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The flavoring agent menthol elicits complex orosensory and behavioral effects including perceived cooling at low concentrations, and irritation and ingestive avoidance at higher intensities. Oral menthol engages the cold-activated transient receptor potential (TRP) ion channel TRP melastatin 8 (TRPM8) on trigeminal fibers, although its aversive feature was discussed to involve activation of TRP ankyrin 1 (TRPA1) associated with nociceptive processing. Here we studied the roles of TRPM8 and TRPA1 in orosensory responding to menthol by subjecting mice gene-deficient for either channel to brief-access exposure tests, which measure immediate licking responses to fluid stimuli to capture sensory/tongue control of behavior. Stimuli included aqueous concentration series of (-)-menthol (0 [water], 0.3, 0.5, 0.7, 1.0, 1.5, and 2.3 mM) and the aversive bitter taste stimulus quinine-HCl (0, 0.01, 0.03, 0.1, 0.3, 1, and 3 mM). Concentration-response data were generated from daily brief-access tests conducted in lickometers, which recorded the number of licks water-restricted mice emitted to a randomly selected stimulus concentration over a block of several 10 sec stimulus presentations. Wild-type mice showed aversive orosensory responses to menthol above 0.7 mM. Oral aversion to menthol was reduced in mice deficient for TRPA1, but not TRPM8. Oral aversion to quinine was similar between TRPA1 mutant and control mice but stronger than avoidance of menthol. This implied menthol avoidance under the present conditions represented a moderate form of oral aversion. These data reveal TRPA1 contributes to the oral sensory valence of menthol and have implications for how input from TRPA1 and TRPM8 shapes somatosensory-guided behaviors. Menthol is used in confectionery, tobacco, and oral consumer products to add a pleasant "coolness" to their flavor appeal. Yet menthol's sensation is complex and includes coolness at low but irritation at high concentrations. Elucidating mechanisms that underlie menthol's aversive flavor component would facilitate understanding of how trigeminal circuits distinguish noxious from innocuous stimuli. Although engaging the cold receptor TRPM8, menthol was discussed to induce oral irritation through its activation of TRPA1, which is expressed on nociceptive fibers usually devoid of TRPM8. Here we found mice gene-deficient for TRPA1, but not TRPM8, show reduced aversion to menthol in an oral sensory-guided behavioral task. These results have implications for how TRPM8 and TRPA1 afferents contribute to hedonic tone during somatosensory-influenced behaviors.
Learn More >The main aim of this work was to identify and to share the lessons learned from the negative outcome of the mirogabalin ALDAY phase 3 clinical program in pain associated with fibromyalgia. These lessons are important to improve planning and design of future phase 3 programs in fibromyalgia. A systematic review from Cochrane Library, Medline, Embase, clinicaltrials.gov, pharmaceutical companies and regulatory agencies' websites, was carried out starting from the development of gabapentin, the first α2δ ligand studied for the treatment of neuropathic pain and ending with the mirogabalin program. Based on the outcome of the main fibromyalgia programs, several differences in design, primary endpoint choice, magnitude of placebo response, presence of an active comparator, and size of the entire clinical program were identified. This analysis focused on the negative primary results of the mirogabalin ALDAY program and identified several contributing factors. Above all, the magnitude of placebo response and the unprecedented size of the program were identified. The number of study visits and procedures was also high and highly demanding for all subjects involved in ALDAY. In terms of main lessons learned from ALDAY, the first was the need for a comprehensive patient-focused strategy to preliminarily identify the challenges of fibromyalgia based on patient perspective and study complexity. Second, there was a need for a harmonized, truly patient-centric, global regulatory guidance accepted by regulatory agencies. Third, ALDAY proved that a phase 2 proof of concept, dose ranging study is necessary before commencing any phase 3 program in fibromyalgia.
