vitro, VF-13 significantly upregulated the phosphorylated level of extracellular signal-regulated kinase 1/2 (ERK1/2) in CHO cells stably expressing CB1 receptors and inhibited forskolin-induced cAMP accumulation in HEK293 cells stably expressing NPFF or NPFF receptors. Moreover, VF-13 induced neurite outgrowth in Neuro 2A cells via CB1 and NPFF receptors. These results suggest that VF-13 exhibits multifunctional agonism at CB1, NPFF and NPFF receptors in vitro. Interestingly, intracerebroventricular VF-13 produced dose-dependent antinociception in mouse models of tail-flick and carrageenan-induced inflammatory pain via the TRPV1 receptor. In contrast, the reference compound (m)VD-Hpα-NH induced CB1 receptor-mediated supraspinal antinociception. Additionally, subcutaneous injection of (m)VD-Hpα-NH and VF-13 produced significant antinociception in carrageenan-induced inflammatory pain model. In the tetrad assay, our data demonstrated that VF-13 elicited hypothermia, but not catalepsy and hypoactivity after intracerebroventricular injection. Notably, VF-13 produced non-tolerance forming antinociception over 6 days treatment in both acute and inflammatory pain models. Furthermore, VF-13 had no apparent effects on gastrointestinal transit, pentobarbitone-induced sedation, food intake, and motor coordination at the supraspinal level. In summary, VF-13, a novel chimeric peptide of VD-Hpα and NPVF, produced non-tolerance forming antinociception in preclinical pain models with reduced cannabinoid-related side effects.
Learn More >Randomized studies have reported a positive effect of candesartan, an angiotensin II receptor antagonist, in migraine prevention. The aim of our study was to explore patient subjective efficacy of candesartan in a real-world sample of migraine patients and try to identify predictors of candesartan response. We audited the clinical records of 253 patients who attended the King's College Hospital, London, from February 2015 to December 2017, looking specifically at their response to candesartan. Univariate and multivariate logistic regression models were used to identify predictors of headache benefit. Odds ratios (OR) with confidence intervals (CI) 95% were calculated. Eighty-one patients (chronic migraine, n = 68) were included in the final analysis. Thirty-eight patients reported a positive response to candesartan, while 43 patients did not have a meaningful therapeutic effect. The median dose of candesartan was 8 mg and the median treatment period was 6 months. In a univariate logistic regression model, the presence of daily headache was associated with reduced odds of headache benefit (OR 0.39, 95% CI 0.16-0.96, p = 0.04). In multivariate logistic regression model, younger age (OR 0.92, 95% CI 0.87-0.98, p = 0.006) and longer disease duration (OR 1.06, 95% CI 1.01-1.12, p = 0.03) were associated with a good response to candesartan, while the presence of daily headache was associated with reduced odds of headache benefit (OR 0.16, 95% CI 0.04-0.71, p = 0.01). Having failed up to nine preventives in patients did not predict a treatment failure with candesartan as well. Candesartan yields clinical benefits in difficult-to-treat migraine patients, irrespective of previous failed preventives.
Learn More >Independent of pain intensity, pain-specific distress is highly predictive of pain treatment needs, including the need for prescription opioids. Given the inherently distressing nature of chronic pain, there is a need to equip individuals with pain education and self-regulatory skills that are shown to improve adaptation and improve their response to medical treatments. Brief, targeted behavioral medicine interventions may efficiently address the key individual factors, improve self-regulation in the context of pain, and reduce the need for opioid therapy. This highlights the critical need for targeted, cost-effective interventions that efficiently address the key psychological factors that can amplify the need for opioids and increased risk for misuse. In this trial, the primary goal is to test the comparative efficacy of a single-session skills-based pain management class to a health education active control group among patients with chronic pain who are taking opioids.
Learn More >Recently, mineralocorticoid receptors (MR) were identified in peripheral nociceptive neurons, and their acute antagonism was responsible for immediate and short-lasting (non-genomic) antinociceptive effects. The same neurons were shown to produce the endogenous ligand aldosterone by the enzyme aldosterone synthase.
Learn More >Transgenic therapy for central neuralgia faces the problems of low expression and weak targeting and affects superficial but not deep neurons. In this study, we generated a lentivirus vector with human preproenkephalin gene (hPPE) expression driven by the transcriptional amplification strategy system (TAS) and established a primary bone marrow-derived mesenchymal stromal cell (BMSC) line stably expressing hPPE for transplantation into a rat model of neuropathic pain rat. The paw thermal withdrawal latency assay and paw mechanical withdrawal threshold assay showed that unlike control BMSCs and BMSCs with hPPE overexpression driven by the CMV or Synapsin 1 (SYN1) promoter, TAS-hPPE BMSCs had a robust and lasting analgesic effect. The TAS-hPPE BMSC-treated group exhibited higher expression of TAS-driven hPPE and a higher ratio of BMSCs in the midbrain, spinal cord and cortex then the CMV-hPPE BMSC- and SYN1-hPPE BMSC-treated groups. Moreover, we also observed that TAS-hPPE BMSCs displayed a greater tendency to differentiate into neurons and exhibit neuronal-like distribution than CMV-hPPE or SYN1-hPPE BMSCs. In conclusion, our study shows that the TAS improves BMSC transgenic therapy for neuropathic pain treatment.
