Molecular mechanisms underlying calcium current modulation by nociceptin

Nociceptin is a non-opioid peptide that modulates pain response. One of mechanism underlying its analgesic action is the inhibition of voltage-dependent calcium current (ICa), similar to that of opioids. We investigated the molecular mechanism by which nociceptin inhibits ICausing sensory neurons and a heterologous expression system. ICainhibition by nociceptin was voltage-dependent, exhibited the slowing of activation kinetics and prepulse facilitation, and was blocked by N-ethylmaleimide, indicating the involvement of GiGo protein. ICainhibition by nociceptin was primarily mediated through binding to its own receptor, ORL-1, but not through affecting other μ-opioid receptors. Thus, our results strongly demonstrate that heterologous cross-talk between ORL1 and μOR is not involved in the ICainhibition by nociceptin.