The chronic use of opioids is often accompanied by the development of tolerance and/or dependence upon these agents due to the adaptive changes in the response of the subject to the agent. On cellular level, these phases of altered responsiveness have been shown to be the sequelae of a combination of multiple independent components acting in concert. Changes in the number, affinity, or membrane trafficking of opioids receptors, the coupling of receptors to G-proteins or in associated second messenger systems have been implicated in underlying the aforementioned phenomena. Several observations have been shown that lithium is able to contradict the expected response in animals pre-treated with morphine. These facts clearly manifest the involvement of lithium in at least one of the diverse pathways that lead to morphine dependence and/or tolerance. The aim of the present study was to investigate the effect of lithium on acute morphine-induced tolerance and dependence in an in vitro model of isolated guinea pig ileum which has been extensively used for the assessment of these effects of opioids. Morphine inhibited electrically stimulated twitch of ileum in a concentration-dependent manner (pD(2)=7.27+/-0.16). Tolerance to this effect was induced by the incubation of ileum with 2xIC(50) of morphine for 2 h that induced a degree of tolerance of 14.7. The co-incubation of ileum with morphine along lithium chloride (1 mM) reduced the degree of tolerance significantly (P<0.001) and restored the sensitivity of ileum to the morphine inhibitory effect. Lithium chloride can also reduce the expression of tolerance to morphine significantly (P<0.01). Dependence was induced by incubation with 4xIC(50) of morphine for 2 h and was assessed based on naloxone-induced contractions (10(-5 )M). Lithium chloride (1 mM) can attenuate the development but not the expression of dependence to morphine as shown by the significant decrease in naloxone-induced contractions (P<0.05). These results suggest that lithium chloride can reduce the development and expression of acute tolerance to and development of dependence on morphine in the myenteric plexus of guinea pig ileum.