Opioid regulation of spinal cord plasticity: Evidence the kappa-2 opioid receptor agonist GR89696 inhibits learning within the rat spinal cord

Spinal cord neurons can support a simple form of instrumental learning. In this paradigm, rats completely transected at the second thoracic vertebra learn to minimize shock exposure by maintaining a hindlimb in a flexed position. Prior exposure to uncontrollable shock (shock independent of leg position) disrupts this learning. This learning deficit lasts for at least 24 h and depends on the NMDA receptor. Intrathecal application of an opioid antagonist blocks the expression, but not the induction, of the learning deficit. A comparison of selective opioid antagonists implicated the kappa-opioid receptor. The present experiments further explore how opioids affect spinal instrumental learning using selective opioid agonists. Male Sprague–Dawley rats were given an intrathecal injection (30 nmol) of a kappa-1 (U69593), a kappa-2 (GR89696), a mu (DAMGO), or a delta opioid receptor agonist (DPDPE) 10 min prior to instrumental testing. Only the kappa-2 opioid receptor agonist GR89696 inhibited acquisition (Experiment 1). GR89696 inhibited learning in a dose-dependent fashion (Experiment 2), but had no effect on instrumental performance in previously trained subjects (Experiment 3). Pretreatment with an opioid antagonist (naltrexone) blocked the GR89696-induced learning deficit (Experiment 4). Administration of GR89696 did not produce a lasting impairment (Experiment 5) and a moderate dose of GR89696 (6 nmol) reduced the adverse consequences of uncontrollable nociceptive stimulation (Experiment 6). The results suggest that a kappa-2 opioid agonist inhibits neural modifications within the spinal cord.