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Supportive touch has remarkable benefits in childbirth and during painful medical procedures. But does social touch influence pain neurophysiology, ie, the brain processes linked to nociception and primary pain experience? What other brain processes beyond primary pain systems mediate their analgesic effects? In this study, women (N = 30) experienced thermal pain while holding their romantic partner's hand or an inert device. Social touch reduced pain and attenuated functional magnetic resonance imaging activity in the Neurologic Pain Signature (NPS)-a multivariate brain pattern sensitive and specific to somatic pain-and increased connectivity between the NPS and both somatosensory and "default mode" regions. Brain correlates of touch-induced analgesia included reduced pain-related activation in (1) regions targeted by primary nociceptive afferents (eg, posterior insula, and anterior cingulate cortex); and (b) regions associated with affective value (orbitofrontal cortex), meaning (ventromedial prefrontal cortex [PFC]), and attentional regulation (dorsolateral PFC). Activation reductions during handholding (vs holding a rubber device) significantly mediated reductions in pain intensity and unpleasantness; greater pain reductions during handholding correlated with greater increases in emotional comfort, which correlated with higher perceived relationship quality and (a trend toward) greater perceived closeness with the romantic partner. The strongest mediators of analgesia were activity reductions in a brain circuit traditionally associated with stress and defensive behavior in mammals, including ventromedial and dorsomedial PFC, rostral anterior cingulate cortex, amygdala/hippocampus, hypothalamus, and periaqueductal gray matter. Social touch affects core brain processes that contribute to pain and pain-related affective distress in females, and should be considered alongside other treatments in medical and caregiving contexts.
Learn More >Migraines are a major health burden, but treatment is limited because of inadequate understanding of neural mechanisms underlying headache. Imaging studies of migraine patients demonstrate changes in both pain-modulatory circuits and reward-processing regions, but whether these changes contribute to the experience of headache is unknown. Here, we demonstrate a direct connection between the ventrolateral periaqueductal gray (vlPAG) and the ventral tegmental area (VTA) that contributes to headache aversiveness in rats. Many VTA neurons receive monosynaptic input from the vlPAG, and cranial nociceptive input increases Fos expression in VTA-projecting vlPAG neurons. Activation of PAG inputs to the VTA induces avoidance behavior, while inactivation of these projections induces a place preference only in animals with headache. This work identifies a distinct pathway that mediates cranial nociceptive aversiveness.
Learn More >Neuropathic pain can be a debilitating condition with both sensory and affective components, the underlying brain circuitry of which remains poorly understood. In the present study, a basolateral amygdala (BLA)-prefrontal cortex (PFC)-periaqueductal gray (PAG)-spinal cord pathway was identified that is critical for the development of mechanical and thermal hypersensitivity after peripheral nerve injury. It was shown that nerve injury strengthens synaptic input from the BLA onto inhibitory interneurons located in the prelimbic medial PFC, by virtue of reduced endocannabinoid modulation. These augmented synaptic connections mediate a feedforward inhibition of projections from the PFC to the ventrolateral PAG region and its downstream targets. Optogenetic approaches combined with in vivo pharmacology reveal that these BLA-PFC-PAG connections alter pain behaviors by reducing descending noradrenergic and serotoninergic modulation of spinal pain signals. Thus, a long-range brain circuit was identified that is crucial for pain processing and that can potentially be exploited toward targeting neuropathic pain.
Learn More >Small-fiber polyneuropathy involves preferential damage to the thinly myelinated A-delta fibers, unmyelinated C sensory fibers, or autonomic or trophic fibers. Although this condition is common, most patients still remain undiagnosed and untreated because of lagging medical and public awareness of research advances. Chronic bilateral neuropathic pain, fatigue, and nausea are cardinal symptoms that can cause disability and dependence, including pain medication dependence.
Learn More >TRPM8 is the primary detector of environmental cold and an important target for treating pathological cold hypersensitivity. Here, we present cryo-EM structures of TRPM8 in ligand-free, antagonist- or calcium-bound forms, revealing how robust conformational changes give rise to two non-conducting states, closed and desensitized. We describe a malleable ligand-binding pocket that accommodates drugs of diverse chemical structures, and delineate the ion permeation pathway, including the contribution of lipids to pore architecture. Furthermore, we show that direct calcium binding mediates stimulus-evoked desensitization, clarifying this important mechanism of sensory adaptation. We observe large rearrangements within the S4-S5 linker that reposition the S1-S4 and pore domains relative to the TRP helix, leading us to propose a distinct model for modulation of TRPM8 and possibly other TRP channels.
Learn More >Chemotherapy-induced neuropathic pain (CINP) in both sexes compromises many current chemotherapeutics and lacks a FDA-approved therapy. We recently identified the sphingosine-1-phosphate receptor subtype 1 (S1PR1) and A3 adenosine receptor subtype (A3AR) as novel targets for therapeutic intervention. Our work in male rodents using paclitaxel, oxaliplatin and bortezomib showed robust inhibition of CINP with either S1PR1 antagonists or A3AR agonists. The S1PR1 functional antagonist FTY720 (Gilenya®) is FDA approved for treating multiple sclerosis and selective A3AR agonists are in advanced clinical trials for cancer and inflammatory disorders, underscoring the need for their expedited trials in CINP patients as chemotherapy adjuncts. Our findings reveal that S1PR1 antagonists and A3AR agonists mitigate paclitaxel and oxaliplatin CINP in female and male rodents, but failed to block or reverse bortezomib-induced neuropathic pain (BINP) in females. Although numerous mechanisms likely underlie these differences, we focused on receptor levels. We found that BINP in male rats, but not female rats, was associated with increased expression of A3AR in spinal cord dorsal horn, while S1PR1 levels were similar in both sexes. Thus, alternative mechanisms beyond receptor expression may account for sex differences in response to S1PR1 antagonists. Morphine and duloxetine, both clinical analgesics, reversed BINP in female mice, demonstrating that the lack of response is specific to S1PR1 and A3AR agents. Our findings suggest that A3AR- and S1PR1-based therapies are not viable approaches in preventing and treating BINP in females and should inform future clinical trials of these drugs as adjuncts to chemotherapy. SUMMARY:: We have found that there are sexually dimorphic responses to S1PR1 antagonists and A3AR agonists for the treatment of bortezomib-induced neuropathic pain.
Learn More >Excessive alcohol consumption is associated with spontaneous burning pain, hyperalgesia and allodynia. Although acetaldehyde has been implicated in the painful alcoholic neuropathy, the mechanism by which the ethanol metabolite causes pain symptoms is unknown. Acute ethanol ingestion caused delayed mechanical allodynia in mice. Inhibition of alcohol dehydrogenase (ADH) or deletion of transient receptor potential ankyrin 1 (TRPA1), a sensor for oxidative and carbonyl stress, prevented allodynia. Acetaldehyde generated by ADH in both liver and Schwann cells surrounding nociceptors was required for TRPA1-induced mechanical allodynia. Plp1-Cre;Trpa1fl/fl mice with a tamoxifen-inducible specific deletion of TRPA1 in Schwann cells revealed that channel activation by acetaldehyde in these cells initiates a NADPH oxidase-1 (NOX-1)-dependent production of hydrogen peroxide (H2O2) and 4-hydroxynonenal (4-HNE), which sustains allodynia by paracrine targeting of nociceptor TRPA1. Chronic ethanol ingestion caused prolonged mechanical allodynia and loss of intraepidermal small nerve fibers in WT mice. While Trpa1-/- or Plp1-Cre;Trpa1fl/fl mice did not develop mechanical allodynia, they did not show any protection from the small fiber neuropathy. Human Schwann cells express ADH/TRPA1/NOX1 and recapitulate the proalgesic functions of mouse Schwann cells. TRPA1 antagonists might attenuate some symptoms of alcohol-related pain.
Learn More >Evidence supports the benefits of resilience among older adults with chronic pain. While numerous factors confer resilience, research has largely examined these measures in isolation, despite evidence of their synergistic effects. Conceptualizing resilience from a multisystem perspective may provide a deeper understanding of adaptive functioning in pain. Sixty adults (ages 60+ years) with chronic low back pain completed measures of physical function, pain intensity, disability, and a performance-based task assessing back-related physical functioning and movement-evoked pain (MEP). Depressive symptoms, quality of life, and general resilience were also evaluated. To examine multisystem resiliency, principal components analysis (PCA) was conducted to create composite domains for psychological (positive affect, hope, positive well-being, optimism), health (waist-hip ratio, body mass index, medical comorbidities), and social (emotional, instrumental, informational support) functioning measures, followed by cluster analysis to identify participant subgroups based upon composites. Results yielded four clusters: Cluster 1 (high levels of functioning across psychological, health, and social support domains); Cluster 2 (optimal health and low psychosocial functioning); Cluster 3 (high psychological function, moderate-to-high social support, and poorer health); and Cluster 4 (low levels of functioning across the three domains). Controlling for sociodemographic characteristics, individuals with a more resilient phenotype (Cluster 1) exhibited lower levels of disability, higher quality of life and psychological functioning, and greater functional performance when compared to those with a lower degree of personal resources (Cluster 4). No significant cluster differences emerged in self-reported pain intensity or MEP. These findings signify the presence of resiliency profiles based upon psychological, social, and health-related functioning. Further examination of the additive effects of multiple adaptive behaviors and resources may improve our understanding of resilience in the context of pain, informing novel interventions for older adults.
