Characteristics of tolerance in the guinea pig ileum produced by chronic in vivo exposure to opioid versus cannabinoid agonists

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.

Chronic opioid treatment induces heterologous tolerance by changing cell excitability while chronic cannabinoid treatment induces homologous tolerance by modifying the receptor population.Figure optionsDownload as PowerPoint slide