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Cytotoxicity and consequent cell death pathways are a critical component of the immune response to infection, disease or injury. While numerous examples of inflammation causing neuronal sensitization and pain have been described, there is a growing appreciation of the role of cytotoxic immunity in response to painful nerve injury. In this review we highlight the functions of cytotoxic immune effector cells, focusing in particular on natural killer (NK) cells, and describe the consequent action of these cells in the injured nerve as well as other chronic pain conditions and peripheral neuropathies. We describe how targeted delivery of cytotoxic factors via the immune synapse operates alongside Wallerian degeneration to allow local axon degeneration in the absence of cell death and is well-placed to support the restoration of homeostasis within the nerve. We also summarize the evidence for the expression of endogenous ligands and receptors on injured nerve targets and infiltrating immune cells that facilitate direct neuro-immune interactions, as well as modulation of the surrounding immune milieu. A number of chronic pain and peripheral neuropathies appear comorbid with a loss of function of cellular cytotoxicity suggesting such mechanisms may actually help to resolve neuropathic pain. Thus while the immune response to peripheral nerve injury is a major driver of maladaptive pain, it is simultaneously capable of directing resolution of injury in part through the pathways of cellular cytotoxicity. Our growing knowledge in tuning immune function away from inflammation toward recovery from nerve injury therefore holds promise for interventions aimed at preventing the transition from acute to chronic pain.
Learn More >Platinum-based chemotherapy-induced peripheral neuropathy is one of the most common causes of dose reduction and discontinuation of life-saving chemotherapy in cancer treatment; it often causes permanent impairment of quality of life in cancer patients. The mechanisms that underlie this neuropathy are not defined, and effective treatment and prevention measures are not available. Here, we demonstrate that SIRT2 protected mice against cisplatin-induced peripheral neuropathy (CIPN). SIRT2 accumulated in the nuclei of dorsal root ganglion sensory neurons and prevented neuronal cell death following cisplatin treatment. Mechanistically, SIRT2, an NAD+-dependent deacetylase, protected neurons from cisplatin cytotoxicity by promoting transcription-coupled nucleotide excision repair (TC-NER) of cisplatin-induced DNA crosslinks. Consistent with this mechanism, pharmacological inhibition of NER using spironolactone abolished SIRT2-mediated TC-NER activity in differentiated neuronal cells and protection of neurons from cisplatin-induced cytotoxicity and CIPN in mice. Importantly, SIRT2's protective effects were not evident in lung cancer cells in vitro or in tumors in vivo. Taken together, our results identified SIRT2's function in the NER pathway as a key underlying mechanism of preventing CIPN, warranting future investigation of SIRT2 activation-mediated neuroprotection during platinum-based cancer treatment.
Learn More >Endometriosis is an estrogen-dependent inflammatory disease that affects approximately 10% of women. Debilitating pelvic or abdominal pain is one of its major clinical features. Current animal models of endometriosis-associated pain require surgery either to implant tissue or to remove the ovaries. Moreover, existing models do not induce spontaneous pain, which is the primary symptom of patients with chronic pain, including endometriosis. A lack of models that accurately recapitulate the disease phenotype must contribute to the high failure rate of clinical trials for analgesic drugs directed at chronic pain, including those for endometriosis. We set out to establish a murine model of endometriosis-associated pain. Endometriosis was induced non-surgically by injecting a dissociated uterine horn into a recipient mouse. The induced lesions exhibited histological features that resemble human lesions along with an increase in pro-inflammatory cytokines and recruitment of immune cells. We also observed the presence of CGRP-, TRPA1-, and TRPV1-expressing nerve fibers in the lesions. This model induced mechanical allodynia, spontaneous abdominal pain, and changes in thermal selection behavior that indicate discomfort. These behavioral changes were reduced by drugs used clinically for endometriosis, specifically letrozole (aromatase inhibitor) and danazol (androgen). Endometriosis also induced neuronal changes as evidenced by activation of the NF-κB signaling pathway in TRPA1- and TRPV1-expressing DRG neurons. In conclusion, we have established a model of endometriosis-associated pain that responds to clinically active drugs and can, therefore, be used to identify novel therapies.
Learn More >The prescription of opioids at discharge after abdominopelvic surgery is variable and often excessive. A lack of guidance for abdominopelvic surgeons may explain the suboptimal nature of current prescribing practices.
Learn More >Neuron-immune interaction in the dorsal root ganglia (DRG) plays a pivotal role in the neuropathic pain development after nerve injury. Sigma-1 receptor (Sig-1R) is expressed by DRG neurons but its role in neuropathic pain is not fully understood. We investigated the effect of peripheral Sig-1R on neuroinflammation in the DRG after spared (sciatic) nerve injury (SNI) in mice. Nerve injury induced a decrease in NeuN staining along with the nuclear eccentricity and ATF3 expression in the injured DRG. Sig-1R was present in all DRG neurons examined, and after SNI this receptor translocated to the periphery of the soma and the vicinity of the nucleus, especially in injured ATF3 + neurons. In WT mice, injured DRG produced the chemokine CCL2, and this was followed by massive infiltration of macrophages/monocytes, which clustered mainly around sensory neurons with translocated Sig-1R, accompanied by robust IL-6 increase and mechanical allodynia. In contrast, Sig-1R knockout (Sig-1R-KO) mice showed reduced levels of CCL2, decreased macrophage/monocyte infiltration into DRG, and less IL-6 and neuropathic mechanical allodynia after SNI. Our findings point to an important role of peripheral Sig-1R in sensory neuron-macrophage/monocyte communication in the DRG after peripheral nerve injury; thus, these receptors may contribute to the neuropathic pain phenotype.
Learn More >Parent responses can have a major impact on their child's pain. The purpose of this systematic review is to (a) identify and describe measures assessing pain-related cognitive, affective, and behavioral responses in parents of children with chronic pain and (b) meta-analyze reported correlations between parent constructs and child outcomes (i.e., pain intensity, functional disability, and school functioning). Prospero protocol registration ID: CRD42019125496.
Learn More >Nocebo hyperalgesia is a clinically relevant phenomenon and may be formed as a result of associative learning, implemented by classical conditioning. This study explored for the first time distinct nocebo conditioning methods and their consequences for nocebo attenuation methods. Healthy participants (N = 140) were recruited and randomized to the following nocebo hyperalgesia induction groups: conditioning with continuous reinforcement (CRF), conditioning with partial reinforcement (PRF), and a sham-conditioning control group. In the attenuation phase, counterconditioning was compared to extinction. During induction, participants experienced increased thermal pain in 100% of nocebo trials in the CRF groups, while in only 70% of nocebo trials in the PRF groups. During evocation, pain stimulation was equivalent across all trials. During attenuation, pain stimulation was decreased on nocebo trials relative to control trials for the counterconditioning groups, while pain remained equivalent across all trials for the extinction groups. Results showed that both PRF and CRF significantly induced nocebo hyperalgesia, but CRF was a more potent nocebo induction method, as compared to PRF. Counterconditioning was more effective than extinction in attenuating nocebo hyperalgesia. Neither CRF nor PRF resulted in resistance to extinction. However, compared to CRF, conditioning with PRF resulted in more resistance to counterconditioning. These findings demonstrate that the more ambiguous learning method of PRF can induce nocebo hyperalgesia and may potentially explain the treatment resistance and chronification seen in clinical practice. Further research is required to establish whether attenuation with counterconditioning is generalizable to clinical settings.
Learn More >EphrinB-EphB receptor tyrosine kinases have been demonstrated to play important roles in pain processing after peripheral nerve injury. We have previously reported that ephrinB-EphB receptor signaling can regulate excitability and plasticity of neurons in spinal dorsal horn, and thus contribute to spinal central sensitization in neuropathic pain. How EphB receptor activation influences excitability of primary neurons in dorsal root ganglion (DRG), however, remains unknown. Here we report that EphB receptor activation facilitates calcium influx through NMDA receptor dependent and independent manners. In cultured DRG cells from adult rats, EphB1 and EphB2 receptors were expressed in neurons, but not the glial cells. Bath application of EphB receptor agonist ephrinB2-Fc induced NMDA-independent Ca influx, which was from the extracellular space rather than endoplasmic reticulum. EphB receptor activation also greatly enhanced NMDA-dependent Ca influx and NR2B phosphorylation, which was prevented by pre-treatment of Src kinase inhibitor PP2. In nerve-injured DRG neurons, elevated expression and activation of EphB1 and EphB2 receptors contributed to the increased intracellular Ca concentration and NMDA-induced Ca influx. Repetitive intrathecal administration of EphB2-Fc inhibited the increased phosphorylation of NR2B and Ca-dependent subsequent signals Src, ERK, and CaMKII as well as behaviorally expressed pain after nerve injury. These findings demonstrate that activation of EphB receptors can modulate DRG neuron excitability by facilitating Ca influx directly or through Src kinase activation-mediated NMDA receptor phosphorylation and that EphB receptor activation is critical to DRG neuron hyperexcitability, which has been considered critical to the subsequent spinal central sensitization and neuropathic pain.