Learn More >The ACCURATE randomized, controlled trial compared outcomes of dorsal root ganglion (DRG) stimulation versus tonic spinal cord stimulation (SCS) in 152 subjects with chronic lower extremity pain due to complex regional pain syndrome (CRPS) type I or II. This ACCURATE sub-study was designed to evaluate whether therapy habituation occurs with DRG stimulation as compared to SCS through 12-months. A modified intention-to-treat analysis was performed to assess percentage pain relief (PPR) and responder rates at follow-up visits (end-of-trial, 1, 3, 6, 9, 12-months post-permanent implant) for all subjects that completed trial stimulation (DRG:N=73, SCS_N=72). For both groups, mean PPR was significantly greater at end-of-trial (DRG:82.2%, SCS:77.0%) than all other follow-ups. Following permanent DRG system implantation, none of the time points were significantly different from one another in PPR (range:69.3-73.9%). For the SCS group, PPR at 9-months (58.3%) and 12-months (57.9%) was significantly less than at 1-month (66.9%). The responder rate also decreased for the SCS group from 1-month (68.1%) to 12-months (61.1%). After stratifying by diagnosis, it was found that only the CRPS-I population had diminishing pain relief with SCS. DRG stimulation resulted in more stable pain relief through 12-months, while tonic SCS demonstrated therapy habituation at 9- and 12-months. Trial Registration: The ACCURATE study was registered at ClinicalTrials.gov with Identifier NCT01923285. Perspective: This article reports on an ACCURATE sub-study, which found that long-term therapy habituation occurred at 12-months with SCS, but not DRG stimulation, in patients with CRPS. The underlying mechanisms of action for these results remain unclear, although several lines of inquiry are proposed.
Learn More >This longitudinal case-control study aims to 1) compare symptoms and functioning in otherwise healthy adolescents with versus without a parent with chronic pain (Parent CP+/Parent CP-) 2) test adolescent sex as a moderator of the relation between parent CP group and child functioning, and 3) determine changes in adolescent pain over one year. Adolescents (n=140; ages 11-15) completed tests of pain responsivity and physical function, as well as self-report measures assessing pain characteristics, somatic symptoms, and physical and psychosocial functioning. Self-reported pain and somatic symptoms were re-assessed one year later. Adolescents in the Parent CP+ group reported greater pain, somatic symptoms, and worse physical health than Parent CP- youth. Parent CP+ youth performed worse on all tests of physical function. Some observed effects were stronger for girls than boys. There were no differences between groups on pain responsivity. Both groups reported increased pain and somatic symptoms from baseline to one-year follow-up, with the Parent CP+ group reporting the highest level of symptoms at both time points. This study highlights the potential impact of parental pain status on children, particularly daughters, and is the first to document objective physical functioning differences in youth at risk for developing chronic pain. Perspective: Adolescents who have a parent with chronic pain demonstrate higher pain and lower physical function than adolescents who have a parent without chronic pain. Group differences in pain and somatic symptoms persist over one year. Family based interventions are needed for comprehensive pain prevention and treatment.
Learn More >Oxytocin has been shown to increase trust, decrease anxiety and affect learning as has been observed in conditioning paradigms. Trust, anxiety and learning are important factors that influence placebo effects. In this study we investigated whether oxytocin can increase placebo analgesia, decrease nocebo hyperalgesia, and influence extinction processes of both. Eighty male volunteers were assigned to a 40 IU of oxytocin nasal spray group, or to a placebo control group. Placebo analgesia and nocebo hyperalgesia were induced by a conditioning procedure in combination with verbal suggestions. The results demonstrate that the conditioning procedure successfully elicited significant placebo analgesia and nocebo hyperalgesia responses (p < .001). Furthermore, extinction was observed (p < .001), although placebo and nocebo responses did not return to baseline and remained significant. Oxytocin did not influence placebo analgesia or nocebo hyperalgesia and had no effect on extinction. This study provides support against the placebo-boosting effects of oxytocin and was the first one to demonstrate that it also did not influence nocebo effects or extinction processes, however, these results pertain to only a male sample. As managing placebo and nocebo effects has widespread clinical implications, further research should investigate other neurobiological or behavioral pathways to boost placebo and decrease nocebo effects. Trial registration: The study protocol was preregistered on the website www.trialregister.nl under the number NTR6506. Perspective: The present study demonstrated that placebo analgesia and nocebo hyperalgesia can be successfully induced by conditioning and verbal suggestions. We could not confirm the hypothesis that oxytocin affects either of these phenomena. Other pharmacological agents and behavioral manipulations for increasing placebo and decreasing nocebo effects should be investigated.
Learn More >Orofacial pain is characterized by its easy spread to adjacent areas, thus presenting with primary hyperalgesia (hypersensitivity at the site of injury) and secondary hyperalgesia (extra-territorial hypersensitivity outside the injured zone). However, the mechanisms behind the secondary hyperalgesia are poorly understood. In the present study, we used a mouse model of partial transection of the infraorbital nerve (pT-ION) to study whether calcium channel subunit α2δ1 (Cavα2δ1) and its downstream signaling contributes to the development of secondary hyperalgesia in the orofacial area. pT-ION caused primary (V2 skin) and secondary (V3 skin) hyperalgesia, which was reversed by the Cavα2δ1 antagonist gabapentin and by the expression of Cavα2δ1-targeting interfering RNA in trigeminal ganglion (TG)-V3 neurons. pT-ION induced increased expression of PKC and TRPA1, which was reversed by Cavα2δ1-targeting interfering RNA, and PKC inhibition reversed the upregulation of TRPA1 and gap junction (GJ) proteins induced by pT-ION. Cavα2δ1 overexpression in TG-V2 neurons induced the upregulation of PKC, TRPA1, and the GJ proteins in the TG and trigeminal subnucleus caudalis and induced hypersensitivity in the V3 skin area, which was reversed by TRPA1, GJ, or PKC blockade. Thus, we conclude that Cavα2δ1 contributes to the development of secondary hyperalgesia through its downstream PKC-TRPA1/GJ signaling pathways. Perspective: This study demonstrates that the activation of Cavα2δ1 and the downstream PKC-TRPA1/GJ signaling pathway contributes greatly to trigeminal nerve injury-induced secondary mechanical and cold hyperalgesia. This suggests that inhibitors of Cavα2δ1, TRPA1, or GJs might be effective treatments for nerve injury-induced spreading of orofacial pain.
Learn More >Mechanisms of below-level pain are discoverable as rostral neural adaptations to spinal injury. Accordingly, the strategy of investigations summarized here has been to characterize behavioral and neural responses to below-level stimulation over time following selective lesions of spinal gray and/or white matter. Assessments of human pain and the pain sensitivity of humans and laboratory animals following spinal injury have revealed common disruptions of pain processing. Interruption of the spinothalamic pathway partially deafferents nocireceptive cerebral neurons, rendering them spontaneously active and hypersensitive to remaining inputs. The spontaneous activity among these neurons is disorganized and unlikely to generate pain. However, activation of these neurons by their remaining inputs can result in chronic pain. Also, injury to spinal gray matter results in a cascade of secondary events, including excitotoxicity, with rostral propagation of excitatory influences that contribute to activation of deafferented neurons and chronic pain. Establishment and maintenance of below-level pain results from combined influences of injured and spared axons in the spinal white matter and injured neurons in spinal gray matter on processing of nociception by hyperexcitable cerebral neurons that are partially deafferented. A model of spinal stenosis suggests that ischemic injury to the core spinal region can generate below-level pain. Additional questions are raised about demyelination, epileptic discharge, autonomic activation, prolonged activity of C nocireceptive neurons and thalamocortical plasticity in the generation of below-level pain. PERSPECTIVE: An understanding of mechanisms can direct therapeutic approaches to prevent development of below-level pain or arrest it following SCI. Among the possibilities covered here are surgical and other means of attenuating gray matter excitotoxicity and ascending propagation of excitatory influences from spinal lesions to thalamocortical systems involved in pain encoding and arousal.
Learn More >The cornea is extensively innervated by trigeminal ganglion cold thermoreceptor neurons expressing TRPM8. These neurons respond to cooling, hyperosmolarity and wetness of the corneal surface. Surgical injury of corneal nerve fibers alters tear production and often causes dry eye sensation. The contribution of TRPM8-expressing corneal cold-sensitive neurons (CCSNs) to these symptoms is unclear. Using extracellular recording of CCSNs nerve terminals combined with confocal tracking of re-innervation, Ca imaging and patch-clamp recordings of fluorescent retrogradely labeled corneal neurons in culture, we analyzed the functional modifications of CCSNs induced by peripheral axonal damage in male mice. After injury, the percentage of CCSNs, the cold- and menthol-evoked intracellular [Ca] rises and TRPM8-current density in CCSNs were larger than in sham animals, with no differences in the brake K current I Active and passive membrane properties of CCSNs from both groups were alike, and corresponded mainly to those of canonical low- and high-threshold cold thermoreceptor neurons. Ongoing firing activity and menthol-sensitivity were higher in CCSN terminals of injured mice, an observation accounted by mathematical modeling. These functional changes developed in parallel with a partial re-innervation of the cornea by TRPM8(+) fibers and with an increase in basal tearing in injured animals compared to sham mice. Our results unveil key TRPM8-dependent functional changes in CCSNs in response to injury, suggesting that increased tearing rate and ocular dryness sensation derived from deep surgical ablation of corneal nerves are due to enhanced functional expression of TRPM8 channels in these injured trigeminal primary sensory neurons.This paper unveils a key role of TRPM8 in the sensory and autonomic disturbances associated with surgical damage of eye surface nerves. We studied the damage-induced functional alterations of corneal cold-sensitive neurons using confocal tracking of re-innervation, extracellular corneal nerve terminal recordings, tearing measurements Ca imaging and patch-clamp recordings of cultured corneal neurons, and mathematical modeling. Corneal nerve ablation upregulates TRPM8 mainly in canonical cold thermoreceptors, enhancing their cold- and menthol-sensitivity, inducing a rise in the ongoing firing activity of TRPM8(+) nerve endings and an increase in basal tearing. Our results suggest that unpleasant dryness sensations together with augmented tearing rate following corneal nerve injury are largely due to upregulation of TRPM8 in cold thermoreceptor neurons.
