Abstract
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.
Footnotes
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Send reprint requests to: David J. Smith, Ph.D., Department of Pharmacology and Toxicology, Box 9223, Robert C. Byrd Health Sciences Center of West Virginia University, Morgantown, WV 26506-9223. E-mail: dsmith5{at}wvu.edu
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↵1 A portion of this work was presented at the International Narcotic Research Conference, 1995, and a report appeared in nonreferred form (Smith et al., 1995).
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↵2 This work was supported in part by Sanofi Recherché, FR; UHA of West Virginia University; and National Institutes of Health Training Grant 2-T-32-GM07039 (M.O.U., A.A.H., J.P.S.).
- Abbreviations:
- PAG
- periaqueductal gray
- RVM
- rostroventral medial medulla
- RMg
- nucleus raphe magnus
- MPE
- maximum possible effect
- AUC
- area under the response curve
- TFL
- tail-flick latency
- CNS
- central nervous system
- DMSO
- dimethylsulfoxide
- ANOVA
- analysis of variance
- Received December 23, 1996.
- Accepted April 21, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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