Neurotensin excites periaqueductal gray neurons projecting to the rostral ventromedial medulla.
Microinjection of neurotensin into the midbrain periaqueductal gray (PAG) produces a potent and naloxone-insensitive analgesic effect. To test the hypothesis that neurotensin induces the analgesic effect by activating the PAG-rostral ventromedial medulla (RVM) descending antinociceptive pathway, PAG neurons that project to RVM (PAG-RVM) were identified by microinjecting DiI(C18), a retrograde tracing dye, into the rat RVM. Subsequently, fluorescently labeled PAG-RVM projection neurons were acutely dissociated and selected for whole cell patch-clamp recordings. During current-clamp recordings, neurotensin depolarized retrogradely labeled PAG-RVM neurons and evoked action potentials. Voltage-clamp recordings indicated that neurotensin excited PAG-RVM neurons by opening the voltage-insensitive and nonselective cation channels. Both SR 48692, a selective NTR-1 antagonist, and SR 142948A, a nonselective antagonist of NTR-1 and NTR-2, failed to prevent neurotensin from exciting PAG-RVM neurons. Neurotensin failed to evoke cationic currents after internally perfusing PAG-RVM projection neurons with GDP-beta-S or anti-G(alpha q/11) antiserum. Cellular Ca(2+) fluorescence measurement using fura-2 indicated that neurotensin rapidly induced Ca(2+) release from intracellular stores of PAG-RVM neurons. Neurotensin-evoked cationic currents were blocked by heparin, an IP(3) receptor antagonist, and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), a fast chelator of Ca(2+). These results suggest that by activating a novel subtype of neurotensin receptors, neurotensin depolarizes and excites PAG-RVM projection neurons through enhancing Ca(2+)-dependent nonselective cationic conductance. The coupling mechanism via G(alpha q/11) proteins is likely to involve the production of IP(3), and subsequent IP(3)-evoked Ca(2+) release leads to the opening of nonselective cation channels.
Li
A H
AH
Department of Anesthesiology, Chang Gung Memorial Hospital, Kwei-San, Tao-Yuan, Taiwan, R.O.C.
Hwang
H M
HM
Tan
P P
PP
Wu
T
T
Wang
H L
HL
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002412:Cations / Q000378:metabolism; D004553:Electric Conductivity; D019204:GTP-Binding Proteins / Q000502:physiology; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D007473:Ion Channels / Q000502:physiology; D008526:Medulla Oblongata / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D009496:Neurotensin / Q000494:pharmacology*; D010487:Periaqueductal Gray / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D018028:Receptors, Neurotensin / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*
D002412:Cations; D007473:Ion Channels; D018028:Receptors, Neurotensin; D009496:Neurotensin; D015544:Inositol 1,4,5-Trisphosphate; D019204:GTP-Binding Proteins; D002118:Calcium