INHIBITION OF THE NEURONAL NICOTINIC RECEPTOR-MEDIATED CURRENT BY KAPPA-OPIOID RECEPTOR AGONISTS IN PC12 CELLS

The authors studied effects of opioid receptor agonists on neuronal ni cotinic-receptor-mediated current in PC12 cells using whole-cell curre nt recording. At 1 mu M, [D-Ala, N-Me, Phe, Gly-ol]-enkephalin (DAMGO) , a selective mu receptor agonist, or 10 mu M methionine-enkephalin, a mu and delta receptor agonist, did not inhibit the current elicited b y 30 mu M nicotine significantly. Dynorphin A (1-17) (0. 1-1 mu M), an endogenous kappa receptor agonist, and U50488 (0.1-10 mu M), a non-pe ptide selective kappa receptor agonist, depressed the nicotine-induced current reversibly in a dose-dependent manner. They accelerated the c urrent decay, resulting in greater effects on the nondesensitized curr ent than the peak current. These effects were not affected by nor-bina ltrophimine, a selective kappa receptor antagonist, or by inclusion of guanosine 5'-O-(2-thiobiphosphate) (GDP[beta-S]), a GTP binding prote in blocker, into the pipette solution. These results demonstrate that two kappa opioid receptor agonists, dynorphin A (1-17) and U50488, inh ibit neuronal nicotinic-receptor-mediated current without the involvem ent of opioid receptors or GTP binding proteins. The acceleration of t he current decay suggests a direct action on nicotinic receptors such as open channel block, or augmentation of desensitization. Modulation of neuronal nicotinic receptors by dynorphins may play a role in some areas where dynorphin release sites and neuronal nicotinic receptors a re colocalized.