MU-OPIOID AND GABA(B) RECEPTORS MODULATE DIFFERENT TYPES OF CA2+ CURRENTS IN RAT NODOSE GANGLION NEURONS

Whole-cell patch-clamp recordings were obtained from nodose ganglion n eurons acutely dissociated from 10-30-day-old rats to characterize the Ca2+ channel types that are modulated by GABA(B) and mu-opioid recept ors. Five components of high-threshold current were distinguished on t he basis of their sensitivity to blockade by omega-conotoxin GVIA, nif edipine, omega-agatoxin TVA and omega-conotoxin MVIIC. Administration of the mu-opioid agonist H-Tyr-D-Ala-Gly-Phe(N-Me)-Gly-ol (0.3-1 mM) o r the GABA(B) agonist baclofen in saturating concentrations suppressed high-threshold Ca2+ currents by 49.9+/-2.4% (n=69) and 18.7+/-2.1% (n =35), respectively. The inhibition by H-Tyr-D-Ala-Gly-Phe(N-Me)-Gly-ol exceeded that by baclofen in virtually all neurons that responded to both agonists (67%), and occlusion experiments revealed that responses to mu-opioid and GABA(B) receptor activation were not linearly additi ve. In addition, administration of staurosporine, a non-selective inhi bitor of protein kinase A and C, did not affect the inhibitory respons es to either agonist or prevent the occlusion of baclofen-induced curr ent inhibition by H-Tyr-D-Ala-Gly-Phe(N-Me)-Gly-ol. Blockade of N-type channels by omega-conotoxin GVIA eliminated current suppression by ba clofen in all cells tested (n=11). mu-Opioid-induced inhibition in cur rent was abolished by omega-conotoxin GVIA in 12 of 30 neurons tested, but was only partially reduced in the remaining 18 neurons. In the la tter cells administration of omega-agatoxin IVA reduced, but did not e liminate the mu-opioid sensitive current component that persisted afte r blockade of N-type channels. This residual component of mu-opioid-se nsitive current was blocked completely by omega-conotoxin MVIIC in nin e neurons, whereas respsonses to H-Tyr-D-Ala-Gly-Phe(N-Me)-Gly-ol were still recorded in the remaining cells after administration of these C a2+ channel toxins and nifedipine. Dihydropyridine-sensitive (L-type) current was not affected by activation of mu-opioid or GABA(B) recepto rs in any of the neurons. These data indicate that in nodose ganglion neurons mu-opioid receptors are negatively coupled to N-, P- and Q-typ e channels as well as to a fourth, unidentified toxin-resistant Ca2+ c hannel. In contrast, GABA(B) receptors are coupled only to N-type chan nels. Furthermore, the results do not support a role for either protei n kinase C or A in the modulatory pathway(s) coupling mu-opioid and GA BA(B) receptors to Ca2+ channels, but rather lend credence to the noti on that the signalling mechanisms utilized by these two receptors migh t simply compete for inhibitory control of a common pool of N-type cha nnels. (C) 1998 IBRO. Published by Elsevier Science Ltd.