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Migraine Age of Onset and Association With Ischemic Stroke in Late Life: 20 Years Follow-Up in ARIC.
To evaluate the association between cumulative exposure to migraine and incidence of ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study.
Learn More >Human immuno-deficiency virus (HIV) associated sensory neuropathy (SN) is a frequent complication of HIV infection. It is extremely difficult to alleviate and hence the quality of life of affected individuals is severely and adversely impacted. Stavudine (d4T) is an antiretroviral drug that was widely used globally prior to 2010 and that is still used today in resource-limited settings. Its low cost and relatively good efficacy when included in antiretroviral dosing regimens means that there is a large population of patients with d4T-induced antiretroviral toxic neuropathy (ATN). As there are no FDA approved drugs for alleviating ATN, it is important to establish rodent models to probe the pathobiology and to identify potentially efficacious new drug treatments. In the model establishment phase, d4T administered intravenously at a cumulative dose of 375 mg/kg in male Wistar Han rats evoked temporal development of sustained mechanical allodynia in the hindpaws from day 10 to day 30 after initiation of d4T treatment. As this d4T dosing regimen was also well tolerated, it was used for ATN model induction for subsequent pharmacological profiling. Both gabapentin at 30-100 mg/kg and morphine at 0.3-2 mg/kg given subcutaneously produced dose-dependent relief of mechanical allodynia with estimated ED's of 19 mg/kg and 0.4 mg/kg, respectively. In contrast, intraperitoneal administration of meloxicam or amitriptyline up to 30 mg/kg and 7 mg/kg, respectively, lacked efficacy. Our rat model of ATN is suitable for investigation of the pathophysiology of d4T-induced SN as well as for profiling novel molecules from analgesic drug discovery programs.
Learn More >To analyse the prevalence and incidence of pregabalin and gabapentin (P/G) prescriptions, typical therapeutic uses of P/G with special attention to pain-related diagnoses and discontinuation rates.
Learn More >Patients diagnosed with chronic fatigue syndrome (CFS) or fibromyalgia experience chronic pain. Concomitantly, the rat model of CFS exhibits microglial activation in the lumbar spinal cord and pain behavior without peripheral tissue damage and/or inflammation. The present study addressed the mechanism underlying the association between pain and chronic stress using this rat model.
Learn More >Chronic muscle pain is a prominent symptom of the hand-arm vibration syndrome, an occupational disease induced by exposure to vibrating power tools, but the underlying mechanism remains unknown. We evaluated the hypothesis that vibration induces an interleukin 6 (IL-6) mediated down-regulation of the potassium voltage-gated channel subfamily A member 4 (KV1.4) in nociceptors leading to muscle pain. Adult male rats were submitted to a protocol of mechanical vibration of the right hind limb. Twenty-four hours after vibration muscle hyperalgesia was observed, concomitant to increased levels of IL-6 in the gastrocnemius muscle and decreased expression of KV1.4 in the dorsal root ganglia. Local injection of neutralizing antibodies against IL-6 attenuated the muscle hyperalgesia induced by vibration, whereas antisense knockdown of this channel in the dorsal root ganglia mimicked the muscle hyperalgesia observed in the model of hand-arm vibration syndrome. Finally, knockdown of the IL-6 receptor signaling subunit glycoprotein 130 (gp130) attenuated both vibration-induced muscle hyperalgesia and down-regulation of KV1.4. These results support the hypothesis that IL-6 plays a central role in the induction of muscle pain in the hand-arm vibration syndrome. This likely occurs through intracellular signaling downstream to the IL-6 receptor subunit gp130, which decreases the expression of KV1.4 in nociceptors.
Learn More >Identification of genetic variants that influence susceptibility to pain is key to identifying molecular mechanisms and targets for effective and safe therapeutic alternatives to opioids. To identify genes and variants associated with persistent pain, we measured late phase response to formalin injection in 275 male and female Diversity Outbred (DO) mice genotyped for over 70 thousand SNPs. One quantitative trait locus (QTL) reached genome-wide significance on chromosome 1 with a support interval of 3.1 Mb. This locus, Nociq4 (nociceptive sensitivity QTL 4; MGI:5661503), harbors the well-known pain gene Trpa1 (transient receptor potential cation channel, subfamily A, member 1). Trpa1 is a cation channel known to play an important role in acute and chronic pain in both humans and mice. Analysis of DO founder strain allele effects revealed a significant effect of the CAST/EiJ allele at Trpa1, with CAST/EiJ carrier mice showing an early, but not late, response to formalin relative to carriers of the seven other inbred founder alleles (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, PWK/PhJ, and WSB/EiJ). We characterized possible functional consequences of sequence variants in Trpa1 by assessing channel conductance, TRPA1-TRPV1 interactions, and isoform expression. The phenotypic differences observed in CAST/EiJ relative to C57BL/6J carriers were best explained by Trpa1 isoform expression differences, implicating a splice junction variant as the causal functional variant. This study demonstrates the utility of advanced, high-precision genetic mapping populations in resolving specific molecular mechanisms of variation in pain sensitivity.
Learn More >We surveyed urine microbiota of females diagnosed with interstitial cystitis/bladder pain syndrome (IC/BPS) and matched control participants enrolled in the National Institutes of Health (NIH) Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network using the culture-independent methodology. Midstream urine specimens were analyzed with the Plex-ID molecular diagnostic platform that utilizes polymerase chain reaction⁻electrospray ionization⁻time-of-flight⁻mass spectrometry (PCR-ESI-TOF MS) to provide a comprehensive identification of bacterial and select fungal species. IC/BPS and control participants were evaluated for differences (presence, diversity, and abundance) in species and genus. Urine specimens obtained from 181 female IC/BPS and 182 female control participants detected a total of 92 species (41 genera). Mean (SD) species count was 2.49 (1.48) and 2.30 (1.28) among IC/BPS and control participants, respectively. Overall species composition did not significantly differ between IC/BPS and control participants at any level ( = 0.726 species level, = 0.222 genus level). IC/BPS participants urine trended to an overabundance of ( = 0.09) detected but had a lower prevalence of compared with control participants ( = 0.002). The relative abundance data analysis mirrored the prevalence data differences with no significant differences in most species or genus abundance other than and ( = 0.08 and = 0.001, respectively). No cause and/or effect conclusion can be drawn from this observation, but it suggests that a more comprehensive evaluation (vaginal, bowel, catheterized bladder and/or tissue-based specimens) of the lower urinary tract microbiota in IC/BPS patients is warranted.
Learn More >In humans, many cases of congenital insensitivity to pain (CIP) are caused by mutations of components of the NGF/TrkA signaling pathway, which is required for survival and specification of nociceptors and plays a major role in pain processing. Mutations in PRDM12 have been identified in CIP patients that indicate a putative role for this transcriptional regulator in pain sensing. Here, we show that Prdm12 expression is restricted to developing and adult nociceptors and that its genetic ablation compromises their viability and maturation. Mechanistically, we find that Prdm12 is required for the initiation and maintenance of the expression of TrkA by acting as a modulator of Neurogenin1/2 transcription factor activity, in frogs, mice, and humans. Altogether, our results identify Prdm12 as an evolutionarily conserved key regulator of nociceptor specification and as an actionable target for new pain therapeutics.
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