Learn More >Patients with liver diseases often suffer from chronic itch, yet the pruritogen(s) and receptor(s) remain largely elusive. Here, we identify bile acids as natural ligands for MRGPRX4. MRGPRX4 is expressed in human dorsal root ganglion (hDRG) neurons and co-expresses with itch receptor HRH1. Bile acids elicited Ca responses in cultured hDRG neurons, and bile acids or a MRGPRX4 specific agonist induced itch in human subjects. However, a specific agonist for another bile acid receptor TGR5 failed to induce itch in human subjects and we find that human TGR5 is not expressed in hDRG neurons. Finally, we show positive correlation between cholestatic itch and plasma bile acids level in itchy patients and the elevated bile acids is sufficient to activate MRGPRX4. Taken together, our data strongly suggest that MRGPRX4 is a novel bile acid receptor that likely underlies cholestatic itch in human, providing a promising new drug target for anti-itch therapies.
Learn More >There are conflicting results about sex differences in the response to opioids for pain control and the role of potential influencing factors of these differences has not been investigated. We meta-analyzed differences and similarities between men and women in opioid response for pain control and investigated the potential influence of baseline pain intensity, age, body weight, and other factors in these findings. PubMed, Scopus, and Cochrane CENTRAL were searched through January 15, 2019, for clinical studies in which opioids were administered for pain control. We included clinical studies in which (a) opioids were used to treat acute or chronic pain, (b) the response to opioids was broken down for men and women, and (c) the response to opioids was reported as (i) difference between baseline and final Visual Analog Scale of Pain Intensity (VASPI) score 30 minutes after opioid administration (Delta-VASPI at 30'), or daily dose of opioids (ii) self-administered by patients (patient-controlled analgesia PCA), or (iii) administered by physicians. Risk of bias was evaluated using ROBINS-I and the overall quality of evidence for primary outcomes was evaluated using the GRADE system. Globally, we included 40 comparisons (6,794 patients). Regarding acute pain, we found moderate quality of evidence that women and men do not differ in their response to opioids 30 minutes after their administration [Delta-VASPI at 30': mean difference, MD = 0.42 (-0.07; 0.91)]. We also found moderate quality of evidence that women self-administer lower daily amounts of opioids [daily PCA: standardized mean difference, SMD = -0.30 (-0.41; -0.18)]. Regarding chronic pain, we found low quality of evidence that women receive lower daily doses for non-cancer pain [MD = -36.42 (-57.86; -14.99)]. By contrast, we found very low quality of evidence that women and men do not differ in the daily dose of opioids for cancer pain [MD = -16.09 (-40.13; 7.94)]. Age, comorbid mental disorders, type of administration, type of opioids, type of patients, and body weight significantly modified these results. In conclusion, the results of the present meta-analysis suggest that men and women may differ in the response to opioids for pain relief, but these differences as well as similarities are significantly influenced by factors like age and comorbid mental disorders. However, the role of these factors is not usually evaluated in the prescription of opioids for pain control. There is an urgent need to conduct clinical trials on the use of opioid medications for pain, in which information about all possible influencing factors are provided and broken down for men and women.
Learn More >Of the fast ionotropic synapses, glycinergic synapses are the least well understood, but are vital for the maintenance of inhibitory signaling in the brain and spinal cord. Glycinergic signaling comprises half of the inhibitory signaling in the spinal cord, and glycinergic synapses are likely to regulate local nociceptive processing as well as the transmission to the brain of peripheral nociceptive information. Here we have investigated the rapid and prolonged potentiation of glycinergic synapses in the superficial dorsal horn of young male and female mice after brief activation of NMDA receptors (NMDARs). Glycinergic inhibitory postsynaptic currents (IPSCs) evoked with lamina II-III stimulation in identified GABAergic neurons in lamina II were potentiated by bath-applied Zn2+ and were depressed by the prostaglandin PGE2, consistent with the presence of both GlyRα1- and GlyRα3-containing receptors. NMDA application rapidly potentiated synaptic glycinergic currents. Whole-cell currents evoked by exogenous glycine were also readily potentiated by NMDA, indicating that the potentiation results from altered numbers or conductance of postsynaptic glycine receptors. Repetitive depolarization alone of the postsynaptic GABAergic neuron also potentiated glycinergic synapses, and intracellular EGTA prevented both NMDA-induced and depolarization-induced potentiation of glycinergic IPSCs. Optogenetic activation of trpv1 lineage afferents also triggered NMDAR-dependent potentiation of glycinergic synapses. Our results suggest that during peripheral injury or inflammation, nociceptor firing during injury is likely to potentiate glycinergic synapses on GABAergic neurons. This disinhibition mechanism may be engaged rapidly, altering dorsal horn circuitry to promote the transmission of nociceptive information to the brain.
Learn More >This study sets out to identify potential daily antecedents and consequences of pain-related activity avoidance and engagement behavior in adolescents with chronic pain.
Learn More >For many people with advanced osteoarthritis, total knee replacement (TKR) is an effective treatment for relieving pain and improving function. Features of perioperative care may be associated with the adverse event of chronic pain 6 months or longer after surgery; effects may be direct, for example, through nerve damage or surgical complications, or indirect through adverse events. This systematic review aims to evaluate whether non-surgical perioperative interventions prevent long-term pain after TKR.
Learn More >Adenosine is a signaling molecule induced under stress such as energy insufficiency and ischemic/hypoxic conditions. Adenosine controls multiple physiological and pathological cellular and tissue function by activation of four G protein-coupled receptors (GPCR). Functional role of adenosine signaling in acute pain has been widely studied. However, the role of adenosine signaling in chronic pain is poorly understood. At acute levels, adenosine can be beneficial to anti-pain whereas a sustained elevation of adenosine can be detrimental to promote chronic pain. In recent years, extensive progress has been made to define the role of adenosine signaling in chronic pain and to dissect molecular new insight underlying the development of chronic pain. In this review, we summarize the differential role of adenosine signaling cascade in acute and chronic pain with a major focus on recent studies revealing adenosine ADORA2B receptor activation in the pathology of chronic pain. We further provide a therapeutic outlook of how multiple adenosine signaling components can be useful to treat chronic pain.
Learn More >Adult brain structures such as the hippocampus are highly plastic to learning and gaining new experiences. Recent studies reveal that cortical areas that respond to sensory noxious stimuli (stimuli that cause pain in humans) are also highly plastic, like the learning-related hippocampus. Long-term potentiation (LTP), a key cellular model for learning and memory, is reported in the anterior cingulate cortex (ACC) and insular cortex (IC), two key cortical areas for pain perception. ACC and IC LTP exist in at least two major forms: presynaptically expressed LTP, and postsynaptically expressed LTP (post-LTP). In this short review, I will review, recent progress made in cortical LTPs, and explore potential roles of other forms of LTPs such as synaptic tagging. Their contribution to chronic pain as well as emotional changes caused by injury will be discussed.
Learn More >Migraine is a major public health problem afflicting approximately 10% of the general population and is a leading cause of disability worldwide, yet our understanding of the basis mechanisms of migraine remains incomplete. About a third of migraine patients have attacks with aura, consisting of transient neurological symptoms that precede or accompany headache, or occur without headache. For patients, aura symptoms are alarming and may be transiently disabling. For clinicians and scientists, aura represents an intriguing neurophysiological event that may provide important insight into basic mechanisms of migraine. Several observations point toward important differences between migraine with and without aura. Compared with migraine without aura, migraine with aura has different heritability, greater association with different conditions including stroke, different alterations of brain structure and function as revealed by imaging studies. A number of studies also indicate that migraine with aura may respond differently to acute and preventive therapies as compared to migraine without aura. The purpose of this review is to provide an overview of these differences in treatment responses, and to discuss the possibility of different therapeutic strategies for migraine with vs. without aura.
