MU-OPIOID AND KAPPA-OPIOID RECEPTORS SELECTIVELY REDUCE THE SAME TRANSIENT COMPONENTS OF HIGH-THRESHOLD CALCIUM CURRENT IN RAT DORSAL-ROOT GANGLION SENSORY NEURONS

Whole-cell patch-clamp recordings were used to examine the regulation of voltage-dependent calcium channels by mu-and kappa-opioid receptors in acutely isolated rat dorsal root ganglion (DRG) sensory neurons. A gonists selective for either mu- (Tyr-Pro-NMePhe-D-Pro-NH2, PLO17) or kappa-opioid receptors (dynorphin A, U69,593) inhibited high-threshold calcium currents in a reversible and naloxone-sensitive manner, where as administration of D-Pen(2,5)-enkephalin, a delta-selective agonist, was without effect. However, none of the opioids reduced low-threshol d T-type currents. The inhibitory effects of PLO17 were blocked by the irreversible mu-opioid antagonist beta-funaltrexamine but not the kap pa-opioid antagonist nor-binaltorphimine, while responses to kappa-opi oid agonists showed the opposite pattern of antagonist sensitivity. In addition, many cells responded to both PLO17 and dynorphin A (or U69, 593), and in these neurons the inhibitory response to one agonist was occluded when tested in the presence of the other. These data suggest that mu- and kappa-opioid receptors are coexpressed on at least some D RG neurons and appear to be functionally coupled to a common pool of c alcium channels. Both rapidly inactivating (transient) and sustained c omponents of high-threshold current, arising from pharmacologically di stinct types of calcium channels, were identified in our neurons. Acti vation of mu-opioid receptors selectively reduced the transient compon ent of currents evoked at +10 mV from V-h = -80 mV, while sparing the sustained component. The transient component was irreversibly blocked by the N-type channel antagonist omega-conotoxin GVIA (omega-CgTx), an d in one-half of the neurons there was a concomitant loss of the respo nse to PLO17. In the remaining neurons, PLO17 continued to reduce a sm all fraction of omega-CgTx-insensitive current and subsequent administ ration of the L-type channel blocker nifedipine in saturating concentr ations failed to reduce the opioid-induced inhibitory effect. These da ta demonstrate that mu-opioid receptors are negatively coupled to seve ral pharmacologically distinct types of calcium channels in DRG sensor y neurons, one that was blocked by omega-CgTx and thus likely to be N- type, and a second that was resistant to blockade by N- and L-type cha nnel blockers.