Vol. 282, Issue 2, 899-908, 1997

Dose-Dependent Pain-Facilitatory and -Inhibitory Actions of Neurotensin Are Revealed by SR 48692, a Nonpeptide Neurotensin Antagonist: Influence on the Antinociceptive Effect of Morphine^1,2

David J. Smith, Alyssa A. Hawranko, Philip J. Monroe, Danielle Gully, Mark O. Urban, Charles R. Craig, Jeffrey P. Smith and Deborah L. Smith

Departments of Pharmacology/Toxicology and Anesthesiology (D.J.S., A.A.H., P.J.M., M.O.U., C.R.C., J.P.S., D.L.S.), Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia; and Sanofi Recherche (D.G.), Toulouse Cedex, France

Neurotensin has bipolar (facilitatory and inhibitory) effects on pain modulation that may physiologically exist in homeostasis. Facilitation predominates at low (picomolar) doses of neurotensin injected into the rostroventral medial medulla (RVM), whereas higher doses (nanomolar) produce antinociception. SR 48692, a neurotensin receptor antagonist, discriminates between receptors mediating these responses. Consistent with its promotion of pain facilitation, the minimal antinociceptive responses to a 30-pmol dose of neurotensin microinjected into the RVM were markedly enhanced by prior injection of SR 48692 into the site (detected using the tail-flick test in awake rats). SR 48692 had a triphasic effect on the antinociception from a 10-nmol dose of neurotensin. Antinociception was attenuated by femtomolar doses, attenuation was reversed by low picomolar doses (corresponded to those blocking the pain-facilitatory effect of neurotensin) and the response was again blocked, but incompletely, by higher doses. The existence of multiple neurotensin receptor subtypes may explain these data. Physiologically, pain facilitation appears to be a prominent role for neurotensin because the microinjection of SR 48692 alone causes some antinociception. Furthermore, pain-facilitatory (i.e., antianalgesic) neurotensin mechanisms dominate in the pharmacology of opioids; the response to morphine administered either into the PAG or systemically was potentiated only by the RVM or systemic injection of SR 48692. On the other hand, reversal of the enhancement of antinociception occurred under certain circumstances with SR 48692, particularly after its systemic administration.