Cannabinoid–vanilloid receptor interactions in pain signaling

Agents that activate cannabinoid CB1 receptors for marijuana's active principal, THC, or vanilloid VR1 receptors for red chilli peppers' pungent ingredient, capsaicin, modulate pain perception. Stimulation of presynaptic CB1 leads to inhibition of glutamate release in the spinal cord, whereas VR1 stimulation causes release of substance P and CGRP from DRG neurons. VR1 undergoes rapid desensitization by its agonists, which makes VR1‐expressing neurons insensitive to subsequent stimulation and results in analgesia. Thus, both CB1 and VR1, which are coexpressed in several spinal and DRG neurons, are targets for analgesic drug development. CB1 and VR1 also share endogenous agonists, namely anandamide, NADA and some of their analogs, and may be regarded as metabotropic and ionotropic receptors for the same family of mediators, with opposing roles in pain perception. The development of ‘hybrid’ CB1/VR1 agonists as potent analgesics and the functional relationships between CB1 and VR1 in sensory neurons will be discussed.