Learn More >Persistent pain is associated with negative affect originating from hypersensitivity and/or allodynia. The spinal cord is a key area for nociception as well as chronic pain processing. Specifically, the dorsal horn neurons in lamina II (substantia gelatinosa: SG) receive nociceptive inputs from primary afferents such as C fibers and/or Aδ fibers. Transient receptor potential vanilloid 1 (TRPV1) is a major receptor to sense heat as well as nociception. TRPV1 are expressed in the periphery and the central axon terminals of C fibers and/or Aδ fibers in the spinal cord. Activating TRPV1 enhances the release of glutamate in the spinal cord from naïve rodents. Here, we studied whether or not chronic pain could alter the response of TRPV1 channels to exogenous, capsaicin through study of synaptic transmission and neural activity in rat SG neurons. Using in vitro whole-cell patch-clamp recording, we found that bath application of capsaicin facilitated both the frequency and amplitude of miniature and spontaneous excitatory postsynaptic currents beyond a nerve injury and a complete Freund's adjuvant injection observed in the naïve group. Strikingly, capsaicin produced larger amplitudes of inward currents in pain models than compared to the naïve group. By contrast, the proportions of neurons that show capsaicin-induced inward currents were similar among naïve and pain groups. Importantly, the capsaicin-induced inward currents were conducted by TRPV1 and required calcium influx that was independent of voltage-gated calcium channels. Our study provides fundamental evidence that chronic inflammation and neuropathic pain models amplify the release of glutamate through the activation of TRPV1 in central axon terminals, and that facilitation of TRPV1 function in rat spinal SG neurons may contribute to enhanced capsaicin-induced inward currents.
Learn More >Itch is a highly prevalent and multi-dimensional symptom. We aimed to analyze the association between itch and mental health in dermatological patients. This multi-center study is observational cross-sectional conducted in dermatological clinics across 13 European countries. A total of 3530 patients and 1094 healthy controls were included. Patients were examined clinically. Outcome measures were itch (presence, chronicity and intensity), the Hospital Anxiety and Depression Scale, EQ5D-VAS, sociodemographics, suicidal ideation, stress (negative life events and economic difficulties). Ethical approval was obtained. Results showed significant association between the presence of itch in patients and clinical depression, suicidal ideation and economic difficulties (odds ratios respectively OR 1.53 (95% CI 1.15 to 2.02), OR 1.27 (95% CI 1.01 to 1.60), OR 1.24 (95% CI 1.10 to 1.50). The mean score of reported generic health status assessed by the EQ5D-VAS was 65.9 (SD=20.1) in patients with itch, compared to 74.7 (SD= 18.0) in patients without itch, p value < .001 and 74.9 (SD= 15.7) in controls with itch compared to 82.9 (SD= 15.6) in controls without itch, p value <.001. Itch contributes substantially to the psychological disease burden in dermatological patients and the management of patients should include access to multidisciplinary care.
Learn More >The amygdala plays a key role in emotional-affective aspects of pain and in pain modulation. The central nucleus (CeA) serves major amygdala output functions related to emotional-affective behaviors and pain modulation. Our previous studies implicated the corticotropin-releasing factor (CRF) system in amygdala plasticity and pain behaviors in an arthritis model. We also showed that serotonin (5-HT) receptor subtype 5-HTR in the basolateral amygdala (BLA) contributes to increased CeA output and neuropathic pain-like behaviors. Here, we tested the novel hypothesis that 5-HTR in the BLA drives CRF1 receptor activation to increase CeA neuronal activity in neuropathic pain. Extracellular single-unit recordings of CeA neurons in anesthetized adult male rats detected increased activity in neuropathic rats (spinal nerve ligation model) compared to sham controls. Increased CeA activity was blocked by local knockdown or pharmacological blockade of 5-HTR in the BLA, using stereotaxic administration of 5-HTR short hairpin RNA (shRNA) viral vector or a 5-HTR antagonist (SB242084), respectively. Stereotaxic administration of a CRF1 receptor antagonist (NBI27914) into the BLA also decreased CeA activity in neuropathic rats and blocked the facilitatory effects of a 5-HTR agonist (WAY161503) administered stereotaxically into the BLA. Conversely, local (BLA) knockdown of 5-HTR eliminated the inhibitory effect of NBI27914 and the facilitatory effect of WAY161503 in neuropathic rats. The data suggest that 5-HTR activation in the BLA contributes to neuropathic pain-related amygdala (CeA) activity by engaging CRF1 receptor signaling.
Learn More >Endometriosis is a chronic inflammatory disease defined as the presence of endometrial tissue outside the uterus, which causes pelvic pain and infertility. This disease should be viewed as a public health problem with a major effect on the quality of life of women as well as being a substantial economic burden. In light of the considerable progress with diagnostic imaging (for example, transvaginal ultrasound and MRI), exploratory laparoscopy should no longer be used to diagnose endometriotic lesions. Instead, diagnosis of endometriosis should be based on a structured process involving the combination of patient interviews, clinical examination and imaging. Notably, a diagnosis of endometriosis often leads to immediate surgery. Therefore, rethinking the diagnosis and management of endometriosis is warranted. Instead of assessing endometriosis on the day of the diagnosis, gynaecologists should consider the patient's 'endometriosis life'. Medical treatment is the first-line therapeutic option for patients with pelvic pain and no desire for immediate pregnancy. In women with infertility, careful consideration should be made regarding whether to provide assisted reproductive technologies prior to performing endometriosis surgery. Modern endometriosis management should be individualized with a patient-centred, multi-modal and interdisciplinary integrated approach.
Learn More >Fatigue is commonly reported by people with chronic pain. The purpose of the current study was to examine Acceptance and Commitment Therapy (ACT), based on the Psychological Flexibility (PF) model, for fatigue in chronic pain. This study included 354 adults attending an interdisciplinary ACT-oriented treatment for chronic pain. T-tests and analyses of clinically meaningful change were used to investigate participant improvements in fatigue interference after the treatment. Pearson's correlations and hierarchical regressions were conducted to investigate associations between improvement in fatigue interference and improvements in PF processes. Finally, mixed effects models were used to explore associations between baseline fatigue interference and changes in treatment outcome measures. Participants improved in fatigue interference (d=.37), pain, some PF processes, and daily functioning (d=.18-1.08). 39.7% of participants demonstrated clinically meaningfully improvements in fatigue interference. Changes in fatigue interference was associated with changes in pain, PF processes and daily functioning, |r|= .20-.46. Change in fatigue interference was associated with change in pain acceptance independent of change in pain, β=-.36, p<.001. However, baseline fatigue interference did not predict any treatment outcome. Overall, people with fatigue appeared to benefit from the ACT-oriented interdisciplinary treatment for chronic pain, and relatively higher levels of fatigue did not appear to impede this benefit. ACT-based treatments may benefit people with chronic pain and fatigue. Future studies including experimental designs, and studies investigating other PF processes, are needed to better understand the utility of ACT for co-morbid fatigue and pain.
Learn More >Small studies and anecdotal evidence suggest marked differences in the use of opioids after surgery internationally; however, this has not been evaluated systematically across populations receiving similar procedures in different countries.
Learn More >The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat breast cancer, is peripheral neuropathy (PIPN). PIPN, which persists into survivorship, has a negative impact on patient's mood, functional status, and quality of life. Currently, no interventions are available to treat PIPN. A critical barrier to the development of efficacious interventions is the lack of understanding of the mechanisms that underlie PIPN. While data from preclinical studies suggest that disrupting cytoskeleton- and axon morphology-related processes are a potential mechanism for PIPN, clinical evidence is limited. The purpose of the present study in breast cancer survivors was to evaluate whether differential gene expression and co-expression patterns in these pathways are associated with PIPN. Signaling pathways and gene co-expression modules associated with cytoskeleton and axon morphology were identified between survivors who received paclitaxel and did (n=25) or did not (n=25) develop PIPN. Pathway impact analysis identified four significantly perturbed cytoskeleton- and axon morphology-related signaling pathways. Weighted gene co-expression network analysis identified three co-expression modules. One module was associated with PIPN group membership. Functional analysis found that this module was associated with four signaling pathways and two ontology annotations related to cytoskeleton and axon morphology. This study, which is the first to apply systems biology approaches using circulating whole blood RNA-seq data in a sample of breast cancer survivors with and without chronic PIPN, provides molecular evidence that cytoskeleton- and axon morphology-related mechanisms identified in preclinical models of various types of neuropathic pain including chemotherapy-induced peripheral neuropathy, are found in breast cancer survivors and suggests pathways and a module of genes for validation and as potential therapeutic targets.
Learn More >Various academic factors are known to influence pain and somatic symptoms in adolescents, but the role of academic goal orientation, school motivational climate, and school engagement are unknown. This study examined how these understudied academic factors are associated with adolescent pain and somatic symptoms and whether gender moderates the relations.
Learn More >The aim of the study is to investigate whether benzodiazepine use differs between patients with favorable and unfavorable spinal cord stimulation (SCS) treatment outcome. We hypothesize that the patients with unfavorable SCS outcome would exhibit a higher level of benzodiazepine use.
Learn More >To identify the factors associated with the excess risk of pain observed among older women compared with men.
