Ellington Heather C, Cotter Mary A, Cameron Norman E, Ross Ruth A
Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, UK.
Neuropharmacology. 2002 Jun;42(7):966-75. doi: 10.1016/s0028-3908(02)00040-0.
Sensory neural dysfunction is common in patients with peripheral neuropathy, a major complication of diabetes mellitus. In animal models of inflammatory and neuropathic pain cannabinoids potently attenuate pain behaviour, cannabinoid (CB) receptors located on nociceptive primary afferent neurones being important in their anti-hyperalgesic actions. A key measure of sensory neurone function is stimulus-evoked neuropeptide release. We investigated the effect of cannabinoid on capsaicin-evoked release of calcitonin gene-related peptide (CGRP) from the rat paw skin in vitro, comparing non-diabetic and streptozotocin-induced diabetic animals. Diabetes caused a greater than two-fold increase in basal and capsaicin-evoked CGRP release. The synthetic CB(1)/CB(2) receptor agonist, CP55940 (100 nM), inhibited capsaicin-evoked CGRP release in both non-diabetic (30.92+/-7.69%, P<0.05) and diabetic animals (37.82+/-9.85%, P<0.05). The CB(1) receptor antagonist SR141716A (100 nM), but not the CB(2) receptor antagonist SR144528 (100 nM), significantly attenuated the inhibitory action of CP55940. The endogenous cannabinoid, anandamide (100 nM) inhibited capsaicin-evoked CGRP release in non-diabetic animals (28.88+/-7.12%, P<0.05) but neither the CB(1) nor the CB(2) receptor antagonist attenuated this action of anandamide. Anandamide (100 nM) did not significantly inhibit capsaicin-evoked CGRP release from the paw skin of diabetic animals, but it did produce a small stimulation of CGRP release at high concentrations (10 microM). These data suggest that peripheral CB(1) receptors mediate inhibition of capsaicin-evoked neuropeptide release from the paw skin of both non-diabetic and diabetic animals. However, pathological changes in the diabetic animals appear to preclude the non-CB(1) receptor mediated inhibitory action of the endogenous cannabinoid, anandamide.
感觉神经功能障碍在患有外周神经病变的患者中很常见，外周神经病变是糖尿病的主要并发症。在炎症性和神经性疼痛的动物模型中，大麻素能有效减轻疼痛行为，伤害性初级传入神经元上的大麻素（CB）受体在其抗痛觉过敏作用中起重要作用。感觉神经元功能的一个关键指标是刺激诱发的神经肽释放。我们研究了大麻素对辣椒素诱发的大鼠爪皮肤中降钙素基因相关肽（CGRP）释放的影响，比较了非糖尿病动物和链脲佐菌素诱导的糖尿病动物。糖尿病导致基础和辣椒素诱发的CGRP释放增加两倍以上。合成的CB(1)/CB(2)受体激动剂CP55940（100 nM）在非糖尿病动物（30.92+/-7.69%，P<0.05）和糖尿病动物（37.82+/-9.85%，P<0.05）中均抑制辣椒素诱发的CGRP释放。CB(1)受体拮抗剂SR141716A（100 nM）而非CB(2)受体拮抗剂SR144528（100 nM）显著减弱了CP55940的抑制作用。内源性大麻素花生四烯乙醇胺（100 nM）在非糖尿病动物中抑制辣椒素诱发的CGRP释放（28.88+/-7.12%，P<0.05），但CB(1)和CB(2)受体拮抗剂均未减弱花生四烯乙醇胺的这一作用。花生四烯乙醇胺（100 nM）未显著抑制糖尿病动物爪皮肤中辣椒素诱发的CGRP释放，但在高浓度（10 microM）时确实对CGRP释放产生了轻微刺激。这些数据表明，外周CB(1)受体介导了对非糖尿病和糖尿病动物爪皮肤中辣椒素诱发的神经肽释放的抑制作用。然而，糖尿病动物的病理变化似乎排除了内源性大麻素花生四烯乙醇胺的非CB(1)受体介导的抑制作用。
