title: Nocistatin excites rostral agranular insular cortex-periaqueductal gray projection neurons by enhancing transient receptor potential cation conductance via G(alphaq/11)-PLC-protein kinase C pathway.
abstract: 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 G(alphai/o). In contrast, NST depolarized 33% of RAIC-PAG glutamatergic neurons by causing the opening of canonical transient receptor potential (TRPC) cation channels through G(alphaq/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 G(alphaq/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.
authors.affiliation: Department of Physiology and Pharmacology, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan.
authors.forename: Y L
authors.initials: YL
authors.lastname: Chen
authors.forename: A H
authors.initials: AH
authors.lastname: Li
authors.forename: T H
authors.initials: TH
authors.lastname: Yeh
authors.forename: A H
authors.initials: AH
authors.lastname: Chou
authors.forename: Y S
authors.initials: YS
authors.lastname: Weng
authors.forename: H L
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D066298:In Vitro Techniques; D008526:Medulla Oblongata / Q000502:physiology; D018847:Opioid Peptides / Q000502:physiology*; D010487:Periaqueductal Gray / Q000166:cytology / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000096:biosynthesis; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000502:physiology*; D010738:Type C Phospholipases / Q000502:physiology*; D000097629:Nociceptin
chemical_list: D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D018847:Opioid Peptides; D024661:Potassium Channels, Inwardly Rectifying; D011493:Protein Kinase C; D011957:Receptors, Opioid; D050052:TRPC Cation Channels; D010738:Type C Phospholipases; D000097629:Nociceptin; C111148:nocistatin