Earlier studies using the guinea pig longitudinal muscle/myenteric plexus (LM/MP) demonstrated that chronic morphine treatment in vivo leads to the development of heterologous tolerance while chronic treatment with WIN 55,212-2 induces homologous tolerance. Few studies have evaluated whether a similar difference in tolerance development exists to the analgesic or hypothermic effects of these agents. Tolerance produced following chronic morphine (7 days) or WIN-55,212-2 (5 days) injection was assessed by determining the alteration in hypothermic response (using a rectal thermometer) or mechanical (paw pressure) or thermal (hot plate) analgesic threshold to challenge doses of WIN-55,212-2 and morphine. The tolerance observed in the hot plate test corresponded closely to that observed in the LM/MP studies where morphine pretreatment produced heterologous tolerance and WIN-55,212-2 pretreatment induced homologous tolerance. In contrast, chronic WIN-55,212-2 pretreatment precipitated tolerance to the analgesic effect of morphine in the paw pressure model despite the absence of an analgesic effect to this agent. Unlike chronic treatment with WIN-55,212-2, no tolerance to the hypothermic effect of WIN-55,212-2 was observed following morphine treatment. However, the hypothermic response observed to morphine challenge was modest suggesting that tolerance to this effect may be difficult to assess or not biologically relevant. The non-uniform character of tolerance observed in different models further suggests that the analysis of tolerance using in vivo test systems involves complex neuronal interactions in which altered responsiveness at one site may produce cascading cellular effects within a neuronal circuit that may differentially impact on tolerance expression.
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