Learn More >Upon transient musculoskeletal diseases, some patients develop persistent pain while others recover from pain. Here we studied whether such heterogeneity also occurs in rats after recovery from unilateral antigen-induced arthritis (AIA) in the knee joint, and which pain phenotype may predict the course of pain. Typically inflammatory swelling lasts about three weeks. Pain-related behaviors were monitored for 84 days after AIA induction. Unbiased cluster analysis of intra-group-differences at day 84 of AIA revealed that about one third of the rats (cluster 1) showed persistent mechanical hyperalgesia at the injected knee joint, whereas the other rats (cluster 2) had recovered from pain. Retrograde analysis of pain-related behaviors revealed that cluster 1 rats exhibited more severe mechanical hyperalgesia at the injected knee from day 3 of AIA, and mechanical hyperalgesia at the contralateral knee. Cluster 1 and 2 rats did not show different inflammatory swelling, secondary mechanical and thermal hyperalgesia at the ipsilateral hindpaw, guarding score and asymmetry of weight bearing during AIA. Thus in particular early severe mechanical hyperalgesia in the inflamed joint and segmental contralateral mechanical hyperalgesia seem to be a risk factor for the development of persistent mechanical hyperalgesia pointing to the importance of spinal mechanisms. However, none of the rats showed an expression of ATF3 in DRG neurons, nor morphological spinal microglia activation thus not suggesting development of neuropathic pain. Both clusters showed a persistent upregulation of pCREB in DRG neurons, inversely correlated with mechanical hyperalgesia at the knee. The role of pCREB needs to be further explored.
Learn More >Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) may play an important role in primary headaches. Preclinical evidence suggests that PACAP38 modulates trigeminal nociceptive activity mainly through PAC1 receptors while clinical studies report that plasma concentrations of PACAP38 are elevated in spontaneous attacks of cluster headache and migraine and normalize after treatment with sumatriptan. Intravenous infusion of PACAP38 induces migraine-like attacks in migraineurs and cluster-like attacks in cluster headache patients. A rodent-specific PAC1 receptor antibody Ab181 was developed and its effect on nociceptive neuronal activity in the trigeminocervical complex was investigated in vivo in an electrophysiological model relevant to primary headaches. Ab181 is potent and selective at the rat PAC1 receptor and provides near maximum target coverage at 10 mg/kg for more than 48 hours. Without affecting spontaneous neuronal activity, Ab181 effectively inhibits stimulus-evoked activity in the trigeminocervical complex. Immunohistochemical analysis revealed its binding in the trigeminal ganglion and sphenopalatine ganglion but not within the CNS suggesting a peripheral site of action. The pharmacological approach using a specific PAC1 receptor antibody could provide a novel mechanism with a potential clinical efficacy in the treatment of primary headaches.
Learn More >Experimental and clinical data strongly support vagus nerve stimulation (VNS) as a novel treatment in migraine. VNS acutely suppresses cortical spreading depression (CSD) susceptibility, an experimental model that has been used to screen for migraine therapies. However, mechanisms underlying VNS efficacy on CSD are unknown. Here, we interrogated the central and peripheral mechanisms using VNS delivered either invasively (iVNS) or non-invasively (nVNS) in male Sprague-dawley rats. CSD susceptibility was evaluated 40 min after the stimulation. iVNS elevated the electrical CSD threshold more than two-fold and decreased KCl-induced CSD frequency by 22% when delivered to intact vagus nerve. Distal vagotomy did not alter iVNS efficacy (2-fold higher threshold and 19% lower frequency in iVNS vs. sham). In contrast, proximal vagotomy completely abolished iVNS effect on CSD. Pharmacological blockade of nucleus tractus solitarius (NTS), the main relay for vagal afferents, by lidocaine or glutamate receptor antagonist CNQX also prevented CSD suppression by nVNS. Supporting a role for both norepinephrine and serotonin, CSD suppression by nVNS was inhibited by more than 50% after abrogating norepinephrinergic or serotonergic neurotransmission alone using specific neurotoxins; abrogating both completely blocked the nVNS effect. Our results suggest that VNS inhibits CSD through central afferents relaying in NTS and projecting to subcortical neuromodulatory centers providing serotonergic and norepinephrinergic innervation to the cortex.
Learn More >Prior studies have demonstrated that parental cognitive, behavioral and emotional factors are related to child functioning in children and adolescents with chronic pain. This is particularly important to understand how to potentially enhance the efficacy of psychological interventions for children by incorporating interventions targeting parents. We conducted a systematic review and meta-analysis to identify the specific parent factors that have been examined in the literature and to quantify the associations observed between parent factors and child pain and disability. A search of the electronic databases EMBASE, PsychINFO, Medline and PubMed was conducted, using search terms related to chronic pain, pediatric population and parents. 54 studies met criteria and were included in the review. Parent pain catastrophizing and protective behavior were the most commonly assessed parental constructs in the literature. Meta-analyses were conducted for associations between: parent pain catastrophizing, parent protective behaviors, parent anxiety and depression and parent stress associated with parenting a child with chronic pain with child pain, disability, school functioning and emotional functioning. Correlation coefficients were pooled using the random-effects model. A medium relationship was observed between higher protective behavior and poorer school functioning (r = -0.39); and small relationships were found between higher parent pain catastrophizing and increased child disability (r = 0.29); higher protective behaviors and increased child disability (r = 0.25); and increased parent depression and anxiety with increased child disability (r = 0.23 and r = 0.24 respectively). Future research is needed to investigate broader parent variables and overcome methodological weaknesses in this field.
Learn More >Mutations in Nav1.9 encoded by SCN11A have been associated with episodic pain, small-fiber neuropathy and congenital insensitivity to pain. In this study, we collected and characterized one Chinese family with episodic pain. The SCN11A mutation (c.664C>A/p.Arg222Ser) was identified and cosegregated with the episodic pain phenotype. In addition, we found that alcohol intake triggered intense pain attacks and detected the ALDH2 polymorphism (c.1510G>A/p.Glu504Lys) in three patients with episodic pain. The alcohol-aggravated pain symptom and this ALDH2 polymorphism were also reconfirmed in our previously reported episodic pain patient with the Nav1.9 mutation (p.Ala808Gly, patient III-2 in HBBJ family). To assess the pathogenicity of the Nav1.9 mutation and the new trigger, we introduced a mutation (p.Ala796Gly) into the mouse (orthologous mutation in human is p.Ala808Gly). The alteration hyperpolarized channel activation, increased the residual current through non-inactivating channels, and induced hyperexcitability of dorsal root ganglion (DRG) neurons in Scn11a mice. The Scn11a mice showed increased sensitivity to mechanical, heat and cold stimuli, and hypersensitivity to acetaldehyde and formalin, which could account for the alcohol intake-induced pain phenotype in patients. Moreover, acetaldehyde increased the mutant mNav1.9 channel current and excitability of Scn11a mouse DRG neurons. Parecoxib (an anti-inflammatory medication) relieved the heat hypersensitivity in Scn11a mice not receiving inflammatory stimuli and significantly decreased the hyperexcitability of DRG neurons in Scn11a mice. These results indicated that Scn11a mice recapitulated many clinical features of patients and suggested that Nav1.9 channel contributes significantly to the inflammatory pain state.
Learn More >Low back pain (LBP) is a highly prevalent and disabling condition whose initiating factors are poorly understood. It is known that psychological and physical stress is associated with LBP but the causal relationship, mechanisms and mediators have not been elucidated, and a preclinical model enabling the investigation of causality and thereby critically contributing to clinical translation does not exist.In the present study, we first established and characterized a myofascial LBP model in mice based on NGF injection into the low back muscles. Secondly, we investigated the effect of two different stress paradigms on this mouse LBP model by applying the chronic unpredictable stress (CUS) and vertical chronic restraint stress (vCRS) paradigms, to mimic psychological and psychophysical stress, respectively. In these studies, we combined longitudinal behavioral tests with gene and protein expression analysis in the muscle, dorsal root ganglia and spinal cord. NGF-induced LBP was characterized by long-lasting local and plantar mechanical hypersensitivity, cold hyperalgesia, decreased grip strength and wheel running activity, and time-dependent changes of neuropeptide and glial markers in the spinal cord. Interestingly, the exposure to CUS slightly worsened pain behavior, whereas vCRS primed and highly aggravated pain in this LBP model, by causing per se the intramuscular upregulation of endogenous NGF and increased spinal astrocyte expression.Our mouse model, particularly the combination of NGF injection and vCRS suggest that similar mechanisms are important in non-specific LBP and might help to investigate certain aspects of stress-induced exacerbation of pain.
Learn More >Vagal afferent sensory nerves, originating in jugular and nodose ganglia, are comprised of functionally distinct subsets whose activation evokes distinct thoracic and abdominal reflex responses. We used Cre-expressing mouse strains to identify specific vagal afferent populations and map their central projections within the brainstem. We show that Pirt is expressed in virtually all vagal afferents; whereas 5HT3 is expressed only in nodose neurons, with little expression in jugular neurons. TRPV1, the capsaicin receptor, is expressed in a subset of small nodose and jugular neurons. Tac1, the gene for tachykinins, is expressed predominantly in jugular neurons, some of which also express TRPV1. Vagal fibers project centrally to the nucleus tractus solitarius (nTS), paratrigeminal complex, area postrema and to a limited extent the dorsal motor nucleus of the vagus. nTS subnuclei preferentially receive projections by specific afferent subsets, with TRPV1+ fibers terminating in medial and dorsal regions predominantly caudal of obex, whereas TRPV1-negative fibers terminate in ventral and lateral regions throughout the rostral-caudal aspect of the medulla. Many vagal Tac1+ afferents (mostly derived from the jugular ganglion) terminate in the nTS. The paratrigeminal complex was the target of multiple vagal afferent subsets. Importantly, lung-specific TRPV1+ and Tac1+ afferent terminations were restricted to the caudal medial nTS, with no innervation of other medulla regions. In summary, this study identifies the specific medulla regions innervated by vagal afferent subsets. The distinct terminations provide a neuroanatomic substrate for the diverse range of reflexes initiated by vagal afferent activation. Vagal afferents transmit sensory information from visceral organs to the brainstem, where their activity alters sensation and visceral reflexes. Vagal afferents are comprised of distinct subsets which serve distinct functions. Little is known of the neuroanatomy of central projections of distinct vagal subsets, thus there remains an incomplete understanding of how visceral events evoke appropriate behavioral and reflex responses. This precludes rationally-developed pharmacological or electroceutical interventions to modify aberrant sensations/reflexes. Here, we used cell-specific reporter expression to identify the brainstem pathways of distinct vagal afferent subsets. We show that TRPV1+ vagal afferents innervate ipsilateral and contralateral dorsal/medial nTS subnuclei and the ipsilateral paratrigeminal complex, whereas TRPV1-negative vagal afferents innervate the ipsilateral rostral/ventral/lateral nTS subnuclei and the ipsilateral paratrigeminal complex.