Learn More >Neurotensin (NT) exerts naloxone-insensitive antinociceptive action through its binding to both NTS and NTS receptors and NT analogs provide stronger pain relief than morphine on a molecular basis. Here, we examined the analgesic/adverse effect profile of a new NT(8-13) derivative denoted JMV2009, in which the Pro residue was substituted by a silicon-containing unnatural amino acid silaproline. We first report the synthesis and in vitro characterization (receptor-binding affinity, functional activity and stability) of JMV2009. We next examined its analgesic activity in a battery of acute, tonic and chronic pain models. We finally evaluated its ability to induce adverse effects associated with chronic opioid use, such as constipation and analgesic tolerance or related to NTS activation, like hypothermia. In in vitro assays, JMV2009 exhibited high binding affinity for both NTS and NTS, improved proteolytic resistance as well as agonistic activities similar to NT, inducing sustained activation of p42/p44 MAPK and receptor internalization. Intrathecal injection of JMV2009 produced dose-dependent antinociceptive responses in the tail-flick test and almost completely abolished the nociceptive-related behaviors induced by chemical somatic and visceral noxious stimuli. Likewise, increasing doses of JMV2009 significantly reduced tactile allodynia and weight bearing deficits in nerve-injured rats. Importantly, repeated agonist treatment did not result in the development of analgesic tolerance. Furthermore, JMV2009 did not cause constipation and was ineffective in inducing hypothermia. These findings suggest that NT drugs can act as an effective opioid-free medication for the management of pain or can serve as adjuvant analgesics to reduce the opioid adverse effects.
Learn More >C-tactile afferents are hypothesized to form a distinct peripheral channel that encodes the affective nature of touch. Prevailing views indicate they project, as with other unmyelinated afferents, in lamina I-spinothalamic pathways that relay homeostatically relevant information from the body toward cortical regions involved in interoceptive processing. However, in a recent study, we found that spinothalamic ablation in humans, while profoundly impairing the canonical spinothalamic modalities of pain, temperature, and itch, had no effect on benchmark psychophysical affective touch metrics. These novel findings appear to indicate that perceptual judgments about the affective nature of touch pleasantness do not depend on the integrity of the lamina I-spinothalamic tract. In this commentary, we further discuss the implications of these unexpected findings. Intuitively, they suggest that signaling of emotionally relevant C-tactile mediated touch occurs in an alternative ascending pathway. However, we also argue that the deficits seen following interruption of a putative C-tactile lamina I-spinothalamic relay might be barely perceptible-a feature that would underline the importance of the C-tactile afferent in neurodevelopment.
Learn More >Novel synthetic opioids are appearing in recreational drug markets worldwide as adulterants in heroin or ingredients in counterfeit analgesic medications. 3,4-Dichloro-N-[(1R,2R)-2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is an example of a non-fentanyl synthetic opioid linked to overdose deaths. Here, we examined the pharmacodynamics and pharmacokinetics of U-47700 in rats. Male Sprague-Dawley rats were fitted with intravenous (i.v.) catheters and subcutaneous (s.c.) temperature transponders under ketamine/xylazine anesthesia. One week later, rats received s.c. injections of U-47700 HCl (0.3, 1.0 or 3.0 mg/kg) or saline, and blood samples (0.3 mL) were withdrawn via i.v. catheters at 15, 30, 60, 120, 240, 480 min post-injection. Pharmacodynamic effects were assessed at each blood withdrawal, and plasma was assayed for U-47700 and its metabolites by liquid chromatography tandem mass spectrometry. U-47700 induced dose-related increases in hot plate latency (ED = 0.5 mg/kg) and catalepsy (ED = 1.7 mg/kg), while the 3.0 mg/kg dose also caused hypothermia. Plasma levels of U-47700 rose linearly as dose increased, with maximal concentration (C) achieved by 15-38 min. C values for N-desmethyl-U-47700 and N,N-didesmethyl-U-47700 were delayed but reached levels in the same range as the parent compound. Pharmacodynamic effects were correlated with plasma U-47700 and its N-desmethyl metabolite. Using radioligand binding assays, U-47700 displayed high affinity for μ-opioid receptors (Ki = 11.1 nM) whereas metabolites were more than 18-fold weaker. Our data reveal that U-47700 induces typical μ-opioid effects which are related to plasma concentrations of the parent compound. Given its high potency, U-47700 poses substantial risk to humans who are inadvertently exposed to the drug.
Learn More >The role of voltage-gated sodium (Na) channels in pain perception is indisputable. Of particular interest as targets for the development of pain therapeutics are the tetrodotoxin-resistant isoforms Na1.8 and Na1.9, based on animal as well as human genetic studies linking these ion channel subtypes to the pathogenesis of pain. However, only a limited number of inhibitors selectively targeting these channels have been reported. HSTX-I is a peptide toxin identified from saliva of the leech Haemadipsa sylvestris. The native 23-residue peptide, stabilised by two disulfide bonds, has been reported to inhibit rat Na1.8 and mouse Na1.9 with low micromolar activity, and may therefore represent a scaffold for development of novel modulators with activity at human tetrodotoxin-resistant Na isoforms. We synthetically produced this hydrophobic peptide in high yield using a one-pot oxidation and single step purification and determined the three-dimensional solution structure of HSTX-I using NMR solution spectroscopy. However, in our hands, the synthetic HSTX-I displayed only very modest activity at human Na1.8 and Na1.9, and lacked analgesic efficacy in a murine model of inflammatory pain.