Learn More >Abdominal and peritoneal pain after surgery is common and burdensome, yet the lack of standardized diagnostic criteria for this type of acute pain impedes basic, translational, and clinical investigations. The collaborative effort among the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM) Pain Taxonomy (AAAPT) provides a systematic framework to classify acute painful conditions. Using this framework, a multidisciplinary working group reviewed the literature and developed core diagnostic criteria for acute abdominal and peritoneal pain after surgery. In this report, we apply the proposed AAAPT framework to four prototypical surgical procedures resulting in abdominal and peritoneal pain as examples: cesarean delivery, cholecystectomy, colorectal surgical procedures, and pancreas resection. These diagnostic criteria address the three most common surgical procedures performed in the United States, capture diverse surgical approaches, and may also be applied to other surgical procedures resulting in abdominal and peritoneal pain. Additional investigation regarding the validity and reliability of this framework will facilitate its adoption in research that advances our comprehension of mechanisms, deliver better treatments, and help prevent the transition of acute to chronic pain after surgery in the abdominal and peritoneal region. Perspective: Using AAAPT pain taxonomy, we present key diagnostic criteria for acute abdominal and peritoneal pain after surgery. We provide a systematic classification using five dimensions for abdominal and peritoneal pain that occurs after surgery, in addition to four specific surgical procedures: cesarean delivery, cholecystectomy, colorectal surgical procedures, and pancreas resection.
Learn More >Patients with temporomandibular disorders (TMDs) often experience persistent facial pain. However, the treatment of TMD pain is still inadequate. In recent years, the disturbance of gut microbiota has been shown to play an important role in the pathogenesis of different neurological diseases including chronic pain. In the present study, we investigated the involvement of gut microbiota in the development of temporomandibular joint (TMJ) inflammation. Intra-temporomandibular joint injection of complete Freund's adjuvant (CFA) was employed to induce TMJ inflammation. Resveratrol (RSV), a natural bioactive compound with anti-inflammatory property, was used to treat the CFA-induced TMJ inflammation. We observed that CFA injection not only induces persistent joint pain, but also causes the reduction of short-chain fatty acids (SCFAs, including acetic acid, propionic acid and butyric acid) in the gut as well as decreases relevant gut bacteria Bacteroidetes and Lachnospiraceae. Interestingly, systemic administration of RSV (i.p.) dose-dependently inhibits CFA-induced TMJ inflammation, reverses CFA-caused reduction of SCFAs and these gut bacteria. Moreover, CFA injection causes blood-brain barrier (BBB) leakage, activates microglia and enhances tumor necrosis factor alpha (TNFα) release in the spinal trigeminal nucleus caudalis (Sp5C). The RSV treatment restores the BBB integrity, inhibits microglial activation and decreases the release of TNFα in the Sp5C. Furthermore, fecal microbiota transplantation with feces from RSV-treated mice significantly diminishes the CFA-induced TMJ inflammation. Taken together, our results suggest that gut microbiome perturbation is critical for the development of TMJ inflammation and that recovering gut microbiome to normal levels could be a new therapeutic approach for treating such pain.
Learn More >Mechanosensation is central to a wide range of functions, including tactile and pain perception, hearing, proprioception, and control of blood pressure, but identifying the molecules underlying mechanotransduction has proved challenging. In , the avoidance response to gentle body touch is mediated by 6 touch receptor neurons (TRNs), and is dependent on MEC-4, a DEG/ENaC channel. We show that hemichannels containing the innexin protein UNC-7 are also essential for gentle touch in the TRNs, as well as harsh touch in both the TRNs and the PVD nociceptors. UNC-7 and MEC-4 do not colocalize, suggesting that their roles in mechanosensory transduction are independent. Heterologous expression of in touch-insensitive chemosensory neurons confers ectopic touch sensitivity, indicating a specific role for UNC-7 hemichannels in mechanosensation. The touch defect can be rescued by the homologous mouse gene gene, thus, innexin/pannexin proteins may play broadly conserved roles in neuronal mechanotransduction.
