NSAIDs, Opioids, Cannabinoids and the Control of Pain by the Central Nervous System

Horacio Vanegas, Enrique Vazquez, Victor Tortorici, Horacio Vanegas, Enrique Vazquez, Victor Tortorici

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) act upon peripheral tissues and upon the central nervous system to produce analgesia. A major central target of NSAIDs is the descending pain control system. The rostral structures of the descending pain control system send impulses towards the spinal cord and regulate the transmission of pain messages. Key structures of the descending pain control system are the periaqueductal gray matter (PAG) and the rostral ventromedial region of the medulla (RVM), both of which are critical targets for endogenous opioids and opiate pharmaceuticals. NSAIDs also act upon PAG and RVM to produce analgesia and, if repeatedly administered, induce tolerance to themselves and cross-tolerance to opioids. Experimental evidence shows that this is due to an interaction of NSAIDs with endogenous opioids along the descending pain control system. Analgesia by NSAIDs along the descending pain control system also requires an activation of the CB1 endocannabinoid receptor. Several experimental approaches suggest that opioids, NSAIDs and cannabinoids in PAG and RVM cooperate to decrease GABAergic inhibition and thus enhance the descending flow of impulses that inhibit pain.

Keywords: NSAID; PAG; RVM; cannabinoid; descending pain control system; opioid.

Figures

Figure 1
Figure 1
Proposed model for the interaction of NSAIDs, opioids and cannabinoids in the descending pain control system to induce analgesia. Minus symbols indicate inhibition. Inhibition of the cyclooxygenases (COX) by NSAIDs reduces the synthesis of prostaglandins (PG) and thromboxanes (TX) and thus increases the availability of arachidonic acid (AA). Opioids also increase the availability of AA by activating the phospholipase A2 via the µ-opioid receptor. Via the 12-lipoxygenases (12-LOX) AA is transformed into hepoxilins, which indirectly inhibit GABA release. By inhibiting COX and FAAH the NSAIDs spare AEA and 2-AG, which bind to the CB1 receptor (The role of the CB2 receptor in this model has not been established.) and thus inhibit GABA release. Removal of inhibition by GABA enhances the activity of output neurons that inhibit pain.

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