Characterization of Neurotensin’s Bipolar Effects on Nociceptive Modulation Using SR 142948A and SR 48692, Two Non-peptide Neurotensin Receptor Antagonists

Results from the current study confirmed that neurotensin has a dose-dependent bipolar effects on nociception within the RVM. Microinjection of low (picomolar) doses of neurotensin into the RVM resulted in a facilitation of nociception and resolved the anti-analgesic properties (tail flick test) of the peptide in models where basal analgesia is established by stressing rats or following PAG administration of opioids (morphine). Whereas microinjection of higher (nanomolar) doses of neurotensin into the RVM produced antinociception. Furthermore, these same pain facilitatory and inhibitory effects of neurotensin were observed following i.c.v. administration.;Direct evaluation and comparisions of the two non-peptide neurotensin receptor antagonists, SR 48692 and SR 142948A, revealed that they differ in their ability to modulate these actions of neurotensin. In contrast to SR 48692, SR 142948A resulted in a complete inhibition of neurotensin-mediated antinociception in a dose-dependent bell-shaped manner. Further discrimination between the two antagonists was demonstrated in their ability to inhibit neurotensin-mediated pain facilitation within the RVM. In contrast to SR 48692, SR 142948A administration into the RVM (1) did not produce a significant antinociceptive effect when administered alone; (2) failed to promote antinociception from microinjection of a low (30 pmol) dose of neurotensin microinjected into the RVM; (3) did not inhibit the anti-analgesic effect of a low (3 pmol) dose of neurotensin administered into the RVM of a stressed rat; (4) microinjection of SR 142948A dose selectively (only a 30 pmol dose) resulted in a potentiation of the antinociceptive response to morphine (6 nmol) administered into the PAG.;Moreover, these direct comparisons demonstrated that the ability of neurotensin to produce its bipolar effects relies on the ability of the peptide to interact with multiple receptors within the RVM. Furthermore, studies performed using levocabastine, a selective antagonist of the NTR2 receptor, demonstrated that the action of neurotensin within the RVM is mediated via receptors or receptor subtypes that do not share the characteristic properties of the NTR2 receptor. Therefore, these studies indicate the existence and involvement of multiple NTR1 receptor subtypes or splice variants in mediating these actions of neurotensin within the RVM.