The partial agonist properties of levocabastine in neurotensin-induced analgesia

Abstract

The antihistaminic drug levocabastine is a ligand for the low affinity neurotensin receptor (NTS2). Its intracerebroventricular administration to mice induced a significant analgesia in the writhing test but not in the hot plate test. In the writhing test, levocabastine decreased neurotensin-induced analgesia to a level not significantly different from the effects of levocabastine alone. In the hot plate test, levocabastine had no analgesic effect but completely reversed the neurotensin-induced analgesia. Mepyramine, another antihistaminic drug, did not share these levocabastine effects. Neither levocabastine nor mepyramine modified the colonic temperature or reversed the neurotensin-induced hypothermia. Thus, levocabastine behaves as a partial agonist at neurotensin NTS2 receptors, which are involved in visceral nociception, but not at yet unidentified neurotensin receptors involved in hypothermia.

Introduction

The neuropeptide neurotensin is widely distributed in the central nervous system and peripheral tissues. When injected in the central nervous system, it induces several effects, including a hypothermia and a naloxone-insensitive analgesia Bissette et al., 1976, Clineschmidt et al., 1979. Two types of neurotensin receptors, previously distinguished by their affinity for neurotensin and their sensitivity to the antihistaminic drug levocabastine (Schotte et al., 1986), have been recently cloned. The high-affinity, levocabastine-insensitive, neurotensin receptor (NTS1) has been the first to be cloned Tanaka et al., 1990, Vita et al., 1993. Then in 1996, the low-affinity levocabastine-sensitive neurotensin receptor (NTS2) was cloned Chalon et al., 1996, Mazella et al., 1996. Recently, a third neurotensin receptor has been cloned (Mazella et al., 1998) and identified as gp95/sortilin, a non G-protein-coupled receptor. There are evidences which argue against the involvement of neurotensin NTS1 receptor in the analgesic and hypothermic effects of neurotensin: (i) These effects are not antagonized by SR48692, a neurotensin receptor antagonist which displays a rather good specificity for neurotensin NTS1 receptor (Dubuc et al., 1994); (ii) the binding affinity of various pseudopeptide neurotensin analogues for neurotensin NTS1 receptor is not correlated with their analgesic and hypothermic potencies (Labbé-Jullié et al., 1994); (iii) the repeated intracerebroventricular (i.c.v.) administration of antisense oligodeoxynucleotides targeted to the mRNA encoding the neurotensin NTS1 receptor does not reduce neurotensin analgesic effect in the writhing test in mice (Dubuc et al., 1999). This latter result is in contrast with that of Tyler et al. (1998a) who recently demonstrated that the inhibition of neurotensin NTS1 receptor synthesis after gene blockade by antisense peptide nucleic acids injected into the periaqueductal grey resulted in a loss of both hypothermic and analgesic responses to neurotensin. However, these authors underlined that the synthesis of another neurotensin receptor, other than neurotensin NTS1 receptor, could be decreased, because the antisense peptide nucleic acids was only a 12-mer, which could be conserved in another neurotensin receptor type. Moreover, the same authors (Tyler et al., 1998b) have shown that levocabastine, injected into the periaqueductal grey of rats, induced neither hypothermia nor antinociception on the hot plate test but antagonized these neurotensin effects. In contrast, neurotensin NTS2 receptor appears a good candidate for mediating the analgesic effect of neurotensin: the blockade of its central expression by repeated i.c.v. injections of antisense oligodeoxynucleotides resulted in a marked reduction in the neurotensin-induced analgesia (Dubuc et al., 1999).

These results prompted us to investigate whether levocabastine displays hypothermic and especially analgesic effects in mice or modifies the neurotensin-induced analgesia. In order to distinguish the effects of levocabastine from those of a pure histamine H1 receptor antagonist, we also compared the effects of levocabastine with those elicited by mepyramine.