Abstract
IntroductionTolerance (TOL) and physical dependence (PD) constitute important limitations of opioid therapy. The aim of our study was to validate research tools to investigate TOL and PD and to characterize the interactions between opioid (OR) and cannabinoid (CB) receptors in these processes in the GI tract.MethodsTOL was assessed through the comparison of morphine ability to inhibit electrically evoked smooth muscles contractility in the mouse ileum that was previously incubated with/without morphine for 1 h. To evaluate the PD, the ileum was incubated with morphine for 10 min, then challenged with naloxone to induce withdrawal response (WR). The OR/CB interactions were evaluated using mixed agonist (PR-38) and AM-251 (CB1 antagonist).ResultsThe inhibitory effect of morphine on ileal contractions was weaker in tissue incubated with this opioid than in tissue incubated without opioid. The opposite was noted for PR-38. In tissues exposed to morphine, but not to PR-38, naloxone induced a WR. The blockage of CB1 receptors with AM-251 before the addition of PR-38 resulted in a naloxone-induced WR.ConclusionThe co-activation of OR and CB reduced development of TOL and PD to opioids in the mouse GI tract and mixed OR/CB agonists are promising alternative to currently used opioid drugs.
Highlights
Tolerance (TOL) and physical dependence (PD) constitute important limitations of opioid therapy
In further studies we evaluated whether a mixed opioid receptors (ORs)/ CB1 agonist (PR-38) differs from morphine in its potency of tolerance development in the mouse ileum
We observed that the effect evoked by PR-38 added into the organ bath at increasing concentrations (10–11–10–6 M) was opposite to that obtained in experiments with morphine: the incubation with PR-38 did not lead to the tolerance development
Summary
Tolerance (TOL) and physical dependence (PD) constitute important limitations of opioid therapy. Conclusion The co-activation of OR and CB reduced development of TOL and PD to opioids in the mouse GI tract and mixed OR/CB agonists are promising alternative to currently used opioid drugs. Development of tolerance and physical dependence to the analgesic effect of opioids is one the most important side effects during chronic therapy with these drugs. Physical dependence is a condition, in which abrupt or gradual drug withdrawal or administration of antagonist (in case of opioids—naloxone) causes unpleasant physical symptoms, such as: weight loss, diarrhea, jumping, teeth chattering. These symptoms disappear after the administration of drug or over time [2, 3]
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