Attenuation of nerve growth factor-induced visceral hyperalgesia via cannabinoid CB(1) and CB(2)-like receptors

Cannabinoids have previously been shown to possess analgesic properties in a model of visceral hyperalgesia in which the neurotrophin, nerve growth factor (NGF), plays a pivotal role. The purpose of this study was to investigate the antihyperalgesic effects of two cannabinoids in NGF-evoked visceral hyperalgesia in order to test the hypothesis that endocannabinoids may modulate the NGF-driven elements of inflammatory hyperalgesia. Intra-vesical installation of NGF replicates many features of visceral hyperalgesia, including a bladder hyper-reflexia and increased expression of the immediate early gene c fos in the spinal cord. We investigated the action of anandamide and palmitoylethanolamide (PEA) on these parameters. Both anandamide (at a dose of 25 mg/kg) and PEA (at a dose of 2.5 mg/kg) attenuated the bladder hyper-reflexia induced by intra-vesical NGF. The use of cannabinoid CB1 receptor (SR141617A) and CB2 receptor (SR144528) antagonists suggested that the effect of anandamide was mediated by both CB1 and CB2 cannabinoid receptors whilst the action of PEA was via CB2 (or CB2-like) receptors only. Furthermore, anandamide (25 mg/kg) and PEA (2.5 mg/kg) reduced intra-vesical NGF-evoked spinal cord Fos expression at the appropriate level (L6) by 35 and 43%, respectively. However, neither CB1 nor CB2 receptor antagonists altered the action of anandamide. PEA-induced reduction in Fos expression was abrogated by SR144528. These data add to the growing evidence of a therapeutic potential for cannabinoids, and support the hypothesis that the endogenous cannabinoid system modulates the NGF-mediated components of inflammatory processes.