Learn More >Definitions of medication overuse headache have changed over time.
Learn More >Pruritus (itch) is a cardinal symptom in atopic dermatitis (AD).
Learn More >Stress exacerbates many chronic pain syndromes including irritable bowel syndrome (IBS). Among these patient populations, many suffer from comorbid or chronic overlapping pain conditions and are predominantly female. Nevertheless, basic studies investigating chronic psychological stress-induced changes in pain sensitivity have been mostly carried out in male rodents. Our laboratory developed a model of comorbid pain hypersensitivity (CPH) (stress in the presence of preexisting orofacial pain inducing chronic visceral pain hypersensitivity that significantly outlasts transient stress-induced pain hypersensitivity (SIH)) facilitating the study of pain associated with IBS. Since CPH and SIH are phenotypically similar until SIH resolves and CPH persists, it is unclear if underlying mechanisms are similar.
Learn More >Because intractable itch reduces quality of life, understanding the fundamental mechanisms of itch is required to develop antipruritic treatments. Itch is mediated by peripheral sensory neurons, which originate from the neural crest (NC) during development. Itch-associated signaling molecules have been detected in genetically engineered animals and in cultures of peripheral neurons from dorsal root ganglia (DRG). Ethical difficulties collecting peripheral neurons from human DRG have limited analysis of itch in humans. This study describes a method of differentiating peripheral neurons from human induced pluripotent stem cells (hiPSCs) for physiological study of itch. This method resulted in the robust induction of p75 and HNK1 double-positive NC cells from hiPSCs. The expression of NC markers TFAP2A, SOX10 and SNAI1 increased during NC induction. The induction efficiency was nearly 90%, and human peripheral neurons expressing peripherin were efficiently differentiated from hiPSC-derived NC cells. Moreover, induced peripheral neurons expressed the sensory neuronal marker BRN3A and the itch-related receptors HRH1, MRGPRX1, IL31R and IL-4R. Calcium imaging analyses indicated that these peripheral neurons included sensory neurons responsive to itch-related stimuli such as histamine, BAM8-22, IL-31 and IL-4. These findings may enable detailed analyses of human DRG neurons and may result in new therapies for intractable itch.
Learn More >Sensory perceptions are coded by complex neural dynamics of regional communication in the brain. Thus, sensory abnormalities such as chronic pain may occur when neural dynamics go awry. Previous studies of cross-network dynamic functional connectivity in chronic pain identified abnormalities but were based on functional MRI which only captures slow temporal features. Here we conducted a magnetoencephalography (MEG) study to investigate fine temporal dynamics of aberrant cross-regional and cross-network communication of the dynamic pain connectome in patients with chronic pain. We also introduced a novel measure, dynamic functional coupling, to quantify the variability of brain communication. The study was performed in 33 people who had chronic pain associated with multiple sclerosis and 30 healthy controls. We found that patients with chronic pain exhibited abnormalities in cross-network functional coupling across multiple frequency bands (theta, alpha, beta, gamma), between the salience network and 3 other networks: the ascending nociceptive pathway, descending anti-nociceptive pathway, and the default mode network. However, these cross-network abnormalities involved different frequency bands in patients with neuropathic versus non-neuropathic chronic pain. Furthermore, cross-network abnormalities were linked to pain severity and pain interference. Our findings implicate broadband cross-network abnormalities as hallmark features of chronic pain in multiple sclerosis.
Learn More >Pulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis (Mtb), manifests with a persistent cough as both a primary symptom and mechanism of transmission. The cough reflex can be triggered by nociceptive neurons innervating the lungs, and some bacteria produce neuron-targeting molecules. However, how pulmonary Mtb infection causes cough remains undefined, and whether Mtb produces a neuron-activating, cough-inducing molecule is unknown. Here, we show that an Mtb organic extract activates nociceptive neurons in vitro and identify the Mtb glycolipid sulfolipid-1 (SL-1) as the nociceptive molecule. Mtb organic extracts from mutants lacking SL-1 synthesis cannot activate neurons in vitro or induce cough in a guinea pig model. Finally, Mtb-infected guinea pigs cough in a manner dependent on SL-1 synthesis. Thus, we demonstrate a heretofore unknown molecular mechanism for cough induction by a virulent human pathogen via its production of a complex lipid.
Learn More >Triptans are the most commonly used acute treatment for migraine. This study evaluated real-world treatment patterns following an initial triptan prescription to understand refill rates and use of non-triptan medications for the acute treatment of migraine.
Learn More >The mechanosensitive Piezo1 and Piezo2 channels convert mechanical force into cation permeation. However, their precise mechanogating and regulatory mechanisms remain elusive. Here, we report that Piezo1 utilizes three lateral ion-conducting portals equipped with physical gates for cooperative gating and splicing regulation. Mutating residues lining the portal converts Piezo1 into an anion-selective channel, demonstrating the portal-based cation-permeating pathway. Intriguingly, the portal is physically blocked with a plug domain, which undergoes alternative splicing in both Piezo1 and Piezo2. The Piezo1 isoform has local openings of the portals, enlarged single-channel conductance and sensitized mechanosensitivity. Remarkably, the three plugs are strategically latched onto the central axis for coordinated gating of the three portals. Disrupting the latching induces three quantal sub-conductance states in Piezo1, but not in the isoform. Together, we propose that Piezo utilizes an elegant plug-and-latch mechanism to physically and coordinately gate the lateral portals through the spliceable plug gates.
Learn More >Metabotropic glutamate receptor 5 (mGluR5) has been reported to contribute to inflammatory pain. The intracellular C-terminal domain has a Homer-binding motif that can form an mGluR5/Homer complex. Phosphorylation of mGluR5 at the Homer binding domain enhances the mGluR5/Homer interaction and modulates intracellular signal transduction. However, the characteristics of this interaction have not been fully elucidated in inflammatory pain. We aimed to evaluate the effects of CFA-induced phosphorylation of mGluR5 at the Homer binding domain on the mGluR5/Homer interaction. Von-frey filaments and thermal latency were used to monitor the development of inflammatory pain. Spinal mGluR5 phosphorylation at Ser and mGluR5/Homer crosslinking were detected. Mutant mGluR5 that could not be phosphorylated at Thr or Ser was evaluated in inflammatory pain. CFA-induced inflammatory pain resulted in obvious phosphorylation at Ser of mGluR5. Moreover, increased phosphorylation at the Homer-binding motif enhanced crosslinking between mGluR5 and Homer. Mutations at Thr and Ser of mGluR5 blocked the development of CFA-induced inflammatory pain. Overall, our findings showed that disruption of the phosphorylation of mGluR5 Thr and Ser alleviated CFA-induced inflammatory pain.
Learn More >Chronic pain is long-lasting nociceptive state, impairing the patient's quality of life. Existing analgesics are generally not effective in the treatment of chronic pain, some of which such as opioids have the risk of tolerance/dependence, overdose death with higher daily opioid doses for increasing analgesic effect. Opioid use disorders have already reached an epidemic level in the United States, therefore, non-opioid analgesic approach and/or use of non-pharmacologic interventions will be employed with increasing frequency. Viral vector mediated gene therapy is promising in clinical trials in the nervous system diseases. Glutamic acid decarboxylase (GAD) enzyme, a key enzyme in biosynthesis of GABA, plays an important role in analgesic mechanism. In the literature review, we used PubMed and BioRxiv to search the studies, and the eligible criteria include (1) manuscript written in English, (2) use of viral vectors expressing GAD67 or GAD65, and (3) preclinical pain models. We identified 13 eligible original research papers, in which the pain models include nerve injury, HIV-related pain, painful diabetic neuropathy, and formalin test. GAD expressed by the viral vectors from all of the reports produced antinociceptive effects. Restoring GABA systems is a promising therapeutic strategy for chronic pain, which provides evidence for the clinical trial of gene therapy for pain in the near future.
Learn More >Cold allodynia is often seen in the acute phase of oxaliplatin treatment, but the underlying pathophysiology remains unclear.
Learn More >The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie the mechanotransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although it can modulate their characteristics. Chemosensory stimuli applied to the lumen can release substances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic sensory neurons in the ENS detect and respond to sensory stimuli and how these mechanisms differ from extrinsic sensory nerve endings in the gut that underlie the gut-brain axis.
Learn More >A relevant subsample of patients with chronic low back pain (CLBP) have manifested augmented central pain processing, central sensitisation (CS). Patients with CLBP have limited functioning and participation. Theoretically, physical functioning in patients with CLBP can plausibly be linked to CS; however, evidence to explain such association is scarce. Moreover, there is no gold standard for CS diagnosis. The objectives of the study are: (1) to analyse the association between instruments assessing reference symptoms and signs attributed to CS; (2) to analyse whether reference symptoms and signs attributed to CS are associated with functioning measurement outcomes; and (3) to analyse whether changes (between baseline and discharge) in reference symptoms and signs attributed to CS are related to changes in each of the functioning measurement outcomes.