Learn More >Spinal cord injury (SCI) causes loss of locomotor function and chronic neuropathic pain (NeP). Hematogenous macrophages and activated microglia are key monocytic lineage cell types in the response to SCI, and each has M1- and M2-phenotypes. To understand the roles of these cells in neuronal regeneration and chronic NeP after SCI, differences in distribution and phenotypes of activated microglia and infiltrated macrophages after SCI were examined at the injured site and the lumbar enlargement, as a remote region. Chimeric mice were used for differentiating activated microglia from hematogenous macrophages. The prevalences of activated microglia and infiltrating macrophages increased at day 14 after SCI, at the time of most severe pain hypersensitivity, with mainly M1-type hematogenous macrophages at the injured site and M2-type activated microglia at the lumbar enlargement. Peak expression of TNF-α, an M1-induced cytokine, occurred on day 4 post-SCI at the injured site, but not until day 14 at the lumbar enlargement. Expression of IL-4, a M2-induced cytokine, peaked at 4 days after SCI at both sites. These results suggest different roles of activated microglia and hematogenous macrophages, including both phenotypes of each cell, in neuronal regeneration and chronic NeP after SCI at the injured site and lumbar enlargement. The prevalence of the M1 over the M2 phenotype at the injured site until the subacute phase after SCI may be partially responsible for the lack of functional recovery and chronic NeP after SCI. Activation of M2-type microglia at the lumbar enlargement in response to inflammatory cytokines from the injured site might be important in chronic below-level pain. These findings are useful for establishment of a therapeutic target for prevention of motor deterioration and NeP in the time-dependent response to SCI.
Learn More >Impaired extinction of pain-related fear memories can lead to persistent or resurging fear of pain, contributing to the development and maintenance of chronic pain conditions. The mechanisms underlying maladaptive pain-related learning and memory processes remain incompletely understood, particularly in the context of interoceptive, visceral pain. Inflammation is known to interfere with learning and memory, but its effects on the extinction of pain-related fear memories have never been tested. In a randomized, double-blind, placebo-controlled study, we assessed the impact of experimental acute inflammation on the extinction and reinstatement of conditioned visceral pain-related fear. Forty healthy male volunteers underwent differential fear conditioning with visceral pain as clinically relevant unconditioned stimulus (US). Participants then received an intravenous injection of either 0.8ng/kg lipopolysaccharide (LPS) as inflammatory stimulus or physiological saline as placebo, and extinction training was conducted at the peak of the inflammatory response. Extinction recall and reinstatement tests were performed after overnight consolidation. Results showed that visceral pain represents an effective US, eliciting pronounced conditioned pain-related fear responses. Repeated unreinforced presentation of the pain-predictive cue during extinction training resulted in full extinction of the conditioned behavioral response. However, unexpected re-exposure to the US during reinstatement test resulted in return of fear. Despite pronounced LPS-induced effects on inflammatory markers, cortisol, and negative affect, we did not find evidence that acute inflammation resulted in altered fear extinction. The findings support the notion that visceral pain-related fear learning establishes a robust aversive memory trace that remains preserved during inhibitory learning, leaving a latent vulnerability for the return of fear. Inflammation during inhibitory learning did neither weaken nor further amplify this aversive memory trace, suggesting that it is rather resistant to acute inflammation-induced effects, at least in healthy individuals with no additional vulnerability factors.
Learn More >Effective analgesic treatment for neuropathic pain remains an unmet need, so previous evidence that epidermal growth factor receptor inhibitors (EGFRIs) provide unexpected rapid pain relief in a clinical setting points to a novel therapeutic opportunity. The present study utilises rodent models to address the cellular and molecular basis for the findings, focusing on primary sensory neurons because clinical pain relief is provided not only by small molecule EGFRIs, but also by the anti-EGFR antibodies cetuximab and panitumumab, which are unlikely to access the central nervous system in therapeutic concentrations. We report robust, rapid and dose-dependent analgesic effects of EGFRIs in two neuropathic pain models, matched by evidence with highly selective antibodies that expression of the EGFR (ErbB1 protein) is limited to small nociceptive afferent neurons. As other ErbB family members can heterodimerise with ErbB1, we investigated their distribution, showing consistent co-expression of ErbB2 but not ErbB3 or ErbB4, with ErbB1 in cell bodies of nociceptors, as well as providing evidence for direct molecular interaction of ErbB1 with ErbB2 in situ. Co-administration of selective ErbB1 and ErbB2 inhibitors produced clear evidence of greater-than-additive, synergistic analgesia; highlighting the prospect of a unique new combination therapy in which enhanced efficacy could be accompanied by minimisation of side-effects. Peripheral (intraplantar) administration of EGF elicited hypersensitivity only following nerve injury and this was reversed by local co-administration of selective inhibitors of either ErbB1 or ErbB2. Investigating how ErbB1 is activated in neuropathic pain, we found evidence for a role of Src tyrosine kinase, which can be activated by signals from inflammatory mediators, chemokines and cytokines during neuroinflammation. Considering downstream consequences of ErbB1 activation in neuropathic pain, we found direct recruitment to ErbB1 of an adapter for PI 3-kinase and Akt signalling together with clear Akt activation and robust analgesia from selective Akt inhibitors. The known Akt target and regulator of vesicular trafficking, AS160 was strongly phosphorylated at a perinuclear location during neuropathic pain in an ErbB1-, ErbB2- and Akt-dependent manner, corresponding to clustering and translocation of an AS160-partner, the vesicular chaperone, LRP1. Exploring whether neuronal ion channels that could contribute to hyperexcitability might be transported by this vesicular trafficking pathway we were able to identify Na1.9, (Na1.8) and Ca1.2 moving towards the plasma membrane or into proximal axonal locations – a process prevented by ErbB1 or Akt inhibitors. Overall these findings newly reveal both upstream and downstream signals to explain how ErbB1 can act as a signalling hub in neuropathic pain models and identify the trafficking of key ion channels to neuronal subcellular locations likely to contribute to hyperexcitability. The new concept of combined treatment with ErbB1 plus ErbB2 blockers is mechanistically validated as a promising strategy for the relief of neuropathic pain.