Learn More >Depression is a well-recognised effect of long-term treatment with interferon-alpha (IFN-α), a widely used treatment for chronic viral hepatitis and malignancy. In addition to the emotional disturbances, high incidences of painful symptoms such as headache and joint pain have also been reported following IFN-α treatment. The endocannabinoid system plays an important role in emotional and nociceptive processing, however it is unknown whether repeated IFN-α administration induces alterations in this system. The present study investigated nociceptive responding in the IFN-α-induced mouse model of depression and associated changes in the endocannabinoid system. Furthermore, the effects of modulating peripheral endocannabinoid tone on inflammatory pain-related behaviour in the IFN-α model was examined. Repeated IFN-α administration (8,000IU/g/day) to male C57/Bl6 mice increased immobility in the forced swim test and reduced sucrose preference, without altering body weight gain or locomotor activity, confirming development of the depressive-like phenotype. There was no effect of repeated IFN-α administration on latency to respond in the hot plate test on day 4 or 7 of treatment, however, formalin-evoked nociceptive behaviour was significantly increased in IFN-α treated mice following 8 days of IFN-α administration. 2-Arachidonoyl glycerol (2-AG) levels in the periaqueductal grey (PAG) and rostroventromedial medulla (RVM), and anandamide (AEA) levels in the RVM, were significantly increased in IFN-α-, but not saline-, treated mice following formalin administration. There was no change in endocannabinoid levels in the prefrontal cortex, spinal cord or paw tissue between saline- or IFNα-treated mice in the presence or absence of formalin. Furthermore, repeated IFN-α and/or formalin administration did not alter mRNA expression of genes encoding the endocannabinoid catabolic enzymes (fatty acid amide hydrolyase or monoacylglycerol lipase) or endocannabinoid receptor targets (CB CB or PPARs) in the brain, spinal cord or paw tissue. Intra plantar administration of PF3845 (1μg/10μl) or MJN110 (1μg/10μl), inhibitors of AEA and 2-AG catabolism respectively, attenuated formalin-evoked hyperalgesia in IFN-α, but not saline-, treated mice. In summary, increasing peripheral endocannabinoid tone attenuates inflammatory hyperalgesia induced following repeated IFN-α administration. These data provide support for the endocannabinoid system in mediating and modulating heightened pain responding associated with IFNα-induced depression.
Learn More >Gene transcription regulation is critical for the development of spinal microgliosis and neuropathic pain after peripheral nerve injury. Using a model of chronic constriction injury (CCI) of the sciatic nerve, this study characterized the role of SET domain containing lysine methyltransferase 7 (SETD7) which monomethylates histone H3 lysine 4 (H3K4me1), a marker for active gene transcription. SETD7 protein expression in the spinal dorsal horn ipsilateral to nerve lesion was increased from one day to 14 days after CCI, concomitantly with the expression of inflammatory genes, Ccl2, Il-6 and Il-1β. The CCI-induced SETD7 expression was predominantly localized to microglia, as demonstrated by immunohistochemistry and western blot from magnetic activated cell sorted spinal microglia. SETD7 knockdown by intrathecal lentivirus shRNA delivery prior to CCI prevented spinal microgliosis and neuropathic pain, whereas lentiviral SETD7 transduction exacerbated these symptoms. In addition, SETD7 regulated H3K4me1 level and expression of inflammatory mediators both in CCI rats and in the HAPI rat microglia cell line. Accordingly, PFI-2, a specific inhibitor of SETD7 monomethylation activity, suppressed the lipopolysaccharides-induced amoeboid morphology of primary microglia and the expression of inflammatory genes, Ccl2, Il-6 and Il-1β. Moreover, intrathecal administration of PFI-2 alleviated CCI-induced neuropathic pain. However, this effect was observed in male but not in female rats. These results demonstrate a critical role of SETD7 in the development of spinal microgliosis and neuropathic pain subsequently to peripheral nerve injury. The pharmacological approach further suggests that SETD7 is a new target for the treatment of neuropathic pain. The underlying mechanisms may involve H3K4me1-dependent regulation of inflammatory gene expression in microglia.
Learn More >Ketamine has been used to treat chronic pain; however, it is still unknown as to what types of chronic pain is ketamine effective against. To identify the effect of administration of subanesthetic-dose ketamine in patients with chronic pain and to clarify the mechanism of the effect, we retrospectively investigated brain functional connectivity using resting-state functional magnetic resonance imaging (rs-fMRI). Patients were divided into responders (Group R: ≥50% improvement on Numerical Rating Scale) and non-responders (Group NR). We compared the differences in terms of brain functional connectivity by seed-to-voxel correlation analysis. Two-sample t-test revealed significant lower connectivity between the medial prefrontal cortex (mPFC) and precuneus in Group R. We also found a significant negative correlation between the improvement rate and functional connectivity strength between the mPFC and precuneus. These findings suggest that subanesthetic-dose ketamine is effective in patients with chronic pain whose brain functional connectivity between the mPFC and precuneus is low. We believe that the current study explored for the first time the correlation between brain functional connectivity and the effect of subanesthetic-dose ketamine for chronic pain and indicated the possibility of use of the predictive marker in pharmacological treatment of chronic pain.
Learn More >Inflammatory response triggered by nerve injury plays important roles in the development of neurological disorders, such as neuropathic pain. The signaling events leading to inflammation in the nervous system remain poorly understood. Here, by deleting Dlk in sensory neurons driven by Wnt1a-Cre, we show that dual leucine zipper kinase (DLK) is required for the neuronal intrinsic immune response to induce cytokines and chemokines such as Ccl2, Ccl7, and Ccl12 upon nerve injury. The DLK-controlled injury response in sensory neurons could regulate CD11b immune cell infiltration in the dorsal root ganglia, as well as microgliosis and astrogliosis in the spinal dorsal horn but not the ventral horn. Deficiency of Dlk drastically alleviates the neuropathic pain elicited by chronic constriction injury of the sciatic nerve. Thus, DLK is an essential component that mediates the neuronal intrinsic immune response to nerve injury in sensory neurons and regulates inflammation in the spinal cord.
Learn More >We have previously demonstrated that the neurosteroid dehydroepiandrosterone sulfate (DHEAS) induces functional potentiation of -methyl-D-aspartate (NMDA) receptors via increases in phosphorylation of NMDA receptor GluN1 subunit (pGluN1). However, the modulatory mechanisms responsible for the expression of the DHEA-synthesizing enzyme, cytochrome P450c17 following peripheral nerve injury have yet to be examined. Here we determined whether oxidative stress induced by the spinal activation of nitric oxide synthase type II (NOS-II) modulates the expression of P450c17 and whether this process contributes to the development of neuropathic pain in rats. Chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the expression of NOS-II in microglial cells and NO levels in the lumbar spinal cord dorsal horn at postoperative day 5. Intrathecal administration of the NOS-II inhibitor, L-NIL during the induction phase of neuropathic pain (postoperative days 0~5) significantly reduced the CCI-induced development of mechanical allodynia and thermal hyperalgesia. Sciatic nerve injury increased the expression of PKCand PKA-dependent pGluN1 as well as the mRNA and protein levels of P450c17 in the spinal cord at postoperative day 5, and these increases were suppressed by repeated administration of L-NIL. Co-administration of DHEAS together with L-NIL restored the development of neuropathic pain and pGluN1 that were originally inhibited by L-NIL administration alone. Collectively these results provide strong support for the hypothesis that activation of NOS-II increases the mRNA and protein levels of P450c17 in the spinal cord, ultimately leading to the development of central sensitization and neuropathic pain induced by peripheral nerve injury.
Learn More >The International Classification of Headache Disorders diagnostic criteria for Headache Attributed to Transient Ischemic Attack (TIA) and many other secondary headaches are based primarily on the opinion of experts. The aim of this study was to field test, for the first time, the diagnostic criteria for headache attributed to TIA of the International Classification of Headache Disorders, 3rd edition (ICHD-3) and in case of their weaknesses to propose new diagnostic criteria.
Learn More >Emerging evidence show that patients with chronic pancreatitis (CP) and abdominal pain have structural and functional alterations in the central nervous system. The aim was to investigate cerebral metabolic signatures in CP and the associations to various risk factors/clinical characteristics and patient outcomes.
Learn More >Mu opioid receptor (MOR)-targeting analgesics are efficacious pain treatments, but notorious for their abuse potential. In preclinical animal models, co administration of traditional kappa opioid receptor (KOR)-targeting agonists with MOR-targeting analgesics can decrease reward and potentiate analgesia. However, traditional KOR-targeting agonists are well known for inducing anti-therapeutic side effects (psychotomimesis, depression, anxiety, dysphoria). Recent data suggest that some functionally selective, or biased, KOR-targeting agonists might retain the therapeutic effects of KOR activation without inducing undesirable side effects. Nalfurafine, used safely in Japan since 2009 for uremic pruritus, is one such functionally selective KOR-targeting agonist. Here, we quantify the bias of nalfurafine and several other KOR agonists relative to an unbiased reference standard (U50,488), and show that nalfurafine and EOM-salvinorin-B demonstrate marked G protein-signaling bias. While nalfurafine (0.015 mg/kg) and EOM-salvinorin-B (1 mg/kg) produced spinal anti-nociception equivalent to 5 mg/kg U50,488, only nalfurafine significantly enhanced the supraspinal analgesic effect of 5 mg/kg morphine. In addition, 0.015 mg/kg nalfurafine did not produce significant conditioned place aversion (CPA), yet retained the ability to reduce morphine-induced conditioned place preference (CPP) in C57BL/6J mice. Nalfurafine and EOM-salvinorin-B each produced robust inhibition of both spontaneous and morphine-stimulated locomotor behavior, suggesting a persistence of sedative effects when co-administered with morphine. Taken together, these findings suggest that nalfurafine produces analgesic augmentation, while also reducing opioid-induced reward with less risk of dysphoria. Thus, adjuvant administration of G protein-biased KOR agonists like nalfurafine may be beneficial in enhancing the therapeutic potential of MOR-targeting analgesics, such as morphine. SIGNIFICANCE STATEMENT: N/A.
