Pain
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The present study examined whether enhancement of endogenous cannabinoid levels by administration of the fatty acid amide hydrolase inhibitor URB597 could modulate joint nociception in 2 rodent models of osteoarthritis (OA). OA-like changes were induced in male Wistar rats by intra-articular injection of monoiodoacetate, while Dunkin-Hartley guinea pigs (age 9-12 months) develop OA naturally and were used as a model of spontaneous OA. Joint nociception was measured by recording electrophysiologically from knee joint primary afferents in response to noxious hyper-rotation of the joint before and after close intra-arterial injection of URB597 (0.03 mg; 0.1 mL bolus); the CB(1) receptor antagonist AM251 (1 mg/kg intraperitoneally) or the CB(2) receptor antagonist AM630 (1 mg/kg intraperitoneally). ⋯ Systemic URB597 administration significantly reduced hindlimb incapacitance in monoiodoacetate joints and co-administration of the CB(1) antagonist abolished this effect. Local injection of URB597 into OA knee joints reduces mechanonociception and pain, and this response is mediated by CB(1) receptors. Targeting endocannabinoid-metabolizing enzymes in the peripheral nervous system could offer novel therapeutic approaches for the treatment of OA pain.
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Transient receptor potential ion channels (TRPs) expressed in the periphery sense and electrically transduce noxious stimuli to transmit the signals to the brain. Many natural and synthetic ligands for the sensory TRPs have been found, but little is known about endogenous inhibitors of these TRP channels. Recently, we reported that farnesyl pyrophosphate, an endogenous substance produced in the mevalonate pathway, is a specific activator for TRPV3. ⋯ Furthermore, local IPP pretreatment significantly reversed mechanical and thermal hypersensitivity of inflamed animals. Taken together, the present study suggests that IPP is a novel endogenous TRPA1 and TRPV3 inhibitor that causes local antinociception. Our results may provide useful chemical information to elucidate TRP physiology in peripheral pain sensation.
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Little is known about the pathophysiological mechanisms of radicular pain. We investigated changes in synaptic transmission of substantia gelatinosa (SG) neurons after an injury to the L5 nerve root using in vivo patch-clamp recording. A total of 141 SG neurons were recorded at L4 and L5 segmental levels of the spinal cord in root constriction rats and sham-operated control rats. ⋯ The mean amplitudes of EPSCs evoked by mechanical stimuli at L4 and L5 segmental levels were larger in the root constriction group than in the control group. The results indicated that injuring the nerve root led to characteristic excitatory synaptic transmission in SG neurons at each segmental level and changed sensory processing in SG neurons at the segment to which the injured nerve projected. These changes could lead to spontaneous pain, mechanical allodynia, and hyperalgesia contributing to the pathogenesis of radicular pain.
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Despite the increasing interest in TRPA1 channel as a pain target, its role in cold sensation and body temperature regulation is not clear; the efficacy and particularly side effects resulting from channel blockade remain poorly understood. Here we use a potent, selective, and bioavailable antagonist to address these issues. A-967079 potently blocks human (IC(50): 51 nmol/L, electrophysiology, 67 nmol/L, Ca(2+) assay) and rat TRPA1 (IC(50): 101 nmol/L, electrophysiology, 289 nmol/L, Ca(2+) assay). ⋯ Unlike TRPV1 antagonists, A-967079 does not alter body temperature. It also does not produce locomotor or cardiovascular side effects. Collectively, these data provide novel insights into TRPA1 function and suggest that the selective TRPA1 blockade may present a viable strategy for alleviating pain without untoward side effects.