The effect of cannabinoids on capsaicin-evoked calcitonin gene-related peptide (CGRP) release from the isolated paw skin of diabetic and non-diabetic rats

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 oil capsaicin-evoked release of calcitonin gene-related peptide (CGRP) from the rat paw skin in vitro. comparing non-diabetic and strepto/otocin-induced diabetic animals. Diabetes caused a, greater than two-fold increase in basal and capsaicin-evoked CGRP release. The synthetic CB1/CB2. receptor agonist. CP55940 (100 nM), inhibited capsaicin-evoked CGRP release in both non-diabetic (3092+/-7.6%, P<0.05) and diabetic animals (37.82+/-9.85%, P<0.05). The CB1 receptor antagonist SR141716A (100 nM), but not the CB, receptor antagonist SR144528 (100 nM), significantly attenuated the inhibitors 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 CB1 nor the CB2 receptor antagonist attenuated thin, 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 muM). These data Suggest that peripheral CB, receptor.,, 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-CB1, receptor mediated inhibitory action of the endo endogenous cannabinoid, anandamide. (C) 2002 Elsevier Science Ltd. All rights reserved.