Learn More >Allergic rhinitis symptoms can be reduced by behaviorally conditioning antihistamine. It is unclear whether these findings extend to histamine-induced itch, or work when participants are informed about the conditioning procedure (open-label conditioning). The current study aims to investigate the efficacy of (open-label) antipruritic behavioral conditioning for histamine-induced itch.
Learn More >Clinicians have the dilemma of prescribing opioid or nonopioid analgesics to chronic pain patients; however, the impact of pain on our endogenous µ-opioid system and how our genetic profile (specifically catechol-O-methyltransferase [] polymorphisms) impacts its activation are currently unknown. Twelve chronic temporomandibular disorder (TMD) patients and 12 healthy controls (HCs) were scanned using positron emission tomography (PET) with [C]carfentanil, a selective radioligand for µ-opioid receptors (µORs). The first 45 min of each PET measured the µOR nondisplaceable binding potential (BP) at resting state, and the last 45 min consisted of a 20-min masseteric pain challenge with an injection of 5% hypertonic saline. Participants were also genotyped for different COMT alleles. There were no group differences in µOR BP at resting state (early phase). However, during the masseteric pain challenge (late phase), TMD patients exhibited significant reductions in µOR BP (decreased [C]carfentanil binding) in the contralateral parahippocampus ( = 0.002) compared to HCs. The µOR BP was also significantly lower in TMD patients with longer pain chronicity ( < 0.001). When considering genotype and chronic pain suffering, TMD patients with the Met substitution had higher pain sensitivity and longer pain chronicity with a 5-y threshold for µOR BP changes to occur in the parahippocampus. Together, the TMD diagnosis, Met substitution, and pain chronicity explained 52% of µOR BP variance in the parahippocampus (cumulative = 52%, < 0.003, and HC vs. TMD Cohen's effect size = 1.33 SD). There is strong evidence of dysregulation of our main analgesic and limbic systems in chronic TMD pain. The data also support precision medicine by helping identify TMD patients who may be more susceptible to chronic pain sensitivity and opioid dysfunction based on their genetic profile.
Learn More >Complex regional pain syndrome (CRPS) is a painful condition of a limb characterized by a constellation of symptoms. Little is known about the clinical features of pediatric CRPS, with fewer than a dozen studies published to date. The aim of this study was to explore the clinical course of pediatric CRPS, with emphasis on clinical features and disease outcomes. A secondary aim was to discern differences in clinical features of pediatric CRPS with and without related movement disorders, and between children who had a favorable and unfavorable outcome.
Learn More >Psychological interventions designed to enhance positive affect are promising ways to promote adaptive functioning in people with chronic pain. However, few studies have addressed the efficacy of positive affect interventions in chronic pain populations and examined which patients can benefit more from them. The aim of the present study was to identify mediators and moderators of the best possible self intervention (BPS) in fibromyalgia patients.
Learn More >Small fiber neuropathy (SFN) is a disease of intraepidermal nerves fibers (IENF) (myelinated Aδ and unmyelinated C-fibers) prevalent in about 53/100,000 people. Mostly idiopathic, SFN can have various etiologies as alcoholism, diabetes, immune-mediated or infectious diseases. SFN commonly affects limbs in a distal to proximal gradient and manifests as various sensory symptoms. The diagnosis of SFN must fulfill following criteria : 1- a symptomatology consistent with neuropathic pains and autonomic complaints; 2- no central or motor involvement; 3- no nervous trunk achievement detected on electromyogram; 4- a reduction of IENF density (IENFD) in the distal area measured on skin biopsy ("gold standard" for diagnosis). This article is protected by copyright. All rights reserved.
Learn More >Central sensitization plays a pivotal role in the maintenance of chronic pain induced by chronic pancreatitis (CP), but cortical modulation of painful CP remains elusive. This study was designed to examine the role of anterior insular cortex (aIC) in the pathogenesis of hyperalgesia in a rat model of CP. CP was induced by intraductal administration of trinitrobenzene sulfonic acid (TNBS). Abdomen hyperalgesia and anxiety were assessed by von Frey filament and open field tests, respectively. Two weeks after surgery, the activation of aIC was indicated by FOS immunohistochemical staining and electrophysiological recordings. Expressions of VGluT1, NMDAR subunit NR2B and AMPAR subunit GluR1 were analyzed by immunoblottings. The regulatory roles of aIC in hyperalgesia and pain-related anxiety were detected via pharmacological approach and chemogenetics in CP rats. Our results showed that TNBS treatment resulted in long-term hyperalgesia and anxiety-like behavior in rats. CP rats exhibited increased FOS expression and potentiated excitatory synaptic transmission within aIC. CP rats also showed up-regulated expression of VGluT1, and increased membrane trafficking and phosphorylation of NR2B and GluR1 within aIC. Blocking excitatory synaptic transmission significantly attenuated abdomen mechanical hyperalgesia. Specifically inhibiting the excitability of insular pyramidal cells reduced both abdomen hyperalgesia and pain-related anxiety. In conclusion, our findings emphasize a key role for aIC in hyperalgesia and anxiety of painful CP, providing a novel insight into cortical modulation of painful CP and shedding light on aIC as a potential target for neuromodulation interventions in the treatment of CP.
Learn More >Galcanezumab is a humanized immunoglobulin G (IgG) monoclonal antibody (mAb) indicated for the prevention of migraine that binds to calcitonin gene-related peptide. A population pharmacokinetic (PK) analysis was performed to characterize galcanezumab PK using data pooled from 7 clinical studies. Clinical studies included healthy individuals and patients with episodic or chronic migraine who were administered between 5 and 300 mg galcanezumab. The PK data were analyzed using nonlinear mixed-effects modeling. Galcanezumab concentration-time data were described with a 1-compartment model with first-order absorption following subcutaneous administration and linear elimination. At the median body weight of 74 kg, the estimated population apparent clearance (CL/F) was 0.00785 L/h (34% IIV), the apparent volume of distribution was 7.33 L (34% IIV), and half-life was 27 days. Patient body weight was found to have a modest effect of CL/F, with median galcanezumab concentrations being lower in the heaviest patients compared to the lightest patients, but this outcome was determined not to be clinically relevant in the context of model-estimated random variability. Dosing adjusted for body weight is not warranted in adults. Age, sex, race/ethnicity, immunogenicity, renal/hepatic markers, and injection-site location did not affect galcanezumab PK. In conclusion, galcanezumab exhibits PK parameters typical for an IgG mAb administered subcutaneously. The population PK model developed in this study demonstrates that galcanezumab exhibits linear PK that was not influenced in a clinically relevant manner by the patient factors evaluated.
Learn More >Retrospective cohort study OBJECTIVE.: To (1) confirm validity of PROMIS physical function and pain interference computer adaptive tests (CATs) and (2) assess the validity of PROMIS Global Health (GH) and five additional PROMIS CATs: social role satisfaction, fatigue, anxiety, depression, and sleep disturbance in a population of chronic low back pain (cLBP) patients who completed a 3-month Interdisciplinary Pain Program (IPP).
Learn More >Non-adherence to prescribed pain medication is common in chronic non-malignant pain patients. Beliefs about pain medication have been reported to be associated with non-adherence behaviour in cross-sectional studies. The aim of this study was to prospectively investigate the relation between patients' beliefs about pain medication and their medication adherence and treatment outcome.
Learn More >The development and maintenance of pediatric chronic pain and anxiety are complex, underscoring the need to better understand the interactive forces contributing to their co-occurrence. The Shared Vulnerability Model (SVM) was developed to explain the co-occurrence of chronic pain and posttraumatic stress disorder in adults. Though many core tenets have been well supported by pediatric research, the SVM has yet to be extended to pediatric pain populations. We propose a developmentally informed pediatric SVM for advancing our understanding of the co-occurrence of pediatric chronic pain and anxiety disorders. The proposed SVM postulates that youth at increased risk for the development of chronic pain and/or anxiety share predisposing vulnerabilities, including anxiety sensitivity, and that these shared vulnerabilities give rise to negative emotional responses (child and parent) in the context of stressful events. Consequences of fear and anxiety, including avoidance behavior, further contribute to the development of chronic pain, anxiety, and their co-occurrence. The parental, school, and peer contexts in which these problems develop and are maintained in youth are pertinent to integrate into a SVM, as pediatric chronic pain and anxiety disorders share several social-contextual risk and maintenance factors. We also highlight new areas of inquiry.
Learn More >Migraine is a complex neurological disorder that affects a significant percentage of the human species, from all geographic areas and cultures. Cognitive symptoms and dysfunctions are interim and disabling components of this disorder and may be related to the brain processes underlying the pathophysiology. Yet they are often undervalued by clinicians. In this review, we present the different types of cognitive dysfunctions associated with migraine and the mechanisms that are potentially causing them.
Learn More >To examine the association between catastrophizing and pain intensity with acute herpes zoster, and the association of treatment-related early changes in depressive symptoms, anxiety, and catastrophizing with postherpetic neuralgia (PHN) development, independent of acute pain intensity.
Learn More >A close and bidirectional relationship between alcohol consumption and pain has been previously reported and discussed in influential reviews. The goal of the present narrative review is to provide an update on the developments in this field in order to guide future research objectives.