Learn More >We have previously reported that the spinal angiotensin (Ang) system is involved in the modulation of streptozotocin (STZ)-induced diabetic neuropathic pain in mice. An important drawback of this model however is the fact that the neuropathic pain is independent of hyperglycemia and produced by the direct stimulation of peripheral nerves. Here, using the leptin deficient ob/ob mouse as a type 2 diabetic model, we examined whether the spinal Ang system was involved in naturally occuring diabetic neuropathic pain. Blood glucose levels were increased in ob/ob mice at 5-15 weeks of age. Following the hyperglycemia, persistent tactile and thermal hyperalgesia were observed at 11-14 and 9-15 weeks of age, respectively, which was ameliorated by insulin treatment. At 12 weeks of age, the expression of Ang-converting enzyme (ACE) 2 in the spinal plasma membrane fraction was decreased in ob/ob mice. Spinal ACE2 was expressed in neurons and microglia but the number of NeuN-positive neurons was decreased in ob/ob mice. In addition, the intrathecal administration of Ang (1-7) and SB203580, a p38 MAPK inhibitor, attenuated hyperalgesia in ob/ob mice. The phosphorylation of spinal p38 MAPK was also attenuated by Ang (1-7) in ob/ob mice. These inhibitory effects of Ang (1-7) were prevented by A779, a Mas receptor antagonist. In conclusion, we revealed that the Ang (1-7)-generating system is downregulated in ob/ob mice and is accompanied by a loss of ACE2-positive neurons. Furthermore, Ang (1-7) decreased the diabetic neuropathic pain through inhibition of p38 MAPK phosphorylation via spinal Mas receptors.
Learn More >Pain is a pervasive problem that affects nearly half of the U.S. Veterans deployed in support of the Global War on Terror (Post-9/11 Veterans) and over half of the Post-9/11 Veterans with diagnosed traumatic brain injury (TBI). The goal of the current study was to identify pain phenotypes based on distinct longitudinal patterns of pain scores in light of pain treatment among Post-9/11 Veterans over five years of care using latent growth mixture analysis stratified by TBI status. Five pain phenotypes emerged: (1) simple low impact stable pain, (2) complex low impact stable pain, (3) complex low impact worsening pain, (4) complex moderate impact worsening pain, and (5) complex high impact stable pain. Baseline pain scores and slopes were significantly higher in Veterans with mild TBI for some phenotypes. The mild TBI cohort was younger, had more men, more whites, less blacks, less education, more unmarried, more Marines and Army, more active duty in comparison to the no TBI cohort. Distinct trajectories in pain treatment were apparent among the pain intensity subgroups. Perspective: The complexity of pain in patients with mTBI is categorically different than those with no TBI. Pain in patients with mTBI is heterogeneous with distinct phenotypes which may explain poor outcomes in this group. Identification of the individual differences may have a significant impact on the success of interventions.
Learn More >Native Americans (NAs) have a higher prevalence of chronic pain than other U.S. racial/ethnic groups, but there have been few attempts to understand the mechanisms of this pain disparity. This study used a comprehensive battery of laboratory tasks to assess peripheral fiber function (cool/warm detection thresholds), pain sensitivity (eg, thresholds/tolerances), central sensitization (eg, temporal summation), and pain inhibition (conditioned pain modulation) in healthy, pain-free adults (N = 155 NAs, N = 150 non-Hispanic Whites [NHWs]). Multiple pain stimulus modalities were used (eg, cold, heat, pressure, ischemic, and electric), and subjective (eg, pain ratings and pain tolerance) and physiological (eg, nociceptive flexion reflex) outcomes were measured. There were no group differences on any measure, except that NAs had lower cold-pressor pain thresholds and tolerances, indicating greater pain sensitivity than NHWs. These findings suggest that there are no group differences between healthy NAs and NHWs on peripheral fiber function, central sensitization, or central pain inhibition, but NAs may have greater sensitivity to cold pain. Future studies are needed to examine potential within-group factors that might contribute to NA pain risk.
Learn More >the ageing global population and concomitant increase in the use of opioid analgesia have highlighted the need to evaluate the effectiveness of opioids for chronic pain in older people.
Learn More >Migraine with aura (MwA) is associated with increased brain hyper-responsiveness to visual stimuli and increased visual network connectivity relative to migraine without aura (MwoA). Despite this, prior studies have provided conflicting results regarding whether MwA is associated with higher photophobia symptom scores compared to MwoA. The relationships between MwA and other types of sensory hypersensitivity, such as phonophobia and cutaneous allodynia (CA), have not been previously investigated. The purpose of this cross-sectional observational study was to investigate whether MwA is associated with greater symptoms of photophobia, phonophobia, and CA compared to MwoA.
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