Inhibition of Calcium Currents in Rat Colon Sensory Neurons by K- But Not μ- or δ-Opioids

Abstract

Su, Xin, R. E. Wachtel, and G. F. Gebhart. Inhibition of calcium currents in rat colon sensory neurons by κ- but not μ- or δ-opioids. J. Neurophysiol. 80: 3112–3119, 1998. We previously reported that κ-, but not μ- or δ-opioid receptor agonists (ORAs) have selective, potentially useful peripheral analgesic effects in visceral pain. To evaluate one potential site and mechanism by which these effects are produced, we studied opioid effects on high-voltage activated (HVA) Ca2+ currents in identified (Di-I) pelvic nerve sensory neurons from the S1 dorsal root ganglion (DRG). Results were compared with opioid effects 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 potential of −60 mV. Neither μ-ORAs (morphine, 10−6 M, n = 16; [D-Ala2, N-Me-Phe4, Gly-ol5] enkephalin, 10−6 M, n = 12) nor δ-ORAs ([D-Pen2, D-Pen5] enkephalin, 10−7 M, n = 16; SNC-80, 10−7 M, n = 7) affected HVA Ca2+ currents in colon sensory neurons. In contrast, the κ-ORAs U50,488 (10−6 M), bremazocine (10−6M), and nalBzoH (10−6 M) significantly attenuated HVA Ca2+ currents in colon sensory neurons; effects on cutaneous sensory neurons were variable. A nonreceptor selective concentration of naloxone (10−5 M) and nor-BNI (10−6 M), a selective κ-opioid receptor antagonist, reversed the inhibitory effect of κ-ORAs. In the presence 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 with pertussis toxin (PTX) prevented the inhibition by U50,488. These results suggest that κ-opioid receptors are coupled to multiple HVA Ca2+ channels in colon sensory neurons by a PTX-sensitive G protein pathway. We conclude that inhibition of Ca2+ channel function likely contributes in part to the peripheral analgesic action of κ-ORAs in visceral nociception.