Learn More >Diabetic peripheral neuropathic pain (DPNP) is the most devastating complication of diabetes mellitus. Unfortunately, successful therapy for DPNP remains a challenge because its pathogenesis is still elusive. However, DPNP is believed to be due partly to abnormal hyperexcitability of dorsal root ganglion (DRG) neurons, but the relative contributions of specific functional subtypes remain largely unknown. Here, using the strepotozotocin (STZ) rat model of DPNP induced by a STZ injection (60 mg/kg, i.p), and intracellular recordings of action potentials (APs) from DRG neurons in anesthetized rats, we examined electrophysiological changes in C-and Aβ-nociceptive and Aβ-low threshold mechanoreceptive (LTM) neurons that may contribute to DPNP. Compared with control, we found in STZ-rats with established pain hypersensitivity (5 weeks post-STZ) several significant changes including: (a) A 23% increase in the incidence of spontaneous activity (SA) in Aβ-LTMs (but not C-mechanosensitive nociceptors) that may cause dysesthesias/paresthesia suffered by DPNP patients, (b) membrane hyperpolarization and a ∼85% reduction in SA rate in Aβ-LTMs by K7 channel activation with retigabine (6 mg/kg, i.v.) suggesting that K7/M channels may be involved in mechanisms of SA generation in Aβ-LTMs, (c) decreases in AP duration and in duration and amplitude of afterhyperpolarization (AHP) in C-and/or Aβ-nociceptors. These faster AP and AHP kinetics may lead to repetitive firing and an increase in afferent input to the CNS and thereby contribute to DPNP development, and (d) a decrease in the electrical thresholds of Aβ-nociceptors that may contribute to their sensitization, and thus to the resulting hypersensitivity associated with DPNP.
Learn More >This article explores the effectiveness of a newly developed Pain Neuroscience Education program for children (PNE4Kids) with functional abdominal pain disorder (FAPD). Children (6-12 years) with FAPD were randomly assigned to 1) the experimental group ( = 14), participating in one hypnotherapy session (i.e., usual care) and one additional PNE4Kids session, or 2) the control group ( = 14), participating in two hypnotherapy sessions. Parental pain catastrophizing, the child's functional disability (parental-proxy), pain-related fear (parent-proxy) and pain intensity, were assessed at baseline and one and three weeks after each therapy session. Pressure algometry and a conditioned pain modulation paradigm were performed at baseline and three weeks after completion of the last therapy session. Parents from both the experimental as well as the control group showed significantly less parental pain catastrophizing ( < 0.01). Children showed significantly less functional disability ( < 0.05), pain-related fear ( < 0.01) and local pressure pain sensitivity ( < 0.05) at short-term follow-up (three weeks after last intervention) in both groups. No significant ( > 0.05) between-group differences were found. Hypnotherapy combined with PNE4Kids did not result in better clinical outcomes compared to hypnotherapy alone. Study limitations include the application of one single PNE4Kids session and the short follow-up time.
Learn More >Peripheral inflammatory hyperalgesia depends on the sensitization of primary nociceptive neurons. Inflammation drives molecular alterations not only locally but also in the dorsal root ganglion (DRG) where interleukin-1 beta (IL-1β) and purinoceptors are upregulated. Activation of the P2X7 purinoceptors by ATP is essential for IL-1β maturation and release. At the DRG, P2X7R are expressed by satellite glial cells (SGCs) surrounding sensory neurons soma. Although SGCs have no projections outside the sensory ganglia these cells affect pain signaling through intercellular communication. Therefore, here we investigated whether activation of P2X7R by ATP and the subsequent release of IL-1β in DRG participate in peripheral inflammatory hyperalgesia. Immunofluorescent images confirmed the expression of P2X7R and IL-1β in SGCs of the DRG. The function of P2X7R was then verified using a selective antagonist, A-740003, or antisense for P2X7R administered in the L5-DRG. Inflammation was induced by CFA, carrageenan, IL-1β, or PGE administered in rat's hind paw. Blockage of P2X7R at the DRG reduced the mechanical hyperalgesia induced by CFA, and prevented the mechanical hyperalgesia induced by carrageenan or IL-1β, but not PGE. It was also found an increase in P2X7 mRNA expression at the DRG after peripheral inflammation. IL-1β production was also increased by inflammatory stimuli and , using SGC-enriched cultures stimulated with LPS. In LPS-stimulated cultures, activation of P2X7R by BzATP induced the release of IL-1β, which was blocked by A-740003. In summary, our data suggest that peripheral inflammation leads to the activation of P2X7R expressed by SGCs at the DRG. Then, ATP-induced activation of P2X7R mediates the release of IL-1β from SGC. This evidence places the SGC as an active player in the establishment of peripheral inflammatory hyperalgesia and highlights the importance of the events in DRG for the treatment of inflammatory diseases.
Learn More >Neuronal-specific enolase (NSE) and protein S100B have gained considerable interest as the markers of CNS injury, glial cell activation, and/or blood-brain barrier (BBB) disruption. No studies have investigated NSE and S100B in cluster headache (CH), but these biomarkers could contribute to the understanding of CH.
