Neuropharmacology
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N-type calcium channels play important roles in the control of neurotransmission release and transmission of pain signals to the central nervous system. Their selective inhibitors are believed to be potential drugs for treating chronic pain. In this study, a novel neurotoxin named Huwentoxin-XVI (HWTX-XVI) specific for N-type calcium channels was purified and characterized from the venom of Chinese tarantula Ornithoctonus huwena. ⋯ Toxin treatment also changed withdrawal latency in hot plate tests. Intriguingly, we found that intramuscular injection of the toxin reduced mechanical allodynia induced by incisional injury in Von Frey test. Thus, our findings suggest that the analgesic potency of HWTX-XVI and its greater reversibility could contribute to the design of a novel potential analgesic agent with high potency and low side effects.
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Dopamine replacement with l-DOPA is the most effective therapy in Parkinson's disease. However, with chronic treatment, half of the patients develop an abnormal motor response including dyskinesias. The specific molecular mechanisms underlying dyskinesias are not fully understood. ⋯ Pharmacological experiments combining buspirone with 5HT1A and DRD3 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required, but not sufficient, for blocking dyskinesias. The correlation between pDARPP32 ratio and dyskinesias was significant but not strong, pointing to the involvement of convergent factors and signalling pathways. Our results suggest that in dyskinetic rats DRD3 striatal over-expression could be instrumental in the activation of DRD1-downstream signalling and demonstrate that the anti-dyskinetic effect of buspirone in this model is correlated with DRD1 pathway normalization.
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Chemokines are associated with both inflammatory and immune responses and play an important role in the pathophysiological process associated with neuropathic pain following peripheral nerve injury. Here, we investigated the involvement of peripheral keratinocyte-derived chemokine (KC) in the pathogenesis of neuropathic pain induced by the partial ligation of the sciatic nerve (PLSN) in mice. PLSN increased KC levels and its mRNA in both the sciatic nerve and spinal cord when compared with sham-operated mice. ⋯ We also demonstrated an increased level of cytokines (IL-1β, IL-6, and MCP-1, but not TNF-α) after i.n. injection of KC in the mouse sciatic nerve. Together, these findings suggest a role for KC in the development of neuropathic pain in mice by attracting neutrophils to the injured site and increasing the production of proinflammatory mediators. Therefore, strategies to inhibit the action or the release of this chemokine could constitute a therapeutic tool for the management of neuropathic pain in humans.
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Oxaliplatin, unlike other platinum anticancer agents, has only mild toxic effects on the hematopoietic, urinary and gastrointestinal systems. Its dose-limiting side effect is neurotoxicity that may evolve to a neuropathic syndrome which is difficult to treat. In this study we treated rats with oxaliplatin (2.4 mg/kg/day intraperitoneally, for 3 weeks), and observed that expression levels of the α7 nicotinic acetylcholine receptor (nAChR) subunit were dramatically decreased both in the peripheral and central nervous system. ⋯ Astrocyte density was enhanced by the agonist treatment in the spinal cord, thalamus and somatosensory area 1 as opposed to the effects of oxaliplatin treatment. (R)-ICH3 and PNU-282987 per se increased glial cell number in a region-specific manner. In summary, α7 nAChR is involved in oxaliplatin-dependent neuropathology and the agonists (R)-ICH3 and PNU-282987 reduce pain and protect nervous tissue with concomitant glial activation. Since glial cells play a role both in pain and in neuroprotection, an α7 AChR-dependent modulation of glial functions is suggested to distinguish rescue signals from the pathological pain-mediating pathway.
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Facilitation of serotonin 2C- and 1A-receptor (5-HT2C-R and 5-HT1A-R) mediated neurotransmission in the basolateral nucleus of the amygdala (BLA) has been associated with anxiogenic and anxiolytic effects, respectively. It has been also shown that stimulation of BLA 5-HT2C-Rs underlies the anxiogenic effect caused by acute systemic administration of the antidepressants imipramine or fluoxetine. Here we investigated whether chronic treatment with these two antidepressants, which causes anxiolytic effects, decreases the responsiveness of these receptors in the BLA. ⋯ Acute administration of imipramine (5 mg/kg) failed to interfere with MK-212 effects in both tests. Intra-BLA injection of the 5-HT1A antagonist WAY-100635 blocked the anxiolytic, but not the panicolytic, effect of imipramine in the tests used. Our findings indicate that both a reduction in 5-HT2C-R- and a facilitation of 5-HT1A-R-mediated neurotransmission in the BLA are involved in the anxiolytic effect of antidepressant drugs.