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A noxious stimulus following a more intense stimulus often feels less painful than continuous noxious stimulation. This effect, known as offset analgesia (OA), may be due to descending inhibitory control, to changes in peripheral neural transmission, or both. The timing and location of noxious thermal stimulation were manipulated to better understand the peripheral and central contributions to OA.
Learn More >Fingertip mechanoreceptors comprise sensory neuron endings together with specialized skin cells that form the end-organ. Exquisitely sensitive, vibration-sensing neurons are associated with Meissner's corpuscles in the skin. In the present study, we found that USH2A, a transmembrane protein with a very large extracellular domain, was found in terminal Schwann cells within Meissner's corpuscles. Pathogenic USH2A mutations cause Usher's syndrome, associated with hearing loss and visual impairment. We show that patients with biallelic pathogenic USH2A mutations also have clear and specific impairments in vibrotactile touch perception, as do mutant mice lacking USH2A. Forepaw rapidly adapting mechanoreceptors innervating Meissner's corpuscles, recorded from Ush2a mice, showed large reductions in vibration sensitivity. However, the USH2A protein was not found in sensory neurons. Thus, loss of USH2A in corpuscular end-organs reduced mechanoreceptor sensitivity as well as vibration perception. Thus, a tether-like protein is required to facilitate detection of small-amplitude vibrations essential for the perception of fine-grained tactile surfaces.
Learn More >The hippocampus is an important region for the interaction between depression and pain. Studies show that the P2X4 receptor plays key role in neuropathic pain. This work investigated the potential implication of the P2X4 receptor in the hippocampus in comorbidity of chronic pain and depression. The rat model induced by chronic constriction injury (CCI) plus unpredictable chronic mild stress (UCMS) was used in this study. Our data showed that CCI plus UCMS treatment resulted in abnormal changes in pain and depressive-like behaviors in the rat, accompanied by the upregulated expression of P2X4, NLRP3 (NOD-like receptor protein 3) inflammasome, and interleukin-1β and the activation of p38 MAPK in the hippocampus. The P2X4 antagonist 5-BDBD reversed these abnormal changes in the hippocampus, relieved hippocampal neuronal damage, and alleviated the abnormal pain and depressive-like behaviors in the CCI plus UCMS treated rats. These findings suggest that the P2X4 receptor in the hippocampus may mediate and significantly contribute to the pathological processes of comorbid pain and depression.
Learn More >In this brief report, we demonstrate that the Ca3.3 T-type voltage-gated calcium channel subtype is involved in our FRICT-ION model of chronic trigeminal neuropathic pain. We first showed that the gene encoding Ca3.3 is significantly upregulated in whole trigeminal ganglia of FRICT-ION mice compared to controls at week 10 post-injury. We confirmed protein upregulation of Ca3.3 compared to controls using Western blot analysis of whole trigeminal ganglia tissues. Finally, we demonstrated that intraperitoneal injection of a selective TAT-based Ca3.3 blocking peptide in FRICT-ION mice significantly reduces Ca3.3 protein expression at the peak anti-allodynic effect (4 hrs post-injection) of the attenuated neuropathic pain behavior. We also suggest that blockade of Ca3.3 may be more effective in attenuating trigeminal neuropathic pain in female than male FRICT-ION mice. Therefore, blocking or attenuating Ca3.3 function may be an effective strategy for treatment of trigeminal neuropathic pain.
Learn More >Itch in patients with chronic kidney disease (CKD) is common, often very distressing and associated with depression, reduced quality of life, and increased death. The most common first-line treatment has been the use of antihistamines despite the lack of substantial evidence for its use for uraemic itch. Few recommendations and guidelines exist for treatment.
Learn More >Our knowledge of the pathophysiology of migraine and the molecules implicated in the disorder have evolved over time. Among these, calcitonin gene-related peptide has shown a crucial role that led to the development of therapies specifically targeting the molecule. Four monoclonal antibodies targeting the calcitonin gene-related peptide pathway are currently available after the US FDA approval of eptinezumab for the indication of migraine prevention. This is the only one of the class to be administered intravenously. The pharmacology of eptinezumab and the four studies that led to the approval, two Phase II and two Phase III clinical trials, are reviewed in this paper. Eptinezumab has demonstrated efficacy, tolerability and safety in patients with episodic and chronic migraine. Studies including migraineurs who have failed previous preventives, and comparison with other options administered quarterly, as well as real-world experience data will all be welcome.
Learn More >The purpose of this study was to compare disability in people with HIV and peripheral neuropathy with those without neuropathy and explore how neuropathy and other relevant factors are associated with disability.
Learn More >Low back pain (LBP) is a leading cause of disability. However, the processes contributing to disability are not well understood. Therefore, this study 1) empirically derived LBP subgroups and 2) validated these subgroups using walking performance, pain, and disability measures. Seventy adults with LBP underwent testing for a priori determined sensory (temporal summation; conditioned pain modulation), psychological (positive coping; negative coping), and motor (trunk extensor muscle activation during forward bending and walking) measures. A hierarchical cluster analysis determined subgroups that were then validated using walking (walking speed; Timed Up and Go (TUG); Timed Up and Go-Cognitive (TUG-Cog); obstacle negotiation) and clinical (Brief Pain Inventory; Oswestry Disability Index; low back pressure pain threshold) measures. Two subgroups were derived: 1) a "Maladaptive" subgroup (n=21) characterized by low positive coping, high negative coping, low pain modulation, and atypical trunk extensor activation; and 2) an "Adaptive" subgroup (n=49) characterized by high positive coping, low negative coping, high pain modulation, and typical trunk extensor activation. There were subgroup differences on 7 out of 12 validation measures. The Maladaptive subgroup had reduced walking performance (slower self-selected walking speed, TUG completion, and obstacle approach and crossing speed) and worse clinical presentation (higher pain intensity, pain interference, and disability) (moderate to large effect sizes; p's<0.05). Findings support the construct validity of this multidimensional subgrouping approach. Longitudinal studies are needed to determine if the Maladaptive subgroup is predictive of poor outcomes, such as pain chronicity or persistent disability.
Learn More >Nerve injury-induced changes in gene expression in the dorsal root ganglion (DRG) contribute to neuropathic pain genesis. Eukaryotic initiation factor 4 gamma 2 (eIF4G2) is a general repressor of cap-dependent mRNA translation. Whether DRG eIF4G2 participates in nerve injury-induced alternations in gene expression and nociceptive hypersensitivity is unknown.
Learn More >Inadequate acute pain management can reduce the quality of life, cause unnecessary suffering and can often lead to the development of chronic pain. Using group-based trajectory modelling, we previously identified six distinct pain intensity trajectories for the first 14-day postemergency department (ED) discharge; two linear ones with moderate or severe pain during follow-up (~40% of the patients) and four cubic polynomial order trajectories with mild or no pain at the end of the 14 days (low final pain trajectories). We assessed if previously described acute pain intensity trajectories over 14 days after ED discharge are predictive of chronic pain 3 months later.
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