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Abstract: 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 (7days) or WIN-55,212-2 (5days) 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. [Copyright &y& Elsevier]

Abstract: Few studies have compared the nature of tolerance that develops following chronic opioid treatment with that which develops after chronic cannabinoid exposure in the same tissue and species. The degree and character of tolerance induced by 7 twice daily injections of morphine or 5 daily injections of the cannabinoid receptor agonist, WIN-55,212-2, was examined by comparing the ability of DAMGO, 2-chloroadenosine (CADO) and WIN-55,212-2 to inhibit neurogenic contractions of the longitudinal muscle/myenteric plexus preparation (LM/MP) and the ability of nicotine to elicit contractions in the LM/MP. Chronic morphine treatment resulted in subsensitivity to all inhibitory agonists (rightward shift in IC50 values of 4–5-fold) and an increased responsiveness to the excitatory effect of nicotine while chronic WIN-55,212-2 exposure resulted in subsensitivity only to WIN-55,212-2 and a reduction in maximum response to both WIN-55,212-2 and DAMGO but no change in responsiveness to CADO. Chronic WIN-55,212-2 treatment significantly reduced CB1 but not MOR receptor protein abundance while chronic morphine treatment did not change either. Assessment of the distribution of MOR and CB1 receptors in myenteric neurons revealed distinct individual receptor expression as well as co-localization which was unaffected by either cannabinoid or opioid treatment. Thus, in contrast to the heterologous tolerance that develops after opioid treatment, tolerance in the LM/MP following chronic in vivo WIN-55,212-2 exposure appears to be homologous in character and is accompanied by a selective decrease in CB1 receptor protein abundance. The data suggest that the cellular basis of tolerance differs between the two systems. [Copyright &y& Elsevier]

Abstract: Since the heterologous tolerance that develops after chronic morphine administration has been proposed to be an adaptive process, it follows that the time course of the change in the cellular components should coincide with the time course of the altered responsiveness. This study correlated the time course over which heterologous tolerance develops with changes in the abundance of selected proteins in the guinea-pig longitudinal muscle/myenteric plexus (LM/MP) preparation. Tissues were obtained at various times following a single surgical implantation procedure and heterologous tolerance confirmed by a significant reduction in the sensitivity of the LM/MP to inhibition of neurogenic twitches by morphine, DAMGO, and 2-CADO. Tolerance developed with a delayed onset (significant 2–5-fold reduction in sensitivity by day 4 after pellet implantation) that reached a maximum by 7 days (4–8-fold reduction in responsiveness) that was maintained through 14 days with normal sensitivity spontaneously returning by 21 days post-implantation. Dot blot analysis was used to examine the abundance of the alpha1 and alpha3 subunit isoforms of the Na+/K+ ATPase and beta-actin over the same time course. The results showed significant decreases in abundance of the alpha3 subunit at 4, 7, and 10 days following pellet implantation but no change in beta-actin or the alpha1 subunit at any time period. These data support the idea that heterologous tolerance following chronic morphine exposure results from a cellular adaptive change that may involve a change in the abundance of the alpha3 subunit isoform of the Na+/K+ ATPase. [Copyright &y& Elsevier]