CHARACTERIZATION OF BIPHASIC MODULATION OF SPINAL NOCICEPTIVE TRANSMISSION BY NEUROTENSIN IN THE RAT ROSTRAL VENTROMEDIAL MEDULLA

Modulation of spinal nociceptive transmission by neurotensin microinje cted in the rostral ventromedial medulla (RVM) was examined in anesthe tized, paralyzed rats. Forty-three spinal dorsal horn neurons in the L -3-L-5 spinal segments responding to mechanical and noxious thermal st imulation (50 degrees C) of the plantar surface of the ipsilateral hin d foot were studied. Spinal units were classified as either wide dynam ic range or nociceptive specific and were located in spinal laminae I- V. Microinjection of neurotensin (0.03 pmol/0.2 mu l) into the RVM pro duced a significant facilitation (135% of control) of spinal unit resp onses to noxious thermal stimulation (50 degrees C) that lasted simila r to 12 min. In contrast, injection of greater doses of neurotensin (3 00 or 3,000 pmol) produced an inhibition of spinal unit responses to n oxious heat (51.7 and 10.6% of control, respectively) that had a longe r duration (60-120 min). The effects of neurotensin on wide-dynamic-ra nge and nociceptive-specific neuron responses to noxious heat were qua litatively and quantitatively similar. Spinal unit responses to graded healing of the skin (42-50 degrees C) were completely inhibited after microinjection of 3,000 pmol of neurotensin into the RVM. Injection o f a lesser dose of neurotensin (300 pmol), however, resulted in a part ial inhibition of spinal unit responses and significantly reduced the slope of the stimulus-response function to graded heating of the skin. Transection of either the ipsilateral or contralateral dorsolateral f uniculus (DLF) significantly reduced the inhibition of spinal nocicept ive transmission produced by neurotensin (3,000 pmol) in the RVM, wher eas bilateral transection of the DLFs completely blocked the effect. I n contrast, bilateral transection of the DLFs had no effect on facilit ation of spinal nociception by neurotensin (0.03 pmol) in the RVM. The inhibition of spinal nociceptive transmission by neurotensin (3,000 p mol) in the RVM was completely blocked by injection of the nonpeptide neurotensin receptor antagonist SR48692 (30 fmol) into the RVM 10 min before neurotensin. To confirm a specific block of neurotensin-recepto r-mediated effects by the antagonist, a subsequent injection of L-glut amate into the RVM was performed. L-Glutamate (100 nmol) was found to inhibit the nociceptive responses of those spinal. units whose respons es were no longer inhibited by neurotensin. In contrast, injection of SR48692 (30 fmol) into the RVM failed to block the facilitation of spi nal unit responses to noxious heat produced by a subsequent injection of neurotensin (0.03 pmol) into the same site. The present series of e xperiments demonstrate a specific role for neurotensin in the RVM in t he modulation of spinal nociceptive transmission, because the peptide was found to birth facilitate and inhibit spinal neuron responses to n oxious thermal stimulation. Additionally, the facilitatory and inhibit ory effects of neurotensin appear to occur via interaction with multip le neurotensin receptors in the RVM that activate independent systems that descend in the ventrolateral funiculi and DLFs, respectively. The results from these experiments are consistent with prior studies demo nstrating that the RVM both facilitates and inhibits spinal nociceptiv e transmission, and they complement previous work showing that neurote nsin in the RVM modulates spinal nociceptive behavioral responses.