CompB (J-113397), selectively and competitively antagonizes nociceptin activation of inwardly rectifying K(+) channels in rat periaqueductal gray slices.

A novel opioid receptor family, the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors, has been identified to be involved in many physiological functions including pain regulation. CompB (also known as J-113397) is the first non-peptide antagonist of NOP receptors. Using the patch-clamp recording technique in brain slices, we have quantitatively studied the interactions of CompB with N/OFQ at native NOP receptors of ventrolateral neurons of the midbrain periaqueductal gray (PAG), a crucial region for N/OFQ-induced reversal of opioid analgesia. N/OFQ concentration-dependently activated inwardly rectifying K(+) channels in response to hyperpolarization ramps from -60 to -140 mV. CompB attenuated the magnitude but not the reversal potential of the K(+) current activated by N/OFQ in a concentration-dependent manner. The presence of CompB produced a parallel right-shift of the concentration-response curve to N/OFQ. The Schild plot analysis yielded a pA(2) value of 8.37. At concentrations up to 1 microM, CompB affected neither the membrane current per se nor the inwardly rectifying K(+) current activated by [D-Ala(2), N-Me-Phe(4),Gly-ol(5)]-enkephalin or baclofen, a mu-opioid and GABA(B) receptor agonist, respectively. It appears that CompB, at nanomolar concentrations, is a pure, selective and competitive antagonist of postsynaptic NOP receptors that mediate inwardly rectifying K(+) channel activation in ventrolateral PAG neurons.