Evaluation of the effects of specific opioid receptor agonists in a rodent model of spinal cord injury

Objective: The current study aimed to evaluate the contribution(s) of specific opioid receptor systems to the analgesic and detrimental effects of morphine, observed after spinal cord injury in prior studies. Study design: We used specific opioid receptor agonists to assess the effects of mu- (DAMGO), delta- (DPDPE) and kappa- (GR89696) opioid receptor activation on locomotor (Basso, Beattie and Bresnahan scale, tapered beam and ladder tests) and sensory (girdle, tactile and tail-flick tests) recovery in a rodent contusion model (T12). We also tested the contribution of non-classic opioid binding using [+]- morphine. Methods: First, a dose-response curve for analgesic efficacy was generated for each opioid agonist. Baseline locomotor and sensory reactivity was assessed 24 h after injury. Subjects were then treated with an intrathecal dose of a specific agonist and re-tested after 30 min. To evaluate the effects on recovery, subjects were treated with a single dose of an agonist and both locomotor and sensory function were monitored for 21 days. Results: All agonists for the classic opioid receptors, but not the [+]- morphine enantiomer, produced antinociception at a concentration equivalent to a dose of morphine previously shown to produce strong analgesic effects (0.32 mu mol). DAMGO and [+]- morphine did not affect long-term recovery. GR89696, however, significantly undermined the recovery of locomotor function at all doses tested. Conclusions: On the basis of these data, we hypothesize that the analgesic efficacy of morphine is primarily mediated by binding to the classic mu-opioid receptor. Conversely, the adverse effects of morphine may be linked to activation of the kappa-opioid receptor. Ultimately, elucidating the molecular mechanisms underlying the effects of morphine is imperative to develop safe and effective pharmacological interventions in a clinical setting.