Nocistatin and nociceptin exert opposite effects on the excitability of central amygdala nucleus-periaqueductal gray projection neurons

Central amygdala nucleus (CeA)-periaqueductal gray (PAG) pathway is the component of descending antinociceptive circuitry. Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) produce supraspinal pronociceptive and antinociceptive effects, respectively. We hypothesized that opposite effects of N/OFQ and NST on supraspinal pain modulation result from their opposing effects on the excitability of CeA-PAG projection neurons. This hypothesis was tested by investigating electrophysiological effects of N/OFQ and NST on medial CeA neurons that project to PAG (CeA M-PAG). N/OFQ hyperpolarized CeA M-PAG projection neurons by enhancing inwardly rectifying potassium conductance. In contrast, NST depolarized CeA M-PAG neurons by causing the opening of TRPC cation channels via G αq/11-PLC-PKC pathway. CeA M-PAG neurons hyperpolarized by N/OFQ express CRF or neurotensin mRNA. NST-responsive CeA M-PAG neurons contain CRF or substance P mRNA. Our study provides the evidence that the molecular and cellular basis for opposite effects of N/OFQ and NST on supraspinal pain regulation is their opposing effects on the excitability of peptidergic CeA M-PAG neurons.