Selective development of tolerance without dependence in multiple opiate receptors of mouse vas deferens

Abstract

Studies with isolated tissues have provided strong indications for a multiplicity of opiate receptors ^1–4. To satisfy the definition of cross-tolerance (tolerance to a specific opioid implying tolerance to all opioids), chronic exposure to an opiate agonist should cause tolerance and dependence in all opiate-sensitive systems. On the other hand, if multiplicity of opiate receptors is defined in terms of multiple recognition sites whose activation by specific opioids cause independent responses, then development of cross-tolerance is less likely. The mouse vas deferens (MVD) provides a useful model to test these considerations. This tissue contains δ-opiate receptors, for which D-Ala²-D-Leu⁵-enkephalin (DADL) represents the most selective agonist, as well as μ-receptors, for which sufentanyl appears highly selective^3,5–7. We report here that isolated vasa deferentia of mice chronically treated with DADL are 800-fold less sensitive to this δ-receptor agonist, whereas there is no cross-tolerance to μ-receptor agonists. On the other hand, chronic exposure of mice to sufentanyl renders their vasa deferentia more than 1,000-fold less sensitive to sufentanyl, but affects their sensitivity to DADL insignificantly. Apparently, such highly tolerant preparations exhibit no detectable sign of dependence when challenged with naloxone or clonidine. These findings favour the notion that opiate tolerance and dependence dissociate in the MVD.