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The Journal of Neuroscience, September 7, 2005, 25(36):8188-8196; doi:10.1523/JNEUROSCI.0810-05.2005

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Behavioral/Systems/Cognitive
Potent Spinal Analgesia Elicited through Stimulation of NTS2 Neurotensin Receptors

Philippe Sarret,¹ Michael J. Esdaile,¹ Amélie Perron,¹ Jean Martinez,² Thomas Stroh,¹ and Alain Beaudet¹

¹Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4, and ²Laboratoire des Aminoacides, Peptides et Protéines, Unité Mixte de Recherche 5810, Faculté de Pharmacie, Université de Montpellier I & II, 34093 Montpellier, France

Intrathecal administration of the neuropeptide neurotensin (NT) was shown previously to exert antinociceptive effects in a variety of acute spinal pain paradigms including hotplate, tail-flick, and writhing tests. In the present study, we sought to determine whether some of these antinociceptive effects might be elicited via stimulation of low-affinity NTS2 receptors. We first established, using immunoblotting and immunohistochemical techniques, that NTS2 receptors were extensively associated with putative spinal nociceptive pathways, both at the level of the dorsal root ganglia and of the superficial layers of the dorsal horn of the spinal cord. We then examined the effects of intrathecal administration of NT or selective NTS2 agonists on acute thermal pain. Both NT and NTS2 agonists, levocabastine and Boc-Arg-Arg-Pro-Tyr(CH₂NH)Ile-Leu-OH (JMV-431), induced dose-dependent antinociceptive responses in the tail-flick test. The effects of levocabastine and of JMV-431 were unaffected by coadministration of the NTS1-specific antagonist 2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxy-phenyl)pyrazol-3-yl)carboxylamino]tricyclo)3.3.1.1.^3.7)-decan-2-carboxylic acid (SR48692), confirming that they were NTS2 mediated. In contrast, the antinociceptive effects of NT were partly abolished by coadministration of SR48692, indicating that NTS1 and NTS2 receptors were both involved. These results suggest that NTS2 receptors play a role in the regulation of spinal nociceptive inputs and that selective NTS2 agonists may offer new avenues for the treatment of acute pain.

Key words: neuropeptide; GPCRs; antinociception; intrathecal; tail-flick; confocal microscopy

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Received March 1, 2005; revised July 15, 2005; accepted July 15, 2005.

This article has been cited by other articles:

				S. Schulz, C. Rocken, M. P A Ebert, and S. Schulz Immunocytochemical identification of low-affinity NTS2 neurotensin receptors in parietal cells of human gastric mucosa. J. Endocrinol., October 1, 2006; 191(1): 121 - 128. [Abstract] [Full Text] [PDF]

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