Learn More >Background and aims Recognition of the biopsychosocial aspects of pain is important for a true understanding of the burden of pain and the necessity of pain management. Biopsychosocial aspects of pain may differ between countries and cultures. Market research methods can be well suited and effective for assessing patient perspectives of pain and biopsychosocial differences. We conducted and combined 3 cross-sectional, international surveys to document the impact of pain on physical and emotional aspects of life, as well as quality of life (QOL). Methods Online panelists from 24 countries took part in our surveys in 2014, 2016, and 2017. Fourteen countries (Australia, Brazil, Canada, China, Germany, Italy, Japan, Poland, Russia, United Kingdom, United States, Mexico, Sweden, Saudi Arabia) contributed data in all 3 surveys and comprise the analysis population. A Global Pain Index (GPI) was constructed using 8 questions in 3 categories: Physical (frequency, duration, intensity of pain), Emotional (anxiety, impact on self-esteem, happiness), and Impact on QOL and ability to enjoy life. Each item was scored as the percentage of respondents meeting a prespecified threshold indicative of a substantial pain impact. Scores for the items within each category were averaged to obtain a category score, category scores were averaged to obtain a total score for each survey, and total scores from each survey were averaged to obtain a final combined score. Scores were assessed for the overall population, by individual countries, by age and gender, and by self-identified pain-treatment status (treat immediately, wait, never treat). Results Of the 50,952 adult respondents, 28,861 (56.6%) had ever experienced musculoskeletal pain; 50% of those with pain had pain with a multifaceted impact based on the GPI (Physical: 51%; Emotional: 40%; QOL Impact: 59%). Russia (57%) and Poland (56%) had the highest scores; Mexico (46%), Germany (47%), and Japan (47%) had the lowest. GPI score was higher in women (52%) than men (48%), and initially increased with age through age 54 (18‒24 years: 45%; 25‒34 years: 52%; 35‒44 years: 53%; 45‒54 years: 54%), after which it decreased again (55‒64 years: 51%; ≥65 years: 45%). A majority (65%) of respondents wait to treat their pain, whereas 21% treat their pain immediately and 14% never treat pain. The most common reason for waiting (asked in survey 3 only) was to avoid taking medication. Conclusions In this combined analysis of 3 international surveys using a novel biopsychosocial pain assessment tool, pain had a substantial impact on ~50% of respondents' lives, spanning physical (51%), emotional (40%), and QOL effects (59%). Despite the substantial impact, a majority of patients tried to avoid treating their pain. Implications Clinicians should take a biopsychosocial approach to pain by asking patients not only about the presence and severity of pain, but the extent to which it affects various aspects of their lives and daily functioning. Patients may also need education about the efficacy and safety of available treatments for self-management of pain. The GPI may be a useful new tool for future studies of the biopsychosocial effects of pain in large populations.
Learn More >Studies document that osteoarthritis-related joint pain is more severe in African American older adults, but research on the personal experience of osteoarthritis pain self-management in this population is limited. Using a qualitative descriptive design, our objective was to extend our understanding of the experience of life with osteoarthritis pain. Eighteen African Americans (50 years and older) were recruited from Louisiana to participate in a single semi-structured, in-depth interview. A conventional content analysis revealed that "Bearing the pain" characterized how older African Americans dealt with osteoarthritis. Bearing the pain comprised three actions: adjusting to pain, sharing pain with others, and trusting God as healer. We discovered that a metapersonal experience subsumes the complex biopsychosocial-cultural patterns and the intricate interaction of self, others, and God in living with and managing osteoarthritis pain. Study findings have implications for application of more inclusive self-management frameworks and interventions.
Learn More >German authorities reimburse migraine prevention with erenumab only in patients who previously did not have therapeutic success with at least five oral prophylactics or have contraindications to such. In this real-world analysis, we assessed treatment response to erenumab in patients with chronic migraine (CM) who failed five oral prophylactics and, in addition, onabotulinumtoxinA (BoNTA). We analyzed retrospective data of 139 CM patients with at least one injection of erenumab from two German headache centers. Patients previously did not respond sufficiently or had contraindications to β-blockers, flunarizine, topiramate, amitriptyline, valproate, and BoNTA. Primary endpoint of this analysis was the mean change in monthly headache days from the 4-weeks baseline period over the course of a 12-weeks erenumab therapy. Secondary endpoints were changes in monthly migraine days, days with severe headache, days with acute headache medication, and triptan intake in the treatment period. Erenumab (starting dose 70 mg) led to a reduction of -3.7 (95% CI 2.4-5.1) monthly headache days after the first treatment and -4.7 (95% CI 2.9-6.5) after three treatment cycles ( < 0.001 for both). All secondary endpoint parameters were reduced over time. Half of patients (51.11%) had a >30% reduction of monthly headache days in weeks 9-12. Only 4.3% of the patients terminated erenumab treatment due to side effects. In this treatment-refractory CM population, erenumab showed efficacy in a real-world setting similar to data from clinical trials. Tolerability was good, and no safety issues emerged. Erenumabis is a treatment option for CM patients who failed all first-line preventives in addition to BoNTA.
Learn More >Nerve growth factor (NGF) is a neurotrophic protein essential for the growth, differentiation, and survival of sympathetic and sensory afferent neurons during development. A substantial body of evidence, based on both animal and human studies, demonstrates that NGF plays a pivotal role in modulation of nociception in adulthood. This has spurred development of a variety of novel analgesics that target the NGF signaling pathway. Here, we present a narrative review designed to summarize how NGF receptor activation and downstream signaling alters nociception through direct sensitization of nociceptors at the site of injury and changes in gene expression in the dorsal root ganglion that collectively increase nociceptive signaling from the periphery to the central nervous system. This review illustrates that NGF has a well-known and multifunctional role in nociceptive processing, although the precise signaling pathways downstream of NGF receptor activation that mediate nociception are complex and not completely understood. Additionally, much of the existing knowledge derives from studies performed in animal models and may not accurately represent the human condition. However, available data establish a role for NGF in the modulation of nociception through effects on the release of inflammatory mediators, nociceptive ion channel/receptor activity, nociceptive gene expression, and local neuronal sprouting. The role of NGF in nociception and the generation and/or maintenance of chronic pain has led to it becoming a novel and attractive target of pain therapeutics for the treatment of chronic pain conditions.
Learn More >Although the Eph receptor plays an important role in the development of neuropathic pain following nerve injury, there has been no evidence of the participation of the ephrin A4 receptor (EphA4) in the development of trigeminal neuropathic pain. The present study investigated the role of EphA4 in central nociceptive processing in rats with inferior alveolar nerve injury.
