Opioid activity of sendide, a tachykinin NK1 receptor antagonist

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Abstract

Sendide, a tachykinin NK1 receptor antagonist, was tested for antagonism against scratching, biting and licking responses elicited by intrathecal (i.t.) injections of various tachykinin receptor agonists, N-methyl-d-aspartate (NMDA), somatostatin and bombesin, in mice. Tachykinin NK1 receptor agonists, substance P, physalaemin and septide, produced a characteristic behavioural response, consisting of scratching, biting and licking. The substance P-induced response was reduced by small doses (0.0625–1.0 pmol) of sendide in a dose-dependent manner. The behavioural response elicited by other tachykinin NK1 receptor agonists, physalaemin and septide, was also reduced significantly by a small dose (1.0 pmol) of sendide. The inhibitory effect of sendide (1.0 pmol) was not affected by pretreatment with the opioid receptor antagonist, naloxone, at doses up to 4.0 mg/kg. Higher doses of sendide were needed to reduce the behavioural response to neurokinin A, a tachykinin NK2 receptor agonist, neurokinin B, a tachykinin NK3 receptor agonist and eledoisin, a tachykinin NK2/NK3 receptor agonist. Pretreatment with naloxone (2.0 mg/kg, i.p.) significantly antagonized sendide (1024 pmol)-induced inhibition of the behavioural responses to neurokinin A, neurokinin B and eledoisin. The behaviours elicited by i.t. injection of NMDA, somatostatin or bombesin were also reduced by a higher dose (1024 pmol) of sendide and this sendide effect was reversed by naloxone. These findings suggest that sendide at higher doses may possess opioid activity in addition to an antagonistic action at tachykinin NK1 receptors in the spinal cord.

Introduction

The undecapeptide, substance P, belongs to a group of related neuropeptides named tachykinins which includes neurokinin A and neurokinin B. There are known to be at least three receptors for the mammalian tachykinins, generally referred to as NK1, NK2 and NK3 (Regoli et al., 1988), which have been cloned and sequenced (Masu et al., 1987; Yokota et al., 1989; Hershey and Krause, 1990; Shigemoto et al., 1990). The endogenous ligands for the three receptors are believed to be substance P, neurokinin A and neurokinin B, respectively, based on their relative agonist potencies (Quirion and Dam, 1988; Helke et al., 1990; Guard and Watson, 1991). Substance P is known to be involved in the spinal processing and transmission of nociceptive primary afferent inputs (Hylden and Wilcox, 1981; Urban and Randic, 1984; Frenk et al., 1988; Fleetwood-Walker et al., 1990; Chen et al., 1991). Intrathecally (i.t.) injected substance P and related compounds can produce reciprocal hindlimb scratching, biting and licking behaviour in mice (Hylden and Wilcox, 1981; Vaught et al., 1984; Takahashi et al., 1987; Sakurada et al., 1987) and tachykinin NK1 receptor antagonists block the behaviour evoked by i.t. injection of substance P (Sakurada et al., 1992c, Sakurada et al., 1994). The i.t. administration of agonists for tachykinin NK1 and/or NK2 (neurokinin A, d-septide, neurokinin B and eledoisin) receptors also produces, behaviour similar to substance P-induced behaviour in mice (Sakurada et al., 1989, Sakurada et al., 1992b). Based on the rank order of potency of these mammalian tachykinins, the spinally mediated behavioural response seems to be mediated by a preferential activation of tachykinin NK1 receptors in the spinal cord (Sakurada et al., 1989). Tachykinin receptors have been the focus of attention of much pharmacological research aimed at the discovery of specific peptide and non-peptide tachykinin receptor antagonists. The first non-peptide tachykinin NK1 receptor antagonist, CP-96,345 [(2S,3S)-cis-2-(diphenyl-methyl)-N-[(2-methoxy-phenyl)-methyl]-1-azabicyclo[2,2,2]octan-3-amine] has been shown to act as a competitive tachykinin NK1 receptor antagonist at central and peripheral substance P binding sites, and in in vitro and in vivo functional assays (McLean et al., 1991; Snider et al., 1991). Recently, a peptide NK1 receptor antagonist, sendide (Try-d-Phe-Phe-d-His-Leu-Met-NH2), has been developed, which has high affinity for tachykinin NK1 receptors in the mouse spinal cord (Sakurada et al., 1992c). It has been shown that this compound competitively antagonizes the spinally mediated behavioural response induced by i.t. injection of substance P. Binding studies have revealed that sendide displaces the binding of [3H]substance P to mouse spinal cord membranes with extremely high potency. Thus, the recent development of selective tachykinin receptor antagonists has enabled investigation of the physiological role of neurokinins (Longmore et al., 1995; Sakurada et al., 1997).

There is evidence that an interaction between neurokinins and opioid systems may exist in the dorsal spinal cord. Opioid receptor agonists were found to inhibit the substance P-induced response in a dose-dependent way which is naloxone-reversible (Hylden and Wilcox, 1982; Takahashi et al., 1987; Sakurada et al., 1988; Johnston and Chahl, 1991). Some substance P analogues have been shown to produce naloxone-reversible antinociception (Post and Folkers, 1985) and inhibit tachykinin NK2- and/or NK3- receptor agonist-induced scratching, biting and licking, which are also reversed by pretreatment with naloxone (Sakurada et al., 1992b). Thus, the aim of the present study was to investigate, using naloxone, an opioid receptor antagonist, whether the spinal action of sendide is mediated through an opioid receptor.

Section snippets

Material and methods

The subjects were experimentally naive, male ddY mice (Shizuoka Laboratory Center, Japan) weighing an average of 23 g at the time of experiment. They were provided with free access to both food and water. The colony room was maintained at 22±0.5°C with an alternating 12-h light–dark cycle. All animals were used only once. This study was conducted during the light phase of the cycle. Studies on the behavioural experiments were performed with the approval of the Ethics Committee of Animal

Effects of sendide on the behavioural response to substance P, neurokinin A and neurokinin B

Fig. 1 shows the effectiveness of sendide for antagonizing the behavioural response elicited by i.t. injections of substance P (100 pmol), neurokinin A (400 pmol) and neurokinin B (1000 pmol). Sendide, given simultaneously with substance P, reduced the substance P-induced behavioural response with an ID50 of 0.3 pmol (0.1–0.8 pmol; 95% confidence limits when co-injected i.t.) (Fig. 1, upper panel). A significant effect of sendide was observed against substance P from 0.25 pmol (P<0.01) onwards.

Discussion

The present study clearly illustrated a dual action of sendide in the spinally mediated behavioural model in mice. An antagonistic effect of sendide on the scratching, biting and licking response induced by tachykinin NK1 receptor agonists was produced with the small pmol dose range (less than 1.0 pmol) of the peptide antagonist. Much higher doses of sendide were required to antagonize the behavioural response to tachykinin NK2 and/or NK3 receptor agonists. These results are consistent with

Acknowledgements

The authors wish to thank Miho Nakayama for her secretarial assistance with preparing the manuscript.

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