Learn More >Itch is an unpleasant feeling that triggers scratching behavior. Much progress has been made in identifying the mechanism of itch at the peripheral and spinal levels, however, itch circuits in the brain remain largely unexplored. We previously found that anterior cingulate cortex (ACC) to dorsal medial striatum (DMS) inputs modulated histamine-induced itch sensation, but how itch information was transmitted to ACC remained unclear. Here, we demonstrated that the anteromedial thalamic nucleus (AM) was activated during histaminergic itch, and there existed reciprocal neuronal projections between AM and ACC. Disconnection between AM and ACC resulted in a significant reduction of histaminergic, but not nonhistaminergic, itch-related scratching behavior. Optogenetic activation of AM-ACC, but not ACC-AM, projections evoked histaminergic itch sensation. Thus, our studies firstly reveal that AM is critical for histaminergic itch sensation and AM-ACC projections modulate histaminergic itch-induced scratching behavior.
Learn More >Pepducins are cell-penetrating, membrane-tethered lipopeptides designed to target the intracellular region of a G protein-coupled receptor (GPCR) in order to allosterically modulate the receptor's signaling output. In this proof-of-concept study, we explored the pain-relief potential of a pepducin series derived from the first intracellular loop of neurotensin receptor type 1 (NTS1), a class A GPCR that mediates many of the effects of the neurotensin (NT) tridecapeptide, including hypothermia, hypotension and analgesia. We used BRET-based biosensors to determine the pepducins' ability to engage G protein signaling pathways associated with NTS1 activation. We observed partial Gα and Gα activation at a 10 µM concentration, indicating that these pepducins may act as allosteric agonists of NTS1. Additionally, we used surface plasmon resonance (SPR) as a label-free assay to monitor pepducin-induced responses in CHO-K1 cells stably expressing hNTS1. This whole-cell integrated assay enabled us to subdivide our pepducin series into three profile response groups. In order to determine the pepducins' antinociceptive potential, we then screened the series in an acute pain model (tail-flick test) by measuring tail withdrawal latencies to a thermal nociceptive stimulus, following intrathecal (i.t.) pepducin administration (275 nmol/kg). We further evaluated promising pepducins in a tonic pain model (formalin test), as well as in neuropathic (Chronic Constriction Injury) and inflammatory (Complete Freund's Adjuvant) chronic pain models. We report one pepducin, PP-001, that consistently reduced rat nociceptive behaviors, even in chronic pain paradigms. Finally, we designed a TAMRA-tagged version of PP-001 and found by confocal microscopy that the pepducin reached the rat dorsal root ganglia post i.t. injection, thus potentially modulating the activity of NTS1 at this location to produce its analgesic effect. Altogether, these results suggest that NTS1-derived pepducins may represent a promising strategy in pain-relief.
Learn More >Recent studies demonstrate that calcitonin gene-related peptide (CGRP) plays critical roles in migraine. Immunohistochemistry and in situ hybridization studies have shown that CGRP and its receptors are expressed in cortical areas that are critical for pain perception including the anterior cingulate cortex (ACC) and insular cortex (IC). Recent studies reported that CGRP enhanced excitatory transmission in the ACC. However, little is known about the possible effect of CGRP on excitatory transmission in the IC. In the present study, we investigated the role of CGRP on synaptic transmission in the IC slices of adult male mice. Bath application of CGRP produced dose-dependent potentiation of evoked excitatory postsynaptic currents (eEPSCs). This potentiation was NMDA receptor (NMDAR) independent. After application of CGRP1 receptor antagonist CGRP or BIBN 4096, CGRP produced potentiation was significantly reduced. Paired-pulse facilitation was significantly decreased by CGRP, suggesting possible presynaptic mechanisms. Consistently, bath application of CGRP significantly increased the frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs). By contrast, amplitudes of sEPSCs and mEPSCs were not significantly affected. Finally, adenylyl cyclase subtype 1 (AC1) and protein kinase A (PKA) are critical for CGRP-produced potentiation, since both selective AC1 inhibitor NB001 and the PKA inhibitor KT5720 completely blocked the potentiation. Our results provide direct evidence that CGRP contributes to synaptic potentiation in the IC, and the AC1 inhibitor NB001 may be beneficial for the treatment of migraine in the future.
Learn More >Pain measures traditionally used in rodents record mere reflexes evoked by sensory stimuli; the results thus may not fully reflect the human pain phenotype. Alterations in physical and emotional functioning, pain-depressed behaviors and facial pain expressions were recently proposed as additional pain outcomes to provide a more accurate measure of clinical pain in rodents, and hence to potentially enhance analgesic drug development. We aimed to review how preclinical pain assessment has evolved since the development of the tail flick test in 1941, with a particular focus on a critical analysis of some nonstandard pain outcomes, and a consideration of how sex differences may affect the performance of these pain surrogates. We tracked original research articles in Medline for the following periods: 1973-1977, 1983-1987, 1993-1997, 2003-2007, and 2014-2018. We identified 606 research articles about alternative surrogate pain measures, 473 of which were published between 2014 and 2018. This indicates that preclinical pain assessment is moving toward the use of these measures, which may soon become standard procedures in preclinical pain laboratories.
Learn More >Transection of the sural and common peroneal branches of the sciatic nerve produces cutaneous hypersensitivity at the tibial innervation territory of the mouse hindpaw that resolves within a few weeks. We report that interruption of endogenous neuropeptide Y (NPY) signaling during remission, with either conditional NPY knockdown in NPY mice or intrathecal administration of the Y1 receptor antagonist BIBO3304, reinstated hypersensitivity. These data indicate that nerve injury establishes a long-lasting latent sensitization of spinal nociceptive neurons that is masked by spinal NPY-Y1 neurotransmission. To determine whether this mechanism extends beyond the sensory component of nociception, we used conditioned place aversion and preference assays to evaluate the affective component of pain. We found that BIBO3304 produced place aversion in mice when administered during remission. Furthermore, the analgesic drug gabapentin produced place preference after NPY knockdown in NPY but not control mice. We then used pharmacological agents and deletion mutant mice to investigate the cellular mechanisms of neuropathic latent sensitization. BIBO3304-induced reinstatement of mechanical hypersensitivity and conditioned place aversion could be prevented with intrathecal administration of an N-methyl-d-aspartate receptor antagonist (MK-801) and was absent in adenylyl cyclase type 1 (AC1) deletion mutant mice. BIBO3304-induced reinstatement could also be prevented with intrathecal administration an AC1 inhibitor (NB001) or a TRPV1 channel blocker (AMG9801), but not vehicle. Intrathecal administration of a TRPA1 channel blocker (HC030031) prevented the reinstatement of neuropathic hypersensitivity produced either by BIBO3304, or by NPY knockdown in NPY but not control mice. Our results confirm new mediators of latent sensitization: TRPA1 and TRPV1. We conclude that NPY acts at spinal Y1 to tonically inhibit a molecular NMDAR➔AC1 intracellular signaling pathway in the dorsal horn that is induced by peripheral nerve injury and drives both the sensory and affective components of chronic neuropathic pain.
Learn More >As many as one third of patients undergoing minimally invasive thoracic surgery and one half undergoing thoracotomy develop chronic pain, defined as pain lasting 2-3 months. There is limited information regarding predictors of chronic pain and even less is known about its impact on health-related quality of life, known as pain interference. Currently, there is a focus on decreased opioid prescribing after surgery. Interestingly thoracic surgical patients are the least likely to be on opioids before surgery and have the highest rate of new persistent opioid use after surgery compared to other surgical cohorts. These studies of opioid use have identified important predictors of new persistent opioid use, but their findings are limited by failing to correlate opioid use with pain. The objectives of this invited review are to present the findings of pertinent studies of chronic pain and opioid use after thoracic surgery, "where we are", and to discuss gaps in our knowledge of these topics and opportunities for research to fill those gaps, "where we need to go".
Learn More >Gastrin-releasing peptide (GRP) receptor-expressing (GRPR) neurons have a central role in the spinal transmission of itch. Because their fundamental regulatory mechanisms are not yet understood, it is important to determine how such neurons are excited and integrate itch sensations. In this study, we investigated the mechanisms for the activation of itch-responsive GRPR neurons in the spinal dorsal horn (SDH). GRPR neurons expressed the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) containing the GluR2 subunit. In mice, peripherally elicited histaminergic and non-histaminergic itch was prevented by intrathecal (i.t.) administration of the AMPAR antagonist NBQX, which was consistent with the fact that firing of GRPR neurons in SDH under histaminergic and non-histaminergic itch was completely blocked by NBQX, but not by the GRPR antagonist RC-3095. Because GRP neurons in SDH contain glutamate, we investigated the role of GRP (GRP/Glu) neurons in regulating itch. Chemogenetic inhibition of GRP neurons suppressed both histaminergic and non-histaminergic itch without affecting the mechanical pain threshold. In nonhuman primates, i.t. administration of NBQX also attenuated peripherally elicited itch without affecting the thermal pain threshold. In a mouse model of diphenylcyclopropenone (DCP)-induced contact dermatitis, GRP, GRPR, and AMPAR subunits were upregulated in SDH. DCP-induced itch was prevented by either silencing GRP neurons or ablation of GRPR neurons. Altogether, these findings demonstrate that GRP and glutamate cooperatively regulate GRPR AMPAR neurons in SDH, mediating itch sensation. GRP-GRPR and the glutamate-AMPAR system may play pivotal roles in the spinal transmission of itch in rodents and nonhuman primates.
