Neurotensin excitation of serotonergic neurons in the rat nucleus raphe magnus: ionic and molecular mechanisms.
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.
Li
A H
AH
Department of Anesthesiology, Chang Gung Memorial Hospital, Kwei-San, Tao-Yuan, Taiwan.
Yeh
T H
TH
Tan
P P
PP
Hwang
H M
HM
Wang
H L
HL
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
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