Changes in G proteins genes expression in rat lumbar spinal cord support the inhibitory effect of chronic pain on the development of tolerance to morphine analgesia

Abstract

There are some reports regarding the inhibitory effect of pain on tolerance development to analgesic effect of opioids. The present study was designed to investigate whether the chronic formalin induced pain is able to reverse analgesic tolerance to morphine and to evaluate the expression of G(alpha i/o) and G(beta) subunits of G proteins in the context of chronic pain, development of morphine tolerance and their combination. Morphine tolerance was induced by chronic systemic (intraperitoneally, i.p.) or spinal (intrathecally, i.t.) administration of morphine to male Wistar rats weighing 200-240 g and analgesia was assessed using tail flick test. Chronic pain was induced by 4 daily intraplantar injections of 50 microl of 5% formalin. Lumbar spinal tissues were assayed for the expression of G(alpha i/o) and G(beta) proteins using "semiquantitative PCR" normalized to beta-actin gene expression. Results showed that chronic formalin induced pain could reduce and reverse the development of tolerance in rats that had received chronic (i.p. or i.t.) administration of morphine. Chronic administration of morphine did not change G(alpha i/o) gene expression, while chronic pain significantly increased its expression. The expression of G(beta), however, was increased after the chronic administration of morphine, but did not change after the induction of chronic pain. None of these increases were observed when morphine and formalin were administered at the same time. Due to synchronous development of morphine tolerance and changes in expression of G(beta), it may be concluded that the development of tolerance to analgesic effect of morphine is partially mediated by increase in G(beta) gene expression. The increase in G(alpha i/o) genes expression produced by chronic pain may facilitate the opioid signaling pathway and compensate for morphine-induced tolerance.