Nociceptin, Phe 1φ-nociceptin 1-13, nocistatin and prepronociceptin 154-181 effects on calcium channel currents and a potassium current in rat locus coeruleus in vitro

1. The actions of the neuropeptide nociceptin, the putative nociceptin receptor antagonist [Phe1φ(CH ₂-NH)Gly ²]-nociceptin-(1-13)NH ₂ (Phe ¹φ-nociceptin _1-13) and the putative nociceptin precursor products nocistatin (rat prepronociceptin _125-132) and rat prepronociceptin _154-181 were examined on membrane properties of rat locus coeruleus (LC) neurons using whole cell patch clamp techniques. 2. Nociceptin inhibited I(Ba) in all LC neurons, (pD ₂ of 8.9, maximum inhibition 50%). The inhibition of I(Ba) by nociceptin was associated with slowing of the activation of I(Ba) and could be significantly reversed by a strong depolarizing prepulse. Phe ¹φ-nociceptin _1-13 also inhibited I(Ba) in LC neurons (notional pD ₂ of 7.6, maximum inhibition 18%). Application of Phe ¹φ-nociceptin _1-13 (1 μM) significantly occluded the subsequent effects of a co-application of nociceptin (3 nM) on I(Ba). 3. As previously reported for nociceptin, Phe ¹φ-nociceptin _1-13 caused an outward current in LC neurons voltage clamped at -60 mV (pD ₂ of 7.1, maximum current 50% of that of methionine enkephalin, 10 μM). The Phe ¹φ-nociceptin _1-13 induced current reversed polarity at -112 mV and exhibited pronounced inward rectification. Phe ¹φ-nociceptin _1-13 (1 μM) reversibly inhibited the current caused by nociceptin (300 nM)by 30%. 4. Neither nocistatin nor rat prepronociceptin _154-181 inhibited I(Ba) in LC neurons, or prevented the subsequent inhibition by nociceptin. Neither nocistatin or prepronociceptin _154-181 affected the membrane properties of LC neurons. 5. This study demonstrates that nociceptin modulates somatic I(Ba) in rat LC neurons. The putative ORL1 antagonist Phe ¹φ-nociceptin _1-13 exhibited partial agonist activity at inhibiting I(Ba) and opening K ⁺ channels in LC. Other putative nociceptin precursor products were without effect on LC cells.