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GABA receptors containing the α6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 μM enhanced GABA currents at recombinant rat α6β3γ2, α6β3δ and α6β3 receptors whereas it was inactive at most GABA receptor subtypes containing other α subunits. DK-I-87-1 at concentrations below 1 μM was inactive at α6-containing receptors and only weakly modulated other GABA receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 h and 13 h, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-h period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery, or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy was already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. This article is protected by copyright. All rights reserved.
Learn More >Does the GnRH antagonist, ASP1707, reduce endometriosis-associated pelvic pain?
Learn More >Numerous studies have examined how alexithymia (difficulty identifying and describing one's emotions and a preference for externally oriented thinking) relates to chronic pain and associated disability. We conducted a systematic review and meta-analysis to summarize individual studies that either assessed alexithymia in individuals with chronic pain vs controls or related alexithymia to pain intensity, physical interference, depression, and anxiety. We searched MEDLINE, Embase, and PsycINFO from inception through June 2017; 77 studies met the criteria (valid assessment of alexithymia in adults or children with any chronic pain condition) and were included in analyses (n = 8019 individuals with chronic pain). Primary analyses indicated that chronic pain samples had significantly higher mean alexithymia scores compared with nonclinical (d = 0.81) and clinical nonpain (d = 0.55) controls. In chronic pain samples, alexithymia was significantly positively associated with pain intensity (d = 0.20), physical interference (d = 0.17), depression (d = 0.46), and anxiety (d = 0.43). Secondary meta-analyses of 14 studies that conducted partial correlations that controlled for negative affect-related measures revealed that alexithymia was no longer significantly related to pain intensity or interference. Meta-analysis findings demonstrated that alexithymia is elevated in individuals with chronic pain and related to greater pain intensity and physical interference, although the latter relationships may be accounted for by negative affect. Critical future work is needed that examines alexithymia assessed using non-self-report measures, develops a person-centered perspective on this construct, and identifies how alexithymia is relevant to the assessment and treatment of individuals with chronic pain.
Learn More >This paper overviews available literature addressing behavioral and psychological aspects of cluster headache. Behavioral correlates of sleep and drug use are explored, as are the psychological correlates pertaining to psychopathology and cognitive functioning. We conclude with a review of the few investigations addressing adjunctive behavioral treatments for cluster headache, and provide suggestions for possible ways to enhance effects of behavioral interventions for this painful and difficult to treat headache disorder.
Learn More >Conditioned Pain Modulation (CPM) and Manipulation Induced Analgesia (MIA) may activate similar neurophysiological mechanisms to mediate their analgesic effects. This study assessed the association between CPM and MIA responses in people with lateral epicondylalgia (LE).
Learn More >Inflammatory pain is associated with peripheral and central sensitization, but the underlying synaptic plasticity at the spinal cord level is poorly understood. Transient receptor potential (TRP) channels expressed at peripheral nerve endings, including TRPA1 and TRPV1, can detect nociceptive stimuli. In this study, we determined the contribution of presynaptic TRPA1 and TRPV1 at the spinal cord level to regulating nociceptive drive in chronic inflammatory pain induced by treatment with complete Freund's adjuvant (CFA) in rats. CFA treatment caused a large increase in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in lamina I, but not lamina II outer zone, dorsal horn neurons. However, blocking NMDA receptors had no effect on spontaneous EPSCs in lamina I neurons of CFA-treated rats. Application of a specific TRPA1 antagonist, AM-0902, or of a specific TRPV1 antagonist, 5'-iodoresiniferatoxin, significantly attenuated the elevated frequency of spontaneous EPSCs and miniature EPSCs, the amplitude of monosynaptic EPSCs evoked from the dorsal root in lamina I neurons of CFA-treated rats. AM-0902 and 5'-iodoresiniferatoxin had no effect on evoked or miniature EPSCs in lamina I neurons of vehicle-treated rats. In addition, intrathecal injection of AM-0902 or 5'-iodoresiniferatoxin significantly reduced pain hypersensitivity in CFA-treated rats but had no effect on acute nociception in vehicle-treated rats. These findings suggest that chronic inflammatory pain is associated with NMDA receptor-independent potentiation in glutamatergic drive to spinal lamina I neurons. Endogenous presynaptic TRPA1 and TRPV1 activity at the spinal level contributes to increased nociceptive input from primary sensory nerves to dorsal horn neurons in inflammatory pain. This article is protected by copyright. All rights reserved.
Learn More >Pain-related cues are evolutionarily primed to capture attention, although evidence of attentional biases towards pain-related information is mixed in healthy individuals. The present study explores whether healthy individuals show significantly different eye-movement behaviours when viewing real-world pain-related scenes compared to neutral scenes. The effect of manipulating via written information the threat value of the pain-related scenes on eye-movement behaviours was also assessed.
Learn More >Vulvodynia is a remarkably prevalent chronic pain condition of unknown etiology. An increase in numbers of vulvar mast cells often accompanies a clinical diagnosis of vulvodynia and a history of allergies amplifies the risk of developing this condition. We previously showed that repeated exposures to oxazolone dissolved in ethanol on the labiar skin of mice led to persistent genital sensitivity to pressure and a sustained increase in labiar mast cells. Here we sensitized female mice to the hapten dinitrofluorobenzene (DNFB) dissolved in saline on their flanks, and subsequently challenged them with the same hapten or saline vehicle alone for ten consecutive days either on labiar skin or in the vaginal canal. We evaluated tactile ano-genital sensitivity, and tissue inflammation at serial timepoints. DNFB-challenged mice developed significant, persistent tactile sensitivity. Allergic sites showed mast cell accumulation, infiltration of resident memory CD8CD103 T cells, early, localized increases in eosinophils and neutrophils, and sustained elevation of serum Immunoglobulin E (IgE). Therapeutic intra-vaginal administration of Δ-tetrahydrocannabinol (THC) reduced mast cell accumulation and tactile sensitivity. Mast cell-targeted therapeutic strategies may therefore provide new ways to manage and treat vulvar pain potentially instigated by repeated allergenic exposures.
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