Role of the opioid system in the behavioral deficit observed after uncontrollable shock

Abstract

Spinal cord neurons can support a simple form of instrumental learning that can be used to assess behavioral potential (plasticity) within this system. In this paradigm, subjects completely transected at the second thoracic vertebra learn to minimize shock exposure by maintaining a hindlimb in a flexed position. Preexposure to uncontrollable shock (shock independent of leg position) disrupts this learning. Activation of opioid receptors seems to contribute to the expression of the behavioral deficit observed after uncontrollable shock. Intrathecal application of naltrexone, a nonselective opioid receptor antagonist, blocked the expression, but not the induction, of the deficit. Treatment with nor-BNI, a kappa receptor antagonist, prior to testing had a similar effect, whereas mu (CTOP) and delta (naltrindole) receptor antagonists did not block the deficit. These findings suggest that prior exposure to uncontrollable shock induces a kappa opioid mediated event that inhibits learning. The current study examined the role of the kappa receptor in the behavioral deficit. Only GR89696, a selective kappa-2 receptor agonist, inhibited learning. This impairment was dose-dependent and, at the highest dose (30 nmol), inhibited learning for 96 hours. However, GR89696 and uncontrollable shock did not interact in an additive fashion. Instead, an intermediate dose attenuated the induction of the deficit. These findings suggest that activation of kappa receptors, specifically the kappa-2 subtype, inhibit instrumental learning and block the induction of the learning deficit. Both effects may be linked to the inhibition of NMDA-mediated plasticity.