Learn More >Effective, non-addictive therapeutics for chronic pain remain a critical need. While there are several potential therapeutics that stimulate anti-inflammatory mechanisms to restore homeostasis in the spinal dorsal horn microenvironment, the effectiveness of drugs for neuropathic pain are still inadequate. The convergence of increasing knowledge about the multi-factorial mechanisms underlying neuropathic pain and the mechanisms of drug action from preclinical studies are providing the ability to create pharmaceuticals with better clinical effectiveness. By targeting and activating the peroxisome proliferator-activated receptor gamma subunit (PPARγ), numerous preclinical studies report pleiotropic effects of thiazolidinediones (TDZ) beyond their intended use of increasing insulin, including their anti-inflammatory, renal, cardioprotective, and oncopreventative effects. Several studies find TDZs reduce pain-related behavioral symptoms, including ongoing secondary hypersensitivity driven by central sensitization. Previous studies find increased PPARγ in the spinal cord and brain regions innervated by incoming afferent nerve endings after the induction of neuropathic pain models. PPARγ agonist treatment provides an effective reduction in pain-related behaviors, including anxiety. Data further suggest that improved brain mitochondrial bioenergetics after PPARγ agonist treatment is a key mechanism for reducing hypersensitivity. This review emphasizes two points relevant for the development of better chronic pain therapies. First, employing neuropathic pain models with chronic duration is critical since they can encompass the continuum of molecular and brain circuitry alterations arising over time when pain persists, providing greater relevance to clinical pain syndromes. Assisting in that effort are preclinical models of chronic trigeminal pain syndromes. Secondly, considering the access to nerve and brain neurons and glia across the blood-brain barrier is important. While many therapies have low brain penetrance, a PPARγ agonist with better brain penetrance, ELB00824, has been developed. Purposeful design and recent comparative testing indicate that ELB00824 is extraordinarily efficient and efficacious. ELB00824 provides greatly improved attenuation of pain-related behaviors, including mechanical hypersensitivity, anxiety, and depression in our chronic trigeminal nerve injury models. Physiochemical properties allowing significant brain access and toxicity testing are discussed.
Learn More >Status migrainosus is a condition with limited epidemiological knowledge, and no evidence-based treatment guideline or rational-driven assessment of successful treatment outcome. To fill this gap, we performed a prospective observational study in which we documented effectiveness of treatment approaches commonly used in a tertiary headache clinic.
Learn More >Phenylethanolamine methyltransferase (PNMT) catalyzes the conversion of sympathetic neurotransmitter norepinephrine to epinephrine. We examined the association of polymorphisms with acute and chronic pain in sickle cell disease (SCD). Utilization of emergency care owing to painful crisis was used as a marker for acute pain in 131 patients with SCD. rs876493 A allele, rs2934965 T allele and rs2941523 G allele were significantly associated with decreased utilization (p ≤ 0.05). rs876493 A allele showed association with utilization in females (p = 0.003), not males (p = 0.803). rs2934965 T allele and rs2941523 G allele were predicted to cause loss of putative transcription factor binding sites. This is the first report of the association of PNMT polymorphisms with acute crisis pain in SCD. Together with our previous findings in catechol-o-methyltransferase, polymorphisms in catecholamine metabolizing enzymes appear to primarily influence acute pain in SCD.
Learn More >The primary aim of this study was to investigate time trends of major headache diagnoses using cross-sectional data from two population-based health surveys. In addition, we aimed to perform a longitudinal assessment of baseline characteristics and subsequent risk for having headache at 22-years' follow-up among those participating in three health surveys.
Learn More >To investigate the pathophysiology of visual snow (VS), through a combined functional neuroimaging and magnetic resonance spectroscopy ( H-MRS) approach.
Learn More >Previous voxel-based morphometry (VBM) studies have revealed changes in brain structure in patients with vestibular migraine (VM); these findings have improved the present understanding of pathophysiology. Few other studies have assessed the association between structural changes and the severity of dizziness in VM. This study aimed to examine the structural changes and cortical morphometric features associated with migraine and vertigo attacks in patients with VM.
Learn More >Several reports in the literature have identified an association between cortisol levels and the presence of chronic pain in conditions such as rheumatoid arthritis, low back pain or whiplash. In contrast, few have examined the association of cortisol and pain in people with osteoarthritis (OA). The purpose of this systematic review was to verify the association between cortisol and pain in the OA population.
Learn More >To evaluate the SUMMIT-07 trial opioid withdrawal results of NKTR-181 (oxycodegol), a new molecular entity mu-opioid receptor agonist.
Learn More >Physician adherence to guideline recommendations for the use of opioids to manage chronic pain is often limited.
Learn More >Switching microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype represents a novel therapeutic strategy for diabetic neuropathic pain (DNP). This study aims to determine the role and mechanism of interleukin (IL)-35 in regulating microglial M1/M2 polarization in DNP. A rat model of DNP was induced by a single streptozocin injection and recombinant IL-35 (rIL-35) was then intrathecally administered to the rats for 14 days. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured to assess the therapeutic effect of IL-35. Highly aggressive proliferating immortalized (HAPI), a rat microglia cell line, was treated with lipopolysaccharide (LPS) for M1 polarization or IL-4 for M2 polarization. The M1 markers (CD68, iNOS, TNF-α, IL-6) and M2 markers (CD206, Arg-1, IL-10) were examined. rIL-35 administration in DNP model rats elevated MWT and TWL, induced microglial polarization toward the M2 phenotype, suppressed JNK signaling and activated JAK2/STAT6 signaling. In vitro assay confirmed that rIL-35 induced microglial M2 polarization in HAPI cells through inhibiting JNK signaling and activating JAK2/STAT6 signaling. Collectively, the mechanism underlying therapeutic effect of IL-35 on DNP may relate to its promotion of microglial M2 polarization by regulating JNK signaling and JAK2/STAT6 signaling.
Learn More >Prolonged use of opioids causes analgesic tolerance and adverse effects including constipation and dependence. Evidence exists that molecules targeting imidazoline-2 receptors (I2Rs) potentiate opioid analgesia in rodents. We investigated whether combination with the I2R ligand CR4056 could improve efficacy and safety of morphine, and explored the mechanisms of CR4056-opioid interaction.
Learn More >The objective of the study was to examine the BIS-BAS model of chronic pain. This model posits that 2 neurophysiological systems-the behavioral inhibition system (BIS) sensitized to and activated by punishment cues and the behavioral activation system (BAS) sensitized to and activated by reward cues-make independent and concurrent contributions to 2 domains of pain-related function: pain interference and positive function despite pain. The study additionally hypothesized that BIS and BAS sensitivity would have different associations with these 2 different aspects of pain-related function. BIS activation would be more strongly correlated with pain interference and BAS would be more strongly correlated with positive function despite pain. Research Method/Design: This was a cohort study consisting of the baseline assessments of 328 veterans enrolled in a large clinical trial examining 3 psychosocial interventions for chronic pain.
Learn More >To compare pain and psychological outcomes in veterans with chronic musculoskeletal pain and comorbid post-traumatic stress disorder (PTSD) or pain alone and to determine if veterans with comorbidity respond differently to a stepped-care intervention than those with pain alone.
Learn More >Chronic pain is a complex multidimensional condition that requires management with multiple professions' expertise. Healthcare training programs tend to adhere to curricula within their own profession with very few interactions with other groups. Project ECHO (Extension for Community Healthcare Outcomes) Chronic Pain and Opioid Stewardship is a model for interprofessional education, using tele-mentoring, case-base discussions and clinically focused presentations. The goal is to improve competency and confidence in managing complex cases in primary care. This qualitative study engaged twenty healthcare practitioners from multiple professions who had participated in ECHO in focus group discussions about managing patients with chronic pain, about their reasons for and the effect of participating in Project ECHO Ontario Chronic Pain/Opioid Stewardship, and about their perspectives on interprofessional care. The results show that participating in ECHO resulted in personal and professional benefit, and increased understanding about their own roles and limitations, as well as other healthcare professionals' roles. The participants described changes in their attitudes toward patients with chronic pain, and their colleagues from other professions. Non-physician participants were more likely to approach physicians to discuss their assessment and diagnosis as well as prescriptions. The interprofessional nature of the program was seen as positive and contributed to perceived changes in practice collaboration. These results show that healthcare professionals from multiple professions expressed mainly positive views of ECHO's emphasis on interprofessional care, with different professions appreciating different aspects of that approach.
Learn More >Psychological stress and ensuing modulation of the immune and nervous systems can have a significant impact on itch. Stress can exacerbate itch and vice versa, resulting in a vicious cycle that can greatly impair a patient's quality of life. This review summarizes the association between stress and itch, elucidates the mechanism by which these two phenomena influence one another, and explores treatment modalities that aim to reduce stress-induced itch.
