Neurodegeneration, Neuroprotection, and Disease-Oriented NeuroscienceResearch PaperNocistatin excites rostral agranular insular cortex-periaqueductal gray projection neurons by enhancing transient receptor potential cation conductance via Gαq/11-PLC-prot

Rostral agranular insular cortex (RAIC) projects to periaqueductal gray (PAG) and inhibits spinal nociceptive transmission by activating PAG-rostral ventromedial medulla (RVM) descending antinociceptive circuitry. Despite being generated from the same precursor prepronociceptin, nocistatin (NST) and nociceptin/orphanin FQ (N/OFQ) produce supraspinal analgesic and hyperalgesic effects, respectively. Prepronociceptin is highly expressed in the RAIC. In the present study, we hypothesized that NST and N/OFQ modulate spinal pain transmission by regulating the activity of RAIC neurons projecting to ventrolateral PAG (RAIC-PAG). This hypothesis was tested by investigating electrophysiological effects of N/OFQ and NST on RAIC-PAG projection neurons in brain slice. Retrogradely labeled RAIC-PAG projection neurons are layer V pyramidal cells and express mRNA of vesicular glutamate transporter subtype 1, a marker for glutamatergic neurons. N/OFQ hyperpolarized 25% of RAIC-PAG pyramidal neurons by enhancing inwardly rectifying potassium conductance via pertussis toxin-sensitive Gαi/o. In contrast, NST depolarized 33% of RAIC-PAG glutamatergic neurons by causing the opening of canonical transient receptor potential (TRPC) cation channels through Gαq/11-phospholipase C-protein kinase C pathway. There were two separate populations of RAIC-PAG pyramidal neurons, one responding to NST and the other one to N/OFQ. Our results suggest that Gαq/11-coupled NST receptor mediates NST excitation of RAIC-PAG glutamatergic neurons, which is expected to cause the supraspinal analgesia by enhancing the activity of RAIC-PAG-RVM antinociceptive pathway. Opposite effects of NST and N/OFQ on supraspinal pain regulation are likely to result from their opposing effects on RAIC-PAG pyramidal neurons.