THE KAPPA-2 OPIOID RECEPTOR AGONIST GR89696 PRODUCES A BEHAVIORAL DEFICIT IN SPINALIZED RATS.

S. N. Washburn and J. W. Grau, Dept. of Psychology, Texas A&M Univ., College Station, TX 77843.

Spinal cord neurons can support a simple form of instrumental learning (Grau et al., 1998, Behav Neurosci, 112, 1366). Rats transected at the second thoracic vertebra receive shock to one hindlimb whenever the leg is extended (controllable shock). These subjects exhibit a systematic increase in flexion duration that reduces net shock exposure. Rats that receive an equal amount of shock independent of leg position (uncontrollable shock) do not exhibit an increase in flexion duration. Rats given uncontrollable shock also fail to learn when later tested with response contingent shock applied to either the same or opposite leg. This behavioral deficit can be induced by just 6 min of intermittent shock to the leg or tail and lasts up to 48 hrs.

Prior studies suggest an opioid peptide contributes to the expression of the behavioral deficit observed after uncontrollable shock. Intrathecal application of the opioid antagonist naltrexone blocked the expression of the deficit, but not its induction (Joynes et al., 2003, Neurobiol Lrn & Mem, 80). The deficit was also eliminated by the kappa antagonist nor-BNI administered prior to testing. Neither a mu (CTOP) nor delta (naltrindole) antagonist blocked the deficit. These results suggest that prior exposure to uncontrollable shock enhances a kappa opioid mediated event that inhibits learning. If this is true, administration of a kappa opioid agonist should prevent instrumental learning. We tested this hypothesis using equal molar concentrations (30 nmol) of a mu (DAMGO), delta (DPDPE), kappa-1 (U69593), or kappa-2 (GR89696) agonist. Subjects received a T2 transection and a catheter was inserted with the tip positioned in the lumbosacral enlargement. The next day, the drug was infused and subjects were tested with controllable shock 10 min later. Only the kappa-2 agonist (GR89696) inhibited instrumental learning. Supported by MH60157 and NS41548 to J.W.G