Learn More >There is a need to reduce exposure to Schedule II opioids in the United States (US) due to the ongoing opioid epidemic. Schedule II opioids have higher potential for abuse and misuse than Schedule IV opioids. This Phase 3, multicenter, single-arm, open-label, multiple-dose US trial evaluated the safety and tolerability of intravenous tramadol 50 mg, a Schedule IV opioid, in the management of postoperative pain in a real-world setting, where intravenous tramadol is not yet approved for use.
Learn More >Chronic pain is often multifactorial and accompanied by psychological distress, catastrophizing thoughts, reduced physical function, and socio-economic worries. In this explorative study, we investigated potential mediators in the relationships of psychological and demographic variables with chronic pain and physical function in women and men.
Learn More >To evaluate the cost-utility of 100 days of antibiotics in patients with chronic low back pain (LBP) and type I or II Modic changes included in the Antibiotic treatment In patients with chronic low back pain and Modic changes (AIM) study.
Learn More >Na1.3 is a subtype of the voltage-gated sodium channel family. It has been implicated in the pathogenesis of neuropathic pain, although the contribution of this channel to neuronal excitability is not well understood. Tf2, a β-scorpion toxin previously identified from the venom of , has been reported to selectively activate Na1.3. Here, we describe the activity of synthetic Tf2 and assess its suitability as a pharmacological probe for Na1.3. As described for the native toxin, synthetic Tf2 (1 µM) caused early channel opening, decreased the peak current, and shifted the voltage dependence of Na1.3 activation in the hyperpolarizing direction by -11.3 mV, with no activity at Na1.1, Na1.2, and Na1.4-Na1.8. Additional activity was found at Na1.9, tested using the hNav1.9_C4 chimera, where Tf2 (1 µM) shifted the voltage dependence of activation by -6.3 mV. In an attempt to convert Tf2 into an Na1.3 inhibitor, we synthetized the analogue Tf2[S14R], a mutation previously described to remove the excitatory activity of related β-scorpion toxins. Indeed, Tf2[S14R](10 µM) had reduced excitatory activity at Na1.3, although it still caused a small -5.8 mV shift in the voltage dependence of activation. Intraplantar injection of Tf2 (1 µM) in mice caused spontaneous flinching and swelling, which was not reduced by the Na1.1/1.3 inhibitor ICA-121431 nor in Na1.9 mice, suggesting off-target activity. In addition, despite a loss of excitatory activity, intraplantar injection of Tf2[S14R](10 µM) still caused swelling, providing strong evidence that Tf2 has additional off-target activity at one or more non-neuronal targets. Therefore, due to activity at Na1.9 and other yet to be identified target(s), the use of Tf2 as a selective pharmacological probe may be limited.
Learn More >Capsaicin, derived from the chilli pepper plant, is available in high concentration (8%) patches to provide topical therapy for neuropathic pain. Its analgesic effects relate to defunctionalisation and nerve terminal retraction of predominantly C fibres in the dermis and epidermis. Systematic reviews and meta-analysis support its use for the management of post-herpetic neuralgia and HIV neuropathy with some evidence for use in painful peripheral diabetic neuropathy. The article concludes with advice on the practicalities of running a topical 8% capsaicin clinic for peripheral neuropathic pain.
Learn More >The gabapentinoids are often recommended as first-line treatments for the management of neuropathic pain. The differing pharmacodynamic and pharmacokinetic profiles can have implications for clinical practice. This article has summarised these key differences. In addition to their use in managing neuropathic pain, gabapentinoids are increasingly being used for off-label conditions despite the lack of evidence. Prescription rates for off-label conditions have overtaken that for on-label use. Similarly, the use of gabapentinoids in the perioperative period is now embedded in clinical practice despite conflicting evidence. This article summarises the risks associated with this increasing use. There is increasing evidence of the potential to cause harm in vulnerable populations such as the elderly and increasing prevalence of abuse. The risk of respiratory depression in combination with opioids is of particular concern in the context of the current opioid crisis. This article describes the practical considerations involved that might help guide appropriate prescribing practices.
Learn More >Sleep disturbance is associated with persistence and exacerbation of chronic pain. As this relationship seems to be bidirectional, factors underpinning sleep disturbance may prove valuable in multimodal rehabilitation approaches. The aim of this cross-sectional study was to examine the impact of psychological symptoms on subjective and objective sleep measures in patients with chronic musculoskeletal pain (CMP) as compared to healthy controls (HC).
Learn More >Amid the ongoing U.S. opioid crisis, achieving safe and effective chronic pain management while reducing opioid-related morbidity and mortality is likely to require multi-level efforts across health systems, including the Military Health System (MHS), Department of Veterans Affairs (VA), and civilian sectors.
Learn More >Endothelin-1 (EDN1) can evoke histamine-independent pruritus in mammals and is upregulated in the lesional epidermis of atopic dermatitis (AD). EDN1 increases the production of interleukin 25 (IL-25) from keratinocytes to accelerate T helper type 2 immune deviation. Plasma EDN1 levels are positively correlated with the clinical severity and itch intensity of AD. Therefore, we hypothesized that the inhibition of EDN1 might be useful for treating atopic inflammation and itch and investigated the effects of the topical application of the EDN1 receptor antagonist bosentan on the skin inflammation and itch in a murine AD model.
Learn More >Pain is associated with emotional and physical suffering that severely impacts quality of life. Many guidelines for the treatment of moderate to severe cancer pain indicate the use of opioids. For a small proportion of the global population, opioids are readily accessible, but are consequently also subject to risk of overuse and misuse. On the other hand, many regions provide limited access to licensed opioid therapeutics and patients struggle for better pain management. The use of prescription opioids for treatment of severe cancer and acute pain is well established, but opioid use in chronic non-cancer pain is controversial and not supported by the literature. The opioid crisis and the increasing overdose fatalities in some countries have resulted in a resurgence of opiophobia in these countries, but even worse, amplified opiophobia in countries with lower opioid consumption. In this narrative review, we highlight how the opioid crisis of overuse in some countries can negatively impact appropriate access to opioids elsewhere. The availability of opioids for clinical and recreational use differs between countries worldwide-this is an important factor in determining the occurrence of a 'crisis of recreational use of opioids' or a 'crisis of under-prescription of opioids' for pain management.
