DOSE-DEPENDENT PAIN-FACILITATORY AND PAIN-INHIBITORY ACTIONS OF NEUROTENSIN ARE REVEALED BY SR-48692, A NONPEPTIDE NEUROTENSIN ANTAGONIST -INFLUENCE ON THE ANTINOCICEPTIVE EFFECT OF MORPHINE

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 th e 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 (d etected using the tail-Rick test in awake rats). SR 48692 had a tripha sic effect on the antinociception from a 10-nmol dose of neurotensin. Antinociception was attenuated by femtomolar doses, attenuation was re versed by low picomolar doses (corresponded to those blocking the pain -facilitatory effect of neurotensin) and the response was again blocke d, but incompletely, by higher doses, The existence of multiple neurot ensin receptor subtypes may explain these data. Physiologically, pain facilitation appears to be a prominent role for neurotensin because th e microinjection of SR 48692 alone causes some antinociception. Furthe rmore, pain-facilitatory (i.e., antianalgesic) neurotensin mechanisms dominate in the pharmacology of opioids; the response to morphine admi nistered either into the FAG or systemically was potentiated only by t he RVM or systemic injection of SR 48692. On the other hand, reversal of the enhancement of antinociception occurred under certain circumsta nces with SR 48692, particularly after its systemic administration.