Effect of tachykinin receptor antagonists in experimental neuropathic pain

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Abstract