Learn More >Here we investigated effects of intramuscular (i.m.) heating-needle stimulation on persistent muscle nociception evoked by i.m. injection of different doses (50-200 µl) of complete Freund's adjuvant (CFA) in rats. Paw withdrawal reflexes evoked by noxious mechanical and heat stimulation as well as hind limb swelling were determined prior to and two weeks after the CFA injection. The unilateral injection of CFA induced a dose-related and long-lasting (5-14d), bilateral secondary mechanical hyperalgesia and heat hypoalgesia associated with long-term limb swelling. A period of 30-45 min 43 °C heating-needle stimulation significantly enhanced the i.m. CFA-induced bilateral heat hypoalgesia and alleviated hind limb swelling. In contrast, 30-45min 46 °C heating-needle stimulation markedly enhanced both mechanical hyperalgesia and heat hypoalgesia, but failed to influence the CFA-induced hind limb swelling. Microinjection of P2X3 receptor antagonist A-317491 (0.5-4.5 nmol/0.5µl) into the thalamic ventromedial (VM) nucleus dose-dependently inhibited the 43 °C and 46 °C heating-needle stimulation-induced heat hypoalgesia, whereas the 46 °C heating-needle stimulation-induced mechanical hyperalgesia was significantly prevented by microinjection of A-317491 into the thalamic mediodorsal (MD) nucleus. In contrast, the hind limb swelling was not affected by the microinjection of A-317491 into the thalamic VM or MD nucleus. The present study indicates that in the CFA-induced persistent muscle nociception condition, 43 °C heating-needle stimulation selectively increases descending inhibition, which effect is modulated by the thalamic VM nucleus. In addition to the antinociceptive role of P2X3 receptors in the thalamic VM nucleus, P2X3 receptors within the thalamic MD nucleus participate in the descending facilitation evoked by i.m. 46 °C heating-needle stimulation.
Learn More >Evaluate the implementation of cognitive-behavioral therapy (CBT) for chronic pain in a clinical setting by comparing youth with sickle cell disease (SCD) who initiated or did not initiate CBT.
Learn More >Cannabidiol (CBD), a major metabolite of Cannabis sativa, is popularized as a medicinal product, with potential for analgesic, anti-inflammatory and antioxidant effects. CBD may hold promise as a treatment in rheumatic diseases, but evidence to date remains preclinical. Preclinical effects on pain and inflammation is encouraging, but clinical study is lacking with only a single study in knee osteoarthritis reporting promising effect on symptoms. CBD products are freely available over the counter and marketed as food supplements or wellness products. The World Health Organization has identified pure CBD as safe and without abuse potential, but products are not subject to drug regulatory standards leading to inconsistency in manufacturing practices and quality of products. Not only have molecular concentrations of CBD been identified as inaccurate, but there are concerns for contaminants including heavy metals, pesticides, microbes and mycotoxins, as well as added THC. Drug-drug interactions pose a potential risk due to metabolism via the CYP P450 enzyme pathway. Patients wishing to use CBD should obtain a product with certification of Good Manufacturing Practices, initiate treatment with a nighttime low dose and have defined outcome goals within a reasonable time frame. Treatments should not be managed by non-medical dispensary personnel. The hope that CBD may be a useful therapy must be substantiated by sound scientific study.
Learn More >We have previously shown that endogenous adenosine 5'-triphosphate (ATP), via P2X3 and P2X2/3 receptors, plays an essential role in carrageenan-induced articular hyperalgesia model in rats' knee joint. In the present study, we used the rat knee joint incapacitation test, Enzyme-Linked Immunosorbent Assay (ELISA), and myeloperoxidase enzyme activity assay, to test the hypothesis that the activation of P2X3 and P2X2/3 receptors by their agonist induces articular hyperalgesia mediated by the inflammatory mediators bradykinin, prostaglandin, sympathomimetic amines, pro-inflammatory cytokines and by neutrophil migration. We also tested the hypothesis that the activation of P2X3 and P2X2/3 receptors contributes to the articular hyperalgesia induced by the inflammatory mediators belonging to carrageenan inflammatory cascade. The non-selective P2X3 and P2X2/3 receptors agonist αβ-meATP induced a dose-dependent articular hyperalgesia, which was significantly reduced by the selective antagonists for P2X3 and P2X2/3 receptors (A-317491), bradykinin B- (DALBK) or B-receptors (bradyzide), β-(atenolol) or β-adrenoceptors (ICI-118,551), by the pre-treatment with cyclooxygenase inhibitor (indomethacin) or with the nonspecific selectin inhibitor (Fucoidan). αβ-meATP induced the release of pro-inflammatory cytokines TNFα, IL-1β, IL-6, and CINC-1, as well as the neutrophil migration. Moreover, the co-administration of A-317491 significantly reduced the articular hyperalgesia induced by bradykinin, prostaglandin E (PGE), and dopamine. These findings suggest that peripheral P2X3 and P2X2/3 receptors activation induces articular hyperalgesia by an indirect sensitization of the primary afferent nociceptor of rats' knee joint through the release of inflammatory mediators. Further, they also indicate that the activation of these purinergic receptors by endogenous ATP mediates the bradykinin-, PGE-, and dopamine-induced articular hyperalgesia.
Learn More >Capsaicin is a widely utilized experimental pain stimulus; however, few studies have reported on ethnic differences in pain responses to capsaicin. The present study used infrared thermography to 1) measure differences in capsaicin-induced neurogenic flare between non-Hispanic black (NHB) and non-Hispanic white (NHW) adults and 2) determine the association between neurogenic flare and secondary hyperalgesia.
Learn More >Myeloid zinc finger 1 (MZF1) belongs to the Kruppel family of zinc-finger transcription factors. Recent studies have demonstrated that in dorsal root ganglion (DRG) neurons, MZF1 is involved in the development and maintenance of neuropathic pain. However, the role of MZF1 in inflammatory pain still remains unknown. In the present study, the mechanism of MZF1 in chronic inflammatory pain was investigated in rats received an intraplantar injection of complete Freund's adjuvant (CFA). Subsequently, a series of assays including Western blotting, qRT-PCR, immunohistochemistry, and chromatin immunoprecipitation (ChIP) were performed. We found that CFA led to MZF1 upregulation in ipsilateral L4/5 DRGs. Pre- and post-microinjection of MZF1 siRNA into the ipsi-L5 DRG blocked the development of CFA-induced chronic inflammatory pain and alleviated the mechanical allodynia and thermal hyperalgesia in the maintenance phase. CFA also increased MMP-2/9 and Nav1.8 expression but reduced Kv1.2 and Cav1.2 expression in L4/L5 DRGs. Microinjection of MZF1 siRNA into DRG diminished the CFA-induced changes in MMP-2/9 and Kv1.2 expression. However, the expressions of Nav1.8 and Cav1.2 were not changed by the treatment. Double immunofluorescence staining showed that MMP-2/9 and Kv1.2 were co-localized with MZF1 in DRGs. The ChIP-PCR results revealed that MZF1 binds directly to the promoter region of MMP-2/9 gene. Together, the above results imply that upregulation of MZF1 in DRGs might contribute to the development and maintenance of CFA-induced chronic inflammatory pain by regulating MMP-2/9 and Kv1.2 expression. Targeting DRG-localized MZF1 might be a promising therapeutic strategy for the treatment of chronic inflammatory pain in the clinic.
Learn More >The objective of this study was to examine the efficacy of complementary and integrative health (CIH) approaches for reducing pain intensity (primary outcome) and depressive symptoms (secondary outcome) as well as improving physical functioning (secondary outcome) among U.S. military personnel living with chronic pain. Studies were retrieved from bibliographic databases, databases of funded research, and reference sections of relevant articles. Studies that (a) evaluated a CIH approach to promote chronic pain management among military personnel, (b) used a randomized controlled trial design, and (c) assessed pain intensity were included. Two coders extracted data from each study and calculated effect sizes. Discrepancies between coders were resolved through discussion. Comprehensive searches identified 12 studies (k = 15 interventions) that met inclusion criteria. CIH practices included cognitive-behavioral therapies (k = 5), positive psychology (k = 3), yoga (k = 2), acupuncture (k = 2), mindfulness-based interventions (k = 2), and biofeedback (k = 1). Across these studies, participants who received the intervention reported greater reductions in pain intensity (d+ = 0.44, 95% CI [0.21, 0.67], k = 15) compared to controls. Statistically significant improvements were also observed for physical functioning (d+ = 0.36, 95% CI [0.11, 0.61], k = 11) but not for depressive symptoms (d+ = 0.21, 95% CI [-0.15, 0.57], k = 8). CIH approaches reduced pain intensity and improved physical functioning. These approaches offer a nonpharmacological, nonsurgical intervention for chronic pain management for military personnel. Future studies should optimize interventions to improve depressive symptoms in military populations experiencing chronic pain. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
Learn More >TWIK-related K+ (TREK) channels are potential analgesic targets. However, selective activators for TREK with both defined action mechanism and analgesic ability for chronic pain have been lacking. Here we report C3001a, a selective activator for TREK against other two-pore domain K+ (K2P) channels. C3001a binds to the cryptic binding site formed by P1 and TM4 in TREK-1, as suggested by computational modeling and experimental analysis. Further, we identify the carboxyl group of C3001a as a structural determinant for the binding to TREK-1/2, and the key residue that defines the subtype-selectivity of C3001a. C3001a targets TREK channels in peripheral nervous system to reduce the excitability of nociceptive neurons. In neuropathic pain, C3001a alleviated spontaneous pain and cold hyperalgesia. In a mouse model of acute pancreatitis, C3001a alleviated mechanical allodynia and inflammation. Together, C3001a represents a lead compound which could advance the rational design of peripherally-acting analgesics targeting K2P channels without opioid-like adverse effects.