Learn More >Osteoarthritis is a common debilitating condition affecting a substantial portion of the population and is an accepted consequence of aging and over use. Whilst surgical interventions are a definitive approach, most cases are managed medically with analgesia. Pharmacological therapies have included acetaminophen, NSAIDs and opiates. Although significant controversies exist in the use of opioids for chronic musculoskeletal pain, many leading guidelines continue to recommend its use despite increasing evidence to suggest an increase in addiction, morbidity and mortality. With the opiate crisis growing, we re-examine the role opiates have in this chronic condition, current data and briefly evaluate alternative therapies.
Learn More >Trigeminal-targeted treatments (TTTs), the most specific and selective therapeutic migraine approach to date, are effective in approximately 60% of patients regardless of treatment type or mechanism, at least if used alone. Sixty percent is also the proportion of migraineurs who develop migraine-like episodes following experimental intravenous administration of trigeminal neuropeptides and roughly 60% is the percentage of patients with a unilateral migraine tracing the area of cutaneous distribution of the trigeminal ophthalmic branch. Hence, mechanisms other than the trigeminovascular activation are probably involved in the 40% of migraineurs who do not respond to TTTs. A closer cooperation between clinical and basic neuroscientists is needed to explore migraine models because only a careful appraisal of migraine endophenotypes may help to unravel their underlying multifaceted pathophysiological machinery.
Learn More >Opioid-induced hyperalgesia is a state of nociceptive sensitization secondary to opioid administration. The objective of this meta-analysis was to test the hypothesis that high-dose intraoperative opioids contribute to increased postoperative pain and hyperalgesia when compared with a low-dose regimen in patients under general anaesthesia.
Learn More >Sickle cell disease (SCD) is one of the most common severe genetic diseases around the world. A majority of SCD patients experience intense pain, leading to hospitalization, and poor quality of life. Opioids form the bedrock of pain management, but their long-term use is associated with severe side effects including hyperalgesia, tolerance and addiction. Recently, excellent research has shown some new potential mechanisms that underlie SCD-associated pain. This review focused on how transient receptor potential vanilloid 1, endothelin-1/ endothelin type A receptor, and cannabinoid receptors contributed to the pathophysiology of SCD-associated pain. Understanding these mechanisms may open a new avenue in managing SCD-associated pain and improving quality of life for SCD patients.
Learn More >The objective of the present analysis was to determine whether changes in Brief Pain Inventory (BPI) average pain by patient global impression of improvement (PGI-I) category and the cut-off for clinically important difference (CID) were different between Asian and Caucasian patients with chronic pain due to osteoarthritis. This analysis used data from 3 (Caucasian) and 2 (Asian) randomized, placebo-controlled, 10- to 14-week duloxetine studies for the treatment of patients aged ≥40 years with osteoarthritis pain. The receiver operating characteristic (ROC) analysis was used to characterize the association between changes in BPI average pain and PGI-I levels at study endpoint. The CID was characterized by PGI-I and the cut-off point for CID in BPI average pain was determined by the intersection of a 45̊ tangent line with each ROC curve. Data from 668 Asian and 868 Caucasian patients were available for analysis. Baseline BPI average pain ratings including worst and least pain were comparable between Asians and Caucasians. Ratings for percentage change from baseline to endpoint for BPI average pain in Asian patients and Caucasian patients were similar across the 7 PGI-I categories, regardless of age, gender, study, and treatment. The ROC analysis results of cut-off points in BPI average pain demonstrated the raw change cut-off was -3.0, and percentage change cut-off was -40% for both Asian and Caucasian patients. Overall, the present analysis concludes changes in BPI average pain by PGI-I category and the cut-off for CID were similar for Asian and Caucasian patients with chronic pain due to osteoarthritis.
Learn More >Treating chronic low back pain (CLBP) with spine-focused interventions is common, potentially dangerous, and often ineffective. This preliminary trial tests the feasibility and efficacy of caring for CLBP in older adults as a geriatric syndrome in Aging Back Clinics (ABC).
Learn More >Chemotherapeutic agents can cause peripheral neuropathy, a deleterious side effect of cancer treatment. Hyperbaric oxygen (HBO2) treatment has shown great potential for decreasing pain in numerous clinical pain conditions and in preclinical studies. This study was designed to test whether HBO2 might also be useful for treating chemotherapy-induced peripheral neuropathy. Male and female Sprague-Dawley rats were injected with 1 mg/kg paclitaxel or vehicle every other day for 7 days to induce allodynia, followed by either one single, or four daily 60-min exposures to HBO2 or room air. Mechanical and cold allodynia as well as locomotor behavior and body weight were assessed intermittently for several weeks. Estrous cycling was also tracked in female rats. Paclitaxel caused pronounced mechanical allodynia in both sexes that was completely reversed by either one or four treatments of HBO2. Females in all treatment groups showed greater cold acetone scores than males, and acetone scores were not reliably reduced by HBO2 treatment. Neither paclitaxel nor HBO2 treatment altered locomotor behavior or estrous cycling. We conclude that HBO2 treatment was highly effective at reducing mechanical allodynia in paclitaxel-treated rats without affecting weight gain, locomotion, or estrous cycling, suggesting that HBO2 may be effective for treating chemotherapy-induced neuropathic pain without producing significant side effects.
Learn More >Inflammatory orofacial pain, in which substance P (SP) plays an important role, is closely related to the cross-talk between trigeminal ganglion (TG) neurons and satellite glial cells (SGCs). SGC activation is emerging as the key mechanism underlying inflammatory pain through different signalling mechanisms, including glial fibrillary acidic protein (GFAP) activation, phosphorylation of mitogen-activated protein kinase (MAPK) signalling pathways, and cytokine upregulation. However, in the TG, the mechanism underlying SP-mediated orofacial pain generated by SGCs is largely unknown. In this study, we investigated whether SP is involved in inflammatory orofacial pain by upregulating interleukin (IL)-1β and tumour necrosis factor (TNF)-α from SGCs, and we explored whether MAPK signalling pathways mediate the pain process. In the present study, complete Freund's adjuvant (CFA) was injected into the whisker pad of rats to induce an inflammatory model in vivo. SP was administered to SGC cultures in vitro to confirm the effect of SP. Facial expression analysis showed that pre-injection of L703,606 (an NK-1 receptor antagonist), U0126 (an inhibitor of MAPK/extracellular signal-regulated kinase [ERK] kinase [MEK] 1/2), and SB203580 (an inhibitor of P38) into the TG to induce targeted prevention of the activation of the NK-1 receptor and the phosphorylation of MAPKs significantly suppressed CFA-induced inflammatory allodynia. In addition, SP promoted SGC activation, which was proven by increased GFAP, p-MAPKs, IL-1β and TNF-α in SGCs under inflammatory conditions. Moreover, the increase in IL-1β and TNF-α was suppressed by L703, 606, U0126 and SB203580 in vivo and in vitro. These present findings suggested that SP, released from TG neurons, activated SGCs through the ERK1/2 and P38 pathways and promoted the production of IL-1β and TNF-α from SGCs, contributing to inflammatory orofacial pain associated with peripheral sensitization.
Learn More >Background and Purpose- Central poststroke pain (CPSP) is a disabling condition in stroke patients, and evidence suggests that altered corticospinal and motor intracortical excitability occurs in neuropathic pain. The objective of this study was to investigate changes in motor cortex excitability and sensorimotor interaction and their correlates with clinical manifestations and alterations in somatosensory systems in CPSP patients. Methods- Fourteen patients with CPSP but no motor weakness were compared with age- and sex-matched healthy controls for motor cortex excitability and sensorimotor interaction assessed by transcranial magnetic stimulation to measure resting motor thresholds, short-interval intracortical inhibition, intracortical facilitation, and afferent inhibitions. The sensory pathway was evaluated by quantitative sensory testing, contact heat evoked potential, and somatosensory evoked potentials. Clinical pain and quality of life were assessed with validated tools. Results- The duration of CPSP was 3.3±3.0 years (ranging 0.5-10 years), and pain significantly impaired quality of life. Compared with the unaffected hemisphere, the stroke hemisphere had higher thermal thresholds, lower contact heat evoked potential amplitudes, and prolonged cortical somatosensory evoked potential latencies. There was no difference in resting motor thresholds between the stroke and unaffected hemisphere or between patients and controls. CPSP patients had a reduction in short-interval intracortical inhibition in the stroke hemisphere compared with that in the unaffected hemispheres of patients and controls. No changes were noted in afferent inhibitions between the stroke and unaffected hemispheres. The short-interval intracortical inhibition of the stroke hemisphere was negatively correlated with self-rated health on a visual analog scale and positively correlated with cortical somatosensory evoked potential latencies. Conclusions- CPSP patients with intact corticospinal tracts showed reduced motor intracortical inhibition in the stroke hemisphere, suggesting defective gamma-aminobutyric acid-ergic inhibition. This disinhibition was associated with impaired quality of life and was related to dorsal column-medial lemniscus pathway dysfunction.
Learn More >Adults with irritable bowel syndrome (IBS) often report extraintestinal pain, fatigue, and sleep disturbances in addition to abdominal pain. Few interventions have sought to reduce these extraintestinal symptoms within the IBS population. To address this, we compared the effects of a comprehensive self-management (CSM) intervention to a control intervention (usual care) on extraintestinal pain, fatigue, and sleep disturbances among patients with IBS.
