The inhibitory effect of pain on tolerance development to analgesic effect of opioids is reported to be mediated by stress aspect of pain and activation of HPA axis. We tried to investigate whether the chronic pain and co-administration of dexamethasone (Dex) is able to reverse the tolerance and to evaluate expression of Gαi/o and Gβ subunits of G proteins following chronic pain, chronic Dex, tolerance and their combination.Tolerance was induced by chronic intraperitoneal (i.p.) administration of morphine to male Wistar rats and analgesia was assessed using tail flick test. Lumbar spinal tissues were assayed for expression of G proteins using "semi-quantitative PCR" normalized to beta-actin.Both chronic pain and chronic Dex could reduce and reverse the tolerance. Chronic morphine did not change Gαi/o gene expression, while chronic pain and Dex both increased its expression. Expression of Gβ was increased following chronic morphine, but not following chronic pain and Dex. None of these increases were observed when morphine was co-administered with pain or Dex. It seems that the development of tolerance to analgesic effect of morphine is partially mediated by increased Gβ gene expression. The increase in Gαi/o genes expression produced by chronic pain and chronic Dex can facilitate opioid signaling pathway and compensate for morphine-induced tolerance. [J Physiol Sci. 2006;56 Suppl:S89]