Learn More >Opioid analgesics remain a treatment option for refractory acute and chronic pain, despite their potential risk for abuse and adverse events (AEs). Opioids are associated with several common AEs, but the most bothersome is opioid-induced constipation (OIC). OIC is often overlooked but has the potential to affect patient quality of life, increase associated symptom burden, and impede long-term opioid compliance. The peripherally acting µ-receptor antagonists (PAMORAs) are a class of drugs that include methylnaltrexone, naloxegol, and naldemedine. Collectively, each is approved for the treatment of OIC. PAMORAs work peripherally in the gastrointestinal tract, without impacting the central analgesic effects of opioids. However, each has unique pharmacokinetic properties that may be impacted by coadministered drugs or food. This review focuses on important metabolic and pharmacokinetic principals that are pertinent to drug interactions involving µ-opioid receptor antagonists prescribed for OIC. It highlights subtle differences among the PAMORAs that may have clinical significance. For example, unlike naloxegol or naldemedine, methylnaltrexone is not a substrate for CYP3A4 or p-glycoprotein; therefore, its plasma concentration is not altered when coadministered with concomitant medications that are CYP3A4 or p-glycoprotein inducers or inhibitors. With a better understanding of pharmacokinetic nuances of each PAMORA, clinicians will be better equipped to identify potential safety and efficacy considerations that may arise when PAMORAs are coadministered with other medications.
Learn More >Recent task-based fMRI studies have shown that Persistent Somatoform Pain Disorder (PSPD) patients demonstrated aberrant activity in a wide range of brain regions associated with sensation, cognition and emotion. However, these specific task-based studies could not clearly uncover the alterations in the spontaneous brain networks that were associated with the general pain-related symptoms in PSPD.
Learn More >To determine the prevalence of hypnic headache.
Learn More >To assess differences in tactile spatial acuity and in sensory-motor control between patients with chronic nonspecific neck pain (CNSNP) with and without neuropathic features (NF), as well as asymptomatic.
Learn More >Identify variables that influence pain reduction following peripheral nerve field stimulation (PNFS) in order to identify a potential responder profile.
Learn More >An important challenge in pain assessment is the inability of an evaluator to corroborate, using objective signs or indicators, the subjective pain report of a patient. In this scenario, the Electronic von Frey (EVF) anaesthesiometer rises as a valuable Quantitative Sensory Testing modality for pain evaluation. Although EVF showed good reproducibility when applied to healthy areas in humans, its use for evaluation of burn-related pain threshold has not yet been validated. The present study demonstrated the concurrent validity of EVF by determining its correlation with the traditionally used Visual Analog Scale (VAS). EVF was compared to VAS through pain measurements obtained from 44 patients with superficial partial thickness burns treated with silver sulfadiazine. A very good and significant positive correlation between both methods was detected. Baseline clinical and demographic parameters did not significantly affect the association between EVF and VAS. Additionally, EVF had significant and moderate positive correlation with the amount of analgesic used and with the Burns Specific Pain Anxiety Scale scores. Regular pain assessment is essential for the establishment of an appropriate treatment plan; thus, it is critical that we continue to refine our pain assessment skills to avoid chronic pain and psychological trauma in burn patients.
Learn More >Eptinezumab is a humanized mAb that targets calcitonin gene-related peptide and is under regulatory review for the prevention of episodic and chronic migraine (EM, CM). It is important to determine whether exposures achieved with intravenous (IV) administration of eptinezumab achieve desired pharmacologic effects. Population pharmacokinetics, including dose- and exposure-response analyses, were performed using patient-level data from the eptinezumab clinical trial program with IV doses ranging from 10 to 1000 mg in pharmacokinetic analyses or 10 to 300 mg in phase 2/3 clinical studies in patients with EM or CM. Exposure-response analysis explored the relationship between eptinezumab exposure metrics and efficacy parameters including monthly migraine days. The pharmacokinetic profile of eptinezumab was characterized by rapid attainment of maximum plasma concentration (ie, end of IV administration) and a terminal half-life of 27 days. Covariate analysis found that patient characteristics had no clinically significant effects on pharmacokinetic parameters and were insufficient to influence dosing. Dose- and exposure-response analyses found exposure with single doses ≥100 mg was associated with greater efficacy compared with doses ≤30 mg and a plateau of effect between 100 and 300 mg. A saturable inhibitory E model found the exposure over 12 weeks produced by single-dose eptinezumab 100 and 300 mg exceeded the exposure estimates required to achieve 90% of the maximal efficacy (EC ). This pharmacokinetic analysis of eptinezumab supports dosing every 12 weeks with no adjustment for patient characteristics, including exposures associated with 100- or 300-mg doses producing optimal efficacy effects. The similar efficacy profiles support 100 mg as the lowest effective dose of eptinezumab.
Learn More >To explore the efficacy of cathodal tDCS applied ipsilateral to the cold patch, as determined by thermographic evaluation, in the treatment of chronic migraine. Transcranial direct current stimulation (tDCS) is a non-invasive and safe technique that modulates the activity of the underlying cerebral cortex. tDCS has been extensively tested as a possible treatment for chronic pain and migraine with controversial results mainly due to the different setting procedure and location of electrodes. Since the presence of a hypothermic patch region detected through thermography has been suggested as a possible support for headache diagnosis, this "cold patch" could considered as possible effective location for tDCS application. Forty-five patients with chronic migraine were randomized to receive either cathodal (25 patients) or sham tDCS, for 5 consecutive daily sessions plus a recall session after 1 month. Cathodal tDCS was delivered at 1.5 mA for 15 min in each session. Subjects were evaluated before treatment (baseline, T0), and after 10 (T10), 60 (T60), and 120 (T120) days after treatment. The number of attacks, duration of attacks, pain intensity, number of days with headache, and number of analgesics were collected at each time evaluation. Patients in the tDCS group showed a significant improvement compared to the sham group, during the whole study period in the frequency of migraine attacks (tDCS vs. sham: -47.8 ± 50.1% vs. -14.2 ± 16.5%, = 0.004), number of days with headache (tDCS vs. sham: -42.7 ± 65.4% vs. -11.3 ± 18.0%, = 0.015), duration of attacks (tDCS vs. sham: -29.1 ± 43.4% vs. -7.5 ± 17.6%, = 0.016), intensity of the pain during an attack (tDCS vs. sham -31.1 ± 36.9% vs. 8.3 ± 13.5%, = 0.004), and number of analgesics (tDCS vs. sham -54.3 ± 37.4% vs. -16.0 ± 19.6%, < 0.0001). Our results suggest that cathodal tDCS is an effective adjuvant technique in migraine provided that an individual correct montage of the electrodes is applied, according to thermographic investigation.
Learn More >Abdominal pain in childhood is extremely common and presents frequently to both primary and secondary care, with many children having recurrent pain which impacts on daily functioning. Despite this most children have no discernible underlying pathology. We discuss the underlying mechanism for functional abdominal pain (visceral hypersensitivity), the evidence base linking parental anxiety and patient symptoms, and how parents can be supported in managing their children's symptoms by addressing questions commonly asked by children and families. We look at the evidence for a one-stop rational approach to investigation including a coeliac screen, inflammatory markers and consideration of stool faecal calprotectin, in the absence of red flags. We evaluate commonly used treatments for functional abdominal pain, within a context of managing family expectations. Given the limitations in pharmacological treatment options, trials of probiotics, peppermint oil, mebeverine and (for short-term use only) hyoscine butylbromide may be appropriate. Psychological interventions including cognitive-behavioural therapy, distraction techniques and hypnotherapy have a better evidence base. There is also some evidence for other complementary therapies in children, including yoga and neurostimulation. Outcome is generally good providing there is child and family acceptance of the multiple factors implicated in the aetiology of the pain.
Learn More >To synthesize the epidemiological findings for the associations between dysmenorrhea, including primary dysmenorrhea and endometriosis-associated dysmenorrhea, and any chronic pain conditions, including chronic pelvic pain, and chronic non-pelvic pain.
Learn More >Dietary patterns may play an important role in musculoskeletal well-being. However, the link between dietary patterns, the components of patients' diet, and chronic musculoskeletal pain remains unclear. Therefore, the purpose of this review was to systematically review the literature on the link between dietary patterns, the components of patients' diet and chronic musculoskeletal pain. This review was conducted following the "Preferred Reporting Items for Systematic reviews and Meta-Analyses" (PRISMA) guidelines and was registered in PROSPERO with the registration number CRD42018110782. PubMed, Web of Science, and Embase online databases were searched. After screening titles and abstracts of 20,316 articles and full texts of 347 articles, 12 eligible articles were included in this review, consisting of nine experimental and three observational studies. Seven out of nine experimental studies reported a pain-relieving effect of dietary changes. Additionally, protein, fat, and sugar intake were found to be associated with pain intensity and pain threshold. In conclusion, plant-based diets might have pain relieving effects on chronic musculoskeletal pain. Patients with chronic rheumatoid arthritis pain can show inadequate intake of calcium, folate, zinc, magnesium, and vitamin B6, whilst patients with fibromyalgia can show a lower intake of carbohydrates, proteins, lipids, vitamin A-E-K, folate, selenium, and zinc. Chronic pain severity also shows a positive relation with fat and sugar intake in osteoarthritis, and pain threshold shows a positive association with protein intake in fibromyalgia.
Learn More >The effectiveness of physiotherapy in patients with chronic low back pain is usually measured through changes in pain and disability domains. However, recent research has suggested that these two domains are not sufficient to capture all the physiotherapy benefits when patients' perspective is considered.
