Pain control between cannabinoid and vanilloid receptors: cooperations and counteractions
The transient receptor potential (TRP) channel of the vanilloidtype 1 (the “capsaicin receptor”) is involved in thermosensation, pain transduction and inflammation. It is expressed in sensory fibers of Aδ and C-type, in dorsal root and trigeminal ganglia and in perivascular neurons, often together with TRP channels of the ankyrin type-1 (TRPA1, the “mustard receptor”). Whilst TRPV1 is activated by high temperatures, low pH (as during inflammatory conditions) and inflammatory mediators, TRPA1 is activated by cold and irritants. TRPV1 activation in sensory neurons leads to release of vasodilatory peptides, thus contributing to neurogenic inflammation. TRPV1 is also expressed in central neurons of the periaqueductal grey (PAG) and rostral ventrolateral medulla (RVM), where it modulates the descending pathway of antinociception. Contrary to its role in the spinal cord and sensory afferents, TRPV1 in the PAG-RVM contributes to descending antinociception by enhancing both glutamatergic signalling/OFF neuron activity in the RVM and μ-opioid receptor-mediated analgesia. TRPV1 is expressed in the prefrontal cortex, where it also participates in neuropathic pain. In both central and sensory neurons, TRPV1 is often co-expressed with cannabinoid CB1 receptors (the Δ9-tetrahydrocannabinol [THC] receptors), with which it shares two endogenous agonists, anandamide and NADA. CB1 receptor activation by these and other endocannabinoids plays a major role in the peripheral and central control of pain. TRPV1 and CB1 can either act in concert or oppose each other at modulating neurotransmitter release and pain. Furthermore, plant cannabinoids, such as THC, cannabidiol or cannabichromene, activate and subsequently desensitize TRPV1 and/or TRPA1 channels, and this property allows these compounds to influence pain and inflammation. These interactions suggest that the “endovanilloid/endocannabinoid” system is a major player in the pathophysiology of pain.
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