Abstract
Neuropathic pain consequent to peripheral nerve injury has been associated with local inflammation. Following noxious stimulation afferent fibres release substance P (SP) and calcitonin-gene related peptide (CGRP), which are closely related to oedema formation and plasma leakage. The effect of the anandamide transport blocker AM404 has been studied on plasma extravasation after chronic constriction injury (CCI) which consists in a unilateral loose ligation of the rat sciatic nerve (Bennett and Xie, 1988). AM404 (1–3–10 mg kg −1) reduced plasma extravasation in the legated paw, measured as μg of Evans Blue per gram of fresh tissue. A strong effect on vascular permeability was also produced by the synthetic cannabinoid agonist WIN 55,212-2 (0.1–0.3–1 mg kg −1). Using specific antagonists or enzyme inhibitors, we demonstrate that cannabinoids act at several levels: data on the 3rd day suggest a strong involvement of substance P (SP) and calcitonin gene-related peptide (CGRP) in the control of vascular tone, whereas at the 7th and 14th days the major role seems to be played by prostaglandins (PGs) and nitric oxide (NO). Capsaicin injection in ligated paws of AM404- or WIN 55,212-2-treated rats resulted in an increase of Evans Blue extravasation, suggesting the involvement of the cannabinergic system in the protective effect of C fibres of ligated paws. Taken together, these data demonstrate the efficacy of cannabinoids in controlling pain behaviour through the modulation of several pain mediators and markers of vascular reactivity, such as SP, CGRP, PGs and NO.
Highlights
The endogenous acylethanolamides are a group of substances generated on demand through stimulus-dependent cleavage of membrane phospholipid precursors and, after their release, undergo a rapid inactivation (Di Marzo et al, 1994; Piomelli et al, 1998)
In this study we have investigated the effect of daily treatment with the anandamide transport blocker AM404 or the direct cannabinergic drug WIN 55,212-2, on plasma extravasation as a parameter of neurogenic inflammation following constriction injury (CCI), and the involvement of cannabinoid receptors and TRPV1 in this effect
Plasma extravasation was inhibited by chronic administration of AM404: in particular this effect was significant at the doses of 3 and 10 mg/kg ( p < 0.05) with a more significant effect at day 14 ( p < 0.01); whereas the dose of 1 mg/kg did not alter plasma extravasation (Fig. 1A)
Summary
The endogenous acylethanolamides are a group of substances generated on demand through stimulus-dependent cleavage of membrane phospholipid precursors and, after their release, undergo a rapid inactivation (Di Marzo et al, 1994; Piomelli et al, 1998). Anandamide (AEA) represents the major endocannabinoid released by neuron stimulation. Small-diameter primary afferent fibres transmit nociceptive messages to central neurons, but are involved in inflammatory response, such as peripheral neurogenic inflammation (White and Helme, 1985). Following noxious stimulation, these fibres release substance P (SP) and calcitonin gene-related peptide (CGRP), related to oedema and plasma leakage (Basile et al, 1993). Richardson et al (1998) demonstrated that AEA inhibited capsaicin-induced release of CGRP from isolated hind paw skin through a peripheral mechanism of neurosecretion inhibition via CB1 receptor
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