Learn More >SHANK3 is one of the scaffolding proteins in the postsynaptic density (PSD). Pain perception and underlying mechanisms were investigated in Shank3 exon 21 deficient (Shank3) mice. Sixty-six mice were attributed according to their genotype to three groups: (1) wild-type (WT), (2) heterozygous Shank3, and (3) homozygous Shank3. Complete Freund's adjuvant (CFA) was used to induce inflammatory pain, and thermal hyperalgesia was determined. CFA treatment reduced the thermal threshold in the WT group; groups expressing mutations of Shank3 ( and ) had higher thresholds after CFA administration compared to the WT group. Mice with Shank3 mutations ( or ) had a lower expression of GluN2A and IPR proteins and a higher expression of mGluR5 protein in the PSD compared to WT mice without changes in GluN1, GluN2B, and Homer expression. The crosslinking of Homer-IPR, but not Homer-mGluR5, was decreased in the total lysate. Deficit of Shank3 exon 21 may lead to impaired perception of thermal pain in mice under inflammatory conditions. This impairment may result from protein dysregulation in the PSD like downregulation of the GluN2A subunit, which may reduce NMDAR-mediated currents, and/or decreased crosslinking between Homer and IPR, which may reduce the release of Ca from intracellular stores.
Learn More >Astrocytes mediate a remarkable variety of cellular functions, including gliotransmitter release. Under pathological conditions, high concentrations of the purinergic receptor agonist adenosine triphosphate (ATP) are released into the extracellular space leading to the activation of the purinergic P2X7 receptor, which in turn can initiate signaling cascades. It is well-established that reactive oxygen species (ROS) increase in macrophages and microglia following P2X7 receptor activation. However, direct evidence that activation of P2X7 receptor leads to ROS production in astrocytes is lacking to date. While it is known that P2X7R activation induces cytokine production, the mechanism involved in this process is unclear. In the present study, we demonstrated that P2X7 receptor activation induced ROS production in spinal astrocytes in a concentration-dependent manner. We also found that P2X7R-mediated ROS production is at least partially through NADPH oxidase. In addition, our ELISA data show that P2X7R-induced IL-6 release was dependent on NADPH oxidase-mediated production of ROS. Collectively, these results reveal that activation of the P2X7 receptor on spinal astrocytes increases ROS production through NADPH oxidase, subsequently leading to IL-6 release. Our results reveal a role of ROS in the P2X7 signaling pathway in mouse spinal cord astrocytes and may indicate a potential mechanism for the astrocytic P2X7 receptor in chronic pain.
Learn More >Chronic pain and opioid use are associated with increased risk for suicidal ideation and behaviors (SIB) in cross-sectional studies, particularly among individuals who catastrophize about their pain. This study examined the longitudinal association between two styles of pain coping, catastrophizing and hoping/praying, as predictors of subsequent SIB, as well as possible mediators of this association among patients with chronic pain receiving long-term opioid therapy. Participants (n = 496) were adults with chronic nonmalignant pain on long-term opioid therapy who did not develop an opioid use disorder. Participants were assessed for pain coping, suicidal ideation, depression, social support and pain interference at baseline, and were reassessed for SI, depression, and pain interference at 6- and 12-month follow-ups. Catastrophizing was a significant predictor of increased subsequent SIB, whereas hoping/praying did not protect against future SIB. The relationship between catastrophizing and future SIB was mediated by depression, but not social support or pain interference. In conclusion, catastrophizing was an important predictor of subsequent SIB due to its effect on increasing depression among patients with chronic nonmalignant pain receiving long-term opioid therapy. Future research should explore the extent to which targeting catastrophizing reduces subsequent depression and suicide risk.
Learn More >Apart from the known efficacy of Botulinum Neurotoxin Type A (BoNT/A) in hyperactive striated and smooth muscles, different pain states have become potential targets of toxin effects. This present study determined the comparative toxin effectiveness in pain reduction among those patients injected with BoNT/A in muscle-based and in non-muscle-based conditions. Randomized controlled trials (RCTs) on the effect of BoNT/A on selected pain conditions were included. The conditions were spasticity and dystonia for muscle-based pain. For non-muscle-based pain, conditions included were painful diabetic neuropathy (PDN), post-herpetic neuralgia (PHN), trigeminal neuralgia (TN), complex regional pain syndrome (CRPS), and spinal cord injury (SCI). In view of possibly differing pathophysiology, myofascial pain, temporomandibular joint (TMJ), other joint or tendon pains, cervicogenic and lumbar pains, migraine and visceral pain syndromes were excluded. Standardized mean difference was used as the effect measure and computed with STATA. 25 RCTs were analyzed. Pooled estimates showed significantly lower pain score in the Treatment group (z = 5.23, p < 0.01, 95% CI = - 0.75, - 0.34). Subgroup analyses showed that BoNT/A significantly reduced both muscle-based (z = 3.78, p < 0.01, 95% CI = - 0.72, - 0.23) and non-muscle-based (z = 3.37, p = 0.001, 95% CI = - 1.00, - 0.27) pain. Meta-regression using four covariates namely dosage, route, frequency and duration was done which revealed that dosage significantly affects standardized mean differences, while the other three covariates were insignificant. The joint F-test was found to be insignificant (p value = 0.1182). The application of the model with these covariates does not significantly explain the derived heterogeneity of standardized mean differences. In conclusion, BoNT/A can be effectively used in muscle-based and non-muscle-based pain disorders. We detected no difference between the presence and magnitude of pain relief favoring muscle-based compared to non-muscle-based pain. Thus, we cannot say whether or not there might be independent mechanisms of toxin-induced pain relief for pain generated from either muscle or nerve hyperactivity.
Learn More >Secondary analysis of health administrative databases is indispensable to enriching our understanding of health trajectories, health care utilization, and real-world risks and benefits of drugs among large populations.
Learn More >Spinal cord injury (SCI) is one of the most devastating diseases with a high incidence rate around the world. SCI-related neuropathic pain (NeP) is a common complication, whereas its pathomechanism is still unclear. The purpose of this study is to identify key genes and cellular components for SCI-related NeP by an integrated transcriptome bioinformatics analysis.
Learn More >Characteristics of the vaginal microbiome in women with and without clinically confirmed vulvodynia.
Vulvodynia (idiopathic vulvar pain) affects up to 8% of women by age 40, has a poorly understood etiology, and variable treatment efficacy. Several risk factors are associated with vulvodynia from history of yeast infections to depression and allergies. Recent work suggests an altered immune inflammatory mechanism plays a role in vulvodynia pathophysiology. As the vaginal microbiome plays an important role in local immune-inflammatory responses, we evaluated the vaginal microbiome among women with vulvodynia compared to controls as one component of the immune system.
Learn More >Chronic pelvic pain (CPP) in women is often associated with marked emotional distress and disability, with particular impairments in sexual functioning. Research supports the efficacy of interdisciplinary chronic pain rehabilitation programs (ICPRPs) in treating chronic pain, however less is known about their utility in CPP. This retrospective study examined pain-related sexual impairment, emotional symptoms, and pain severity in CPP patients before and after completing a 3-4 week ICPRP. Predictors of post-treatment sexual impairment were also investigated. Participants included 58 female CPP patients and 58 age-matched females with non-pelvic chronic pain (NPCP). All participants reported robust improvements across outcome measures. Women with CPP reported greater pre- and post-treatment impairment in sexual function than NPCP patients, despite significant treatment-related improvements. In contrast, CPP patients also reported higher levels of depression at baseline but showed greater treatment related-improvements. In participants with CPP, treatment-related improvements in depression, alexithymia, and pain severity significantly explained decreases in pain-related sexual impairment following treatment, whereas none of these variables explained sexual impairment outcomes in women with NPCP. Results demonstrate that ICPRPs can effectively treat CPP, particularly through changes in depression and alexithymia. Future research should examine whether specific interventions can be added in ICPRPS to address CPP-related sexual impairment.
Learn More >The signs and symptoms of persistent temporomandibular joint (TMJ)/muscle disorder (TMJD) pain suggest the existence of a central neural dysfunction or a problem of pain amplification. The etiology of chronic TMJD is not known; however, female sex hormones have been identified as significant risk factors. Converging lines of evidence indicate that the junctional region between the trigeminal subnucleus caudalis (Vc) and the upper cervical spinal cord, termed the Vc/C1-2 region, is the primary site for the synaptic integration of sensory input from TMJ nociceptors. In this paper, the mechanisms behind the estrogen effects on the processing of nociceptive inputs by neurons in the Vc/C1-2 region reported by human and animal studies are reviewed. The Vc/C1-2 region has direct connections to endogenous pain and autonomic control pathways, which are modified by estrogen status and are suggested to be critical for somatomotor and autonomic reflex responses of TMJ-related sensory signals.
Learn More >Recently, clinicians have been using repetitive transcranial magnetic stimulation (rTMS) for treating various pain conditions. This systematic narrative review aimed to examine the use and efficacy of rTMS for controlling various pain conditions. A PubMed search was conducted for articles that were published until June 7, 2019 and used rTMS for pain alleviation. The key search phrase for identifying potentially relevant articles was (repetitive transcranial magnetic stimulation AND pain). The following inclusion criteria were applied for article selection: (1) patients with pain, (2) rTMS was applied for pain management, and (3) follow-up evaluations were performed after rTMS stimulation to assess the reduction in pain. Review articles were excluded. Overall, 1,030 potentially relevant articles were identified. After reading the titles and abstracts and assessing eligibility based on the full-text articles, 106 publications were finally included in our analysis. Overall, our findings suggested that rTMS is beneficial for treating neuropathic pain of various origins, such as central pain, pain from peripheral nerve disorders, fibromyalgia, and migraine. Although data on the use of rTMS for orofacial pain, including trigeminal neuralgia, phantom pain, low back pain, myofascial pain syndrome, pelvic pain, and complex regional pain syndrome, were promising, there was insufficient evidence to determine the efficacy of rTMS for treating these conditions. Therefore, further studies are needed to validate the effects of rTMS on pain relief in these conditions. Overall, this review will help guide clinicians in making informed decisions regarding whether rTMS is an appropriate option for managing various pain conditions.
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