Learn More >Pediatric chronic pain is common and can be related to reduced functioning in many domains for the young person and their parents. Existing psychological treatments such as Acceptance and Commitment Therapy (ACT) have shown to be effective, but improvements are needed. Qualitative approaches can help improve our understanding of treatment processes and outcomes. The aim of the present qualitative interview study was to explore the lived experiences of young people and parents who had participated in ACT for pediatric chronic pain. Four young persons and four parents were interviewed, and data was analyzed using Interpretative Phenomenological Analysis (IPA). Three themes were generated, each comprising two subthemes: (1) 'Warning system', which included experiences from being offered this psychological intervention, and the alternative explanations provided for pain; (2) 'Change and challenges', which suggested the importance of the values-based work, and of individual adaptation; and (3) 'A common language' in which the interaction with others and new ways to communicate around the pain experience were described. Findings highlight the importance of pain education, formulating and acting in line with personal values, and communication around the pain experience, as well as the need for developmental and individual adaptations of interventions.
Learn More >To determine whether the successful treatment of chronic migraine (CM) with onabotulinumA (BotoxA) may be followed by a continued respite from headache once therapy has been discontinued.
Learn More >Mas-related G-protein-coupled receptor X1 (MRGPRX1) is a human sensory neuron-specific receptor and has been actively investigated as a therapeutic target for the treatment of pain. By use of two HTS screening hit compounds, 4-(4-(benzyloxy)-3-methoxybenzylamino)benzimidamide () and 4-(2-(butylsulfonamido)-4-methylphenoxy)benzimidamide (), as molecular templates, a series of human MRGPRX1 agonists were synthesized and evaluated for their agonist activity using HEK293 cells stably transfected with human MrgprX1. Conversion of the benzamidine moiety into a 1-aminoisoquinoline moiety carried out in the later stage of structural optimization led to the discovery of a highly potent MRGPRX1 agonist, -(2-(1-aminoisoquinolin-6-yloxy)-4-methylphenyl)-2-methoxybenzenesulfonamide (), not only devoid of positively charged amidinium group but also with superior selectivity over opioid receptors. In mice, compound displayed favorable distribution to the spinal cord, the presumed site of action for the MRGPRX1-mediated analgesic effects.
Learn More >Chronic pain is a prevalent and burdensome condition. Reboot Online was developed to address treatment barriers traditionally associated with accessing face-to-face chronic pain management programs. It is a comprehensive multidisciplinary online treatment program, based on an existing and effective face-to-face multidisciplinary pain program (the Reboot program).
Learn More >In recent years, several melatonin (MLT) receptor agonists have been approved by FDA for the treatment of sleep disorders and depression. Very few studies have shed light on their efficacy against neuropathic pain (NP). IIK-7 is an MT-2 agonist known to promote sleep. Whether IIK-7 suppresses NP has not been reported, and the signaling profile is unknown.
Learn More >Pain catastrophizing is linked to a range of negative health and treatment outcomes, although debate continues about how best to define and treat it, since most interventions produce only modest benefit. This study aimed to contribute to theory-driven development of these treatments by exploring the role of perseverative thinking in pain catastrophizing, along with the higher order beliefs, called metacognitions, that might shape it.
Learn More >Trigeminal Neuralgia (TN) is a chronic neuropathic pain syndrome characterized by paroxysmal unilateral shock-like pains in the trigeminal territory most frequently attributed to neurovascular compression of the trigeminal nerve at its root entry zone. Recent advances in the study of TN suggest a possible central nervous system (CNS) role in modulation and maintenance of pain. TN and other chronic pain patients commonly experience alterations in cognition and affect, as well as abnormalities in CNS volume and microstructure in regions associated with pain perception, emotional modulation, and memory consolidation. However, the microstructural changes in the hippocampus, an important structure within the limbic system, have not been previously studied in TN patients. Here, we use grey matter analysis to assess whether TN pain is associated with altered hippocampal subfield volume in patients with classic TN. Anatomical magnetic resonance (MR) images of twenty-two right-sided TN patients and matched healthy controls underwent automated segmentation of hippocampal subfields using FreeSurfer v6.0. Right-sided TN patients had significant volumetric reductions in ipsilateral cornu ammois 1 (CA1), CA4, dentate gyrus, molecular layer, and hippocampus-amygdala transition area – resulting in decreased whole ipsilateral hippocampal volume, compared to healthy controls. Overall, we demonstrate selective hippocampal subfield volume reduction in patients with classic TN. These changes occur in subfields implicated as neural circuits for chronic pain processing. Selective subfield volume reduction suggests aberrant processes and circuitry reorganization, which may contribute to development and/or maintenance of TN symptoms.
Learn More >The opioid epidemic is a significant public health crisis and prescription opioids are often used to manage chronic pain, despite questionable long-term efficacy. Furthermore, co-substance (mis)use is also common among individuals with chronic pain who use opioids. Alcohol has been consistently used to manage chronic pain, partly due to its acute analgesic properties. Cannabis has also recently garnered attention in the context of pain management, though research examining its efficacy for pain has produced mixed results. Nevertheless, there is accumulating evidence that concurrent substance co-use is positively associated with use and misuse of additional substances, particularly among individuals with chronic pain. Thus, the goal of this study was to examine the main and interactive effects of alcohol use problems and cannabis use problems in relation to opioid misuse among adults with chronic pain who use opioids.
Learn More >Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) has recently been shown to promote inflammation in peripheral tissues and the central nervous system (CNS), contributing to the pathogenesis of various human diseases. Here, we examined whether the presence of high levels of circulating TMAO would influence central and peripheral inflammation and inflammatory hyperalgesia in a carrageenan (CG)-induced rat model of inflammation. Rats were treated with vehicle or TMAO in drinking water. After 2 weeks of treatment, rats received intraplantar injection of saline or CG into the hind paw. Acute nociception was unaltered in TMAO-treated rats that had elevated plasma TMAO. Following CG injection, TMAO-treated rats were significantly more sensitive to thermal and mechanical stimulation of the inflamed paw and displayed greater paw edema. Molecular studies revealed that CG injection induced increases in recruitment of neutrophils/macrophages in the paw and activation of microglia in the spinal cord, along with increased activation of nuclear factor (NF)-kB and production of proinflammatory mediators in both vehicle-treated rats and TMAO-treated rats. However, the increases in the above parameters were more pronounced in TMAO-treated rats. Moreover, TMAO treatment decreased protein levels of anti-inflammatory mediator regulator of G protein signaling (RGS)-10 in both saline-injected rats and CG-injected rats. These findings suggest that the presence of high levels of circulating TMAO downregulates anti-inflammatory mediator RGS10 in both peripheral tissues and the CNS, which may increase the susceptibility to inflammatory challenge-induced NF-kB activity, leading to greater increase in production of inflammatory mediators and consequent exacerbation of peripheral inflammation and inflammatory hyperalgesia.
Learn More >The bidirectional interplay between chronic pain and negative affect is well-established in patient samples. However, less is known about the day-to-day relationship between pain and affect of older adults without severe illnesses and to what extent this association differs within and between individuals. A total of 224 participants (M = 77.6, SD = 6.2) reported their daily experience of pain, impairment by their pain and affect during 21 consecutive days. Multilevel modeling results showed that on days with increased pain individuals also reported less positive affect and more negative affect. Time-lagged results indicated a temporal carry-over from yesterday's pain to today's negative affect but not to today's positive affect. Moreover, on days when individuals reported stronger impairment by their pain, they showed a stronger within-person coupling between daily pain and affect in contrast to days with a weaker experience of daily impairment. Yesterday's pain and today's negative affect were more strongly associated within individuals who reported higher levels of impairment. Interindividual differences in the within-person coupling between daily pain and affect were found with regard to general physical health conditions and general satisfaction with health. This study demonstrated the importance of focusing on within-person couplings between daily pain and affect beyond patient samples in order to better understand the maintenance of emotional stability despite daily hassles in older adults' everyday lives.
Learn More >The clinical management of inflammatory pain requires an optimal balance between effective analgesia and associated safety risks. To date, mechanisms associated with inflammatory pain are not completely understood because of their complex nature and the involvement of both peripheral and central mechanisms. This Expert Consensus document is intended to update clinicians about evolving areas of clinical practice and/or available treatment options for the management of patients with inflammatory pain.
Learn More >Post-herpetic neuralgia (PHN) is a well-established clinical problem with potential severe personal and socioeconomic implications. GTP cyclohydrolase 1 (GCH1) gene, which encodes the rate-limiting enzyme in tetrahydrobiopterin synthesis, has been strongly implicated to be associated with neuropathic pain in previous animal and human studies. The rs3783641 (T > A) single-nucleotide polymorphism (SNP) in the GCH1 gene is functional. Here we examine the association between rs3783641 and PHN. A total of 292 subjects including 103 PHN patients, 87 herpes zoster (HZ) patients and 102 healthy controls were enrolled in this study. The rs3783641 polymorphisms were detected via the high-resolution melting curve (HRM) method. There were statistical differences between PHN group and the other two groups in genotype distribution (P = 0.029 and 0.017, respectively) and allele frequency (P = 0.032 and 0.005, respectively) of rs3783641. The proportion of subjects with AA genotype in the PHN group was significantly lower compared to HZ group and control group (P = 0.026 and 0.016, respectively). The frequency of A allele was lower in the PHN group than in control group (P = 0.005), and the frequency of T allele in the PHN group was higher than in HZ group and control group (P = 0.001 and 0.003, respectively). The results of this study suggest that the rs3783641 SNP in the GCH1 gene is associated with PHN, and the AA genotype showed a protective effect in PHN.
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