Mechanism of Analgesic Drug Action: Evidence for Involvement of Prostaglandins *

Abstract

The isolated, electrically stimulated guinea pig longitudinal muscle-myenteric plexus has proven to be an excellent model system for understanding the mode of action of morphine-type drugs in the CNS. These drugs block electrically-induced contractions by inhibiting release of acetylcholine. We have shown that postaglandins (PGS), particularly of the E series, are highly potent in reversing the effect of these opiates on this preparation, and have suggested that opiates exert their effect via a prostaglandin mechanism. In support of this concept we have shown that various inhibitors of prostaglandin synthesis also block these contractions. Their potency is directly correlated with inhibition of prostaglandin synthetase, the enzyme directly involved with prostaglandin synthesis. This block is also reversed by very small amounts of PGE, or E₂ PGE, and E₂ are highly effective in reversing block of contractions by the enkephalins, newly discovered naturally occurring opiate-like peptides of brain. It is considered that analgesia may be produced by interruption of some key pathways in the CNS for which PGE, or E₂ act as modulators of synaptic transmission in a manner similar to that in the ileum. In support of this concept, we have recently shown (not discussed in the paper) that analgesia produced by direct application of morphine into the periaquaductal gray region of the CNS is very effectively counteracted by small amounts of PGE, or E₂.