Learn More >Adenosine triphosphate (ATP) and glutamate are associated with some headache conditions, and purinergic (P2X) and glutamatergic N-methyl-D-aspartate (NMDA) receptor-related processes in the medulla can modulate the effects of trigeminal nociceptive afferent inputs into the brainstem on craniofacial sensorimotor circuits. This study aimed to test whether neck muscle activity can be induced in rats by noxious stimulation of the frontal dura or superior sagittal sinus that involves P2X or NMDA receptor-dependent mechanisms.
Learn More >Paclitaxel-induced neuropathic pain (PINP) is a dose-limiting side effect and is refractory to widely used analgesic drugs. Previous studies have demonstrated a protective role of peroxisome proliferator-activated receptor gama (PPARγ) in neuropathic pain. However, whether PPARγ activation could alleviate PINP remains to be elucidated. Our previous study has validated the analgesic effect of oltipraz, an nuclear factor erythroid-2 related factor 2 (Nrf2) activator, in a rat model of PINP. In this study, we tested the hypothesis that rosiglitazone, a selective agonist of PPARγ, could attenuate PINP through induction of Nrf2/heme oxygenase-1 (HO-1) signaling pathway. Paclitaxel was injected intraperitoneally on four alternate days to induce neuropathic pain. Paw withdrawal threshold was used to evaluate mechanical allodynia. Western blot and immunofluorescence were used to examine the expression and distribution of PPARγ, Nrf2 and HO-1 in the spinal cord. Our results showed that rosiglitazone attenuated established PINP and delayed the onset of PINP via activation of PPARγ, which were reversed by PPARγ antagonist GW9662. Moreover, rosiglitazone inhibited downregulation of PPARγ in the spinal cord of PINP rats. Furthermore, the analgesic effect of rosiglitazone against PINP was abolished by trigonelline, an Nrf2 inhibitor. Finally, rosiglitazone significantly increased expression of Nrf2 and HO-1 in the spinal cord of PINP rats. Collectively, these results indicated that PPARγ activation might mitigate PINP through activating spinal Nrf2/HO-1 signaling pathway. Our results may provide an alternative option for PINP patients.
Learn More >To describe the core elements of a Whole Health Primary Care Pain Education and Opioid Monitoring Program (PC-POP) and examine its effectiveness at increasing adherence to six of the Veteran Affairs/Department of Defense (VA/DoD) recommended guidelines for long-term opioid therapy (LOT) among chronic noncancer patients seen in primary care (i.e., urine drug screens [UDS], prescription drug monitoring program [PDMP] queries, informed consent, naloxone education/prescriptions, morphine equivalent daily dose [MEDD], and referrals to nonpharmacological pain interventions).
Learn More >Traumatic spinal cord injury (SCI) impedes signal transmission by disrupting both the local neurons and their surrounding synaptic connections. Although the majority of SCI patients retain spared neural tissue at the injury site, they predominantly suffer from complete autonomic and sensorimotor dysfunction. While there have been significant advances in the characterization of the spared neural tissue following SCI, the functional role of injury-induced interneuronal plasticity remains elusive. In healthy individuals, spinal interneurons are responsible for relaying signals to coordinate both sympathetic and parasympathetic functions. However, the spontaneous synaptic loss following injury alters these intricate interneuronal networks in the spinal cord. Here, we propose the synaptopathy hypothesis of SCI based on recent findings regarding the maladaptive role of synaptic changes amongst the interneurons. These maladaptive consequences include circuit inactivation, neuropathic pain, spasticity, and autonomic dysreflexia. Recent preclinical advances have uncovered the therapeutic potential of spinal interneurons in activating the dormant relay circuits to restore sensorimotor function. This review will survey the diverse role of spinal interneurons in SCI pathogenesis as well as treatment strategies to target spinal interneurons.
Learn More >Monoacylglycerol lipase (MAGL) is the enzyme that is primarily responsible for hydrolyzing the endocannabinoid 2-arachidononylglycerol (2-AG) to arachidonic acid (AA). It has emerged in recent years as a potential drug target for a number of diseases. Herein, we report the discovery of compound 6g from a series of azetidine-piperazine di-amide compounds as a potent, selective, and reversible inhibitor of MAGL. Oral administration of compound 6g increased 2-AG levels in rat brain and produced full efficacy in the rat complete Freund's adjuvant (CFA) model of inflammatory pain.
Learn More >Fibromyalgia is a chronic disorder characterized by widespread pain and by several non-pain symptoms. Autoimmunity, small fiber neuropathy and neuroinflammation have been suggested to be involved in the pathogenesis of the disease. We have investigated the gene expression profile in peripheral blood mononuclear cells obtained from ten patients and ten healthy subjects. Of the 545,500 transcripts analyzed, 1673 resulted modulated in fibromyalgic patients. The majority of these genes are involved in biological processes and pathways linked to the clinical manifestations of the disease. Moreover, genes involved in immunological pathways connected to interleukin-17 and to Type I interferon signatures were also modulated, suggesting that autoimmunity plays a role in the disease. We then aimed at identifying differentially expressed Long non-coding RNAs (LncRNAs) functionally connected to modulated genes both directly and via microRNA targeting. Only two LncRNAs of the 298 found modulated in patients, were able to target the most highly connected genes in the fibromyalgia interactome, suggesting their involvement in crucial gene regulation. Our gene expression data were confirmed by real time PCR, by autoantibody testing, detection of soluble mediators and Th-17 polarization in a validation cohort of 50 patients. Our results indicate that genetic and epigenetic mechanisms as well as autoimmunity play a pivotal role in the pathogenesis of fibromyalgia.
