title: Neurotensin excitation of serotonergic neurons in the rat nucleus raphe magnus: ionic and molecular mechanisms.
abstract: To understand the cellular and molecular mechanisms by which neurotensin (NT) induces an analgesic effect in the nucleus raphe magnus (NRM), whole-cell patch-clamp recordings were performed to investigate the electrophysiological effects of NT on acutely dissociated NRM neurons. Two subtypes of neurons, primary serotonergic and secondary non-serotonergic cells, were identified from acutely isolated NRM neurons. During current-clamp recordings, NT depolarized NRM serotonergic neurons and evoked action potentials. Voltage-clamp recordings showed that NT excited serotonergic neurons by enhancing a voltage-insensitive and non-selective cationic conductance. Both SR48692, a selective antagonist of subtype 1 neurotensin receptor (NTR-1), and SR 142948A, a non-selective antagonist of NTR-1 and subtype 2 neurotensin receptor (NTR-2), failed to prevent neurotensin from exciting NRM serotonergic neurons. NT-evoked cationic current was inhibited by the intracellular administration of GDP-beta-S. NT failed to induce cationic currents after dialyzing serotonergic neurons with the anti-G(alphaq/11) antibody. Cellular Ca(2+) imaging study using fura-2 showed that NT induced the calcium release from the intracellular store. NT-evoked current was blocked after the internal perfusion of heparin, an IP(3) receptor antagonist, or BAPTA, a fast Ca(2+) chelator. It is concluded that neurotensin enhancement of the cationic conductance of NRM serotonergic neurons is mediated by a novel subtype of neurotensin receptors. The coupling mechanism via G(alphaq/11) proteins is likely to involve the generation of IP(3), and subsequent IP(3)-evoked Ca(2+) release from intracellular stores results in activating the non-selective cationic conductance.
authors.affiliation: Department of Anesthesiology, Chang Gung Memorial Hospital, Kwei-San, Tao-Yuan, Taiwan.
authors.forename: A H
authors.initials: AH
authors.lastname: Li
authors.forename: T H
authors.initials: TH
authors.lastname: Yeh
authors.forename: P P
authors.initials: PP
authors.lastname: Tan
authors.forename: H M
authors.initials: HM
authors.lastname: Hwang
authors.forename: H L
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007473:Ion Channels / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009496:Neurotensin / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors / Q000502:physiology; D012701:Serotonin / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D007093:Imidazoles; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007473:Ion Channels; C099727:Ntsr2 protein, rat; D011720:Pyrazoles; D011804:Quinolines; D018160:Receptors, Cytoplasmic and Nuclear; D018028:Receptors, Neurotensin; C104418:SR 142948A; D013873:Thionucleotides; C114036:neurotensin type 1 receptor; D006153:Guanosine Diphosphate; C079087:SR 48692; D012701:Serotonin; D009496:Neurotensin; C023427:guanosine 5'-O-(2-thiodiphosphate); D000218:Adamantane; D002118:Calcium