Inhibition of calcium currents in rat colon sensory neurons by K- but not mu- or delta-opioids

We previously reported that kappa-, but not mu- or delta-opioid receptor ag onists (ORAs) have selective, potentially useful peripheral analgesic effec ts in visceral pain. To evaluate one potential site and mechanism by which these effects are produced, we studied opioid effects on high-voltage activ ated (HVA) Ca2+ currents in identified (Di-I) pelvic nerve sensory neurons from the S1 dorsal root ganglion (DRG). Results were compared with opioid e ffects on cutaneous neurons from L5 or L6 DRG. Di-I-labeled DRG cells were voltage clamped (perforated whole cell patch clamp), and HVA Ca2+ currents were evoked by depolarizing 240-ms test pulses to +10 mV from a holding pot ential of -60 mV. Neither mu-ORAs (morphine, 10(-6) M, n = 16; [D-Ala(2), N -Me-Phe(4), Gly-ol(5)] enkephalin, 10(-6) M, n = 12) nor delta-ORAs ([D-Pen (2), D-Pen(5)] enkephalin, 10(-7) M, n = 16; SNC-80, 10(-7) M, n = 7) affec ted HVA Ca2+ currents in colon sensory neurons. In contrast, the kappa-ORAs U50,488 (10(-6) M), bremazocine (10(-6)M), and nalBzoH (10(-6) M) signific antly attenuated HVA Ca2+ currents in colon sensory neurons; effects on cut aneous sensory neurons were variable. A nonnceptor selective concentration of naloxone (10(-5) M) and nor-BNI (10(-6) M), a selective kappa-opioid rec eptor antagonist, reversed the inhibitory effect of kappa-ORAs. In the pres ence of N-, P-, or Q-, but not L-type Ca2+ channel antagonists, the effect of U50,488 on HVA Ca2+ currents was significantly reduced. Pretreatment wit h pertussis toxin (PTX) prevented the inhibition by U50,488. These results suggest that kappa-opioid receptors are coupled to multiple HVA Ca2+ channe ls in colon sensory neurons by a PTX-sensitive G protein pathway. We conclu de that inhibition of Ca2+ channel function likely contributes in part to t he peripheral analgesic action of kappa-ORAs in visceral nociception.