Learn More >The continued prevalence of chronic low back pain (CLBP) is a testament to our lack of understanding of the potential causes, leading to significant treatment challenges. CLBP is the leading cause of years lived with disability and the fifth leading cause of disability-adjusted life-years. No single non-pharmacologic, pharmacologic, or interventional therapy has proven effective as treatment for the majority of patients with CLBP. Although non-pharmacologic therapies are generally helpful, they are often ineffective as monotherapy and many patients lack adequate access to these treatments. Noninvasive treatment measures supported by evidence include physical and chiropractic therapy, yoga, acupuncture, and non-opioid and opioid pharmacologic therapy; data suggest a moderate benefit, at most, for any of these therapies. Until our understanding of the pathophysiology and treatment of CLBP advances, clinicians must continue to utilize rational multimodal treatment protocols. Recent Centers for Disease Control and Prevention guidelines for opioid prescribing recommend that opioids not be utilized as first-line therapy and to limit the doses when possible for fear of bothersome or dangerous adverse effects. In combination with the current opioid crisis, this has caused providers to minimize or eliminate opioid therapy when treating patients with chronic pain, leaving many patients suffering despite optimal nonopioid therapies. Therefore, there remains an unmet need for effective and tolerable opioid receptor agonists for the treatment of CLBP with improved safety properties over legacy opioids. There are several such agents in development, including opioids and other agents with novel mechanisms of action. This review critiques non-pharmacologic and pharmacologic treatment modalities for CLBP and examines the potential of novel opioids and other analgesics that may be a useful addition to the treatment options for patients with chronic pain.
Learn More >We aimed to examine associations of cardiometabolic risk factors, and (pre)diabetes, with (sensorimotor) peripheral nerve function.
Learn More >An imbalance in perioperative cytokine response may cause acute pain and postoperative complications. Anesthetic drugs modulate this cytokine response, but their role in non-major breast cancer surgery is unclear. In an exploratory study, we investigated whether intravenous lidocaine and dexamethasone could modulate the cytokine response into an anti-inflammatory direction. We also evaluated interrelationships between cytokine levels, pain scores and postoperative complications. Our goal is to develop multimodal analgesia regimens optimizing outcome after breast cancer surgery.
Learn More >CPP affects approximately 15% of women worldwide and has significant psychological, physical and financial impact on the lives of sufferers. Psychological interventions are often recommended as adjuncts to medical treatment for women with chronic pelvic pain (CPP). This is as women with CPP experience higher rates of mental health concerns and difficulties coping with their pain.. However, recent systematic reviews have highlighted that the efficacy of psychological interventions is not conclusive in this population. This review aimed to identify predictors of mental health outcomes and effective psychological techniques and interventions in women with CPP to inform the development of future psychological therapies.
Learn More >Despite advances in the management of headache disorders, some patients with migraine do not experience adequate pain relief with acute and preventive treatments. It is the aim of the present document to provide a definition of those migraines which are difficult-to-treat, to create awareness of existence of this group of patients, to help Healthcare Authorities in understanding the implications, and to create a basis to develop a better pathophysiological understanding and to support further therapeutic advances.
Learn More >Central sensitization (CS) is a form of neuroplasticity characterized by changes in the neural sensitivity, responsiveness and/or output that are not contingent on peripheral input nor activity dependent. CS is characterized by activation of unmyelinated C-fibers resulting in a cascade of events at molecular and cellular levels which eventuate into generation of synaptic currents at rest. CS therefore, contributes to heightened generalized pain sensitivity, further complicates the process of reaching a diagnosis, and increases the possibility of treatment failure. BODY: Trigeminal nerve is the main sensory supplier of the anterior part of the head, including the intraoral structures. Primary afferent nociceptors of the trigeminal nerve and low threshold mechanoreceptors synapse with wide dynamic range (WDR) neurons in the pons. This multifaceted network of nerve interactions which is further complicated by the modulatory circuits that can suppress or heighten the activity of WDR neurons is one of the main contributors to CS. The importance of CS in orofacial pain disorders is emphasized in the context of chronic pain development. As for all chronic pain conditions, it is crucial to consider the biopsychosocial aspects of chronic orofacial pain in managing this diverse group of conditions. This review highlights current understanding of the biopsychosocial model and central mechanisms contributing to the pathogenesis of chronic orofacial pain.
Learn More >Neuropathic pain (NP) remains a major debilitating condition affecting more than 26% of breast cancer survivors worldwide. NP is diagnosed using a validated 10-items Douleur Neuropathique – 4 screening questionnaire which is administered 3 months after surgery and requires patient-doctor interaction. To develop an effective prognosis model admissible soon after surgery, without the need for patient-doctor interaction, we sought to [1] identify specific pain characteristics that can help determine which patients may be susceptible to NP after BC surgery, and 2) assess the utility of machine learning models developed in objective [1] as a knowledge discovery tool for downstream analysis.
Learn More >Many headache smartphone applications (apps) are commercially available. A Modified Delphi Study aimed to determine specialists' expectations of what a headache app should entail but consumer expectations of headache apps have not been evaluated extensively.
Learn More >Functional restoration programs (FRPs) are integrative programs to improve function in chronic low back pain (cLBP). They are costly and time-consuming. The aim was to assess the effectiveness of a condensed FRP (CFRP) for patients with cLBP in professional activity.
Learn More >This review intends to characterize the recent literature pertaining to the role of aerobic exercise in the prevention of migraine. Areas of consensus within that literature may be used to guide clinical practice, allowing for the promulgation of evidence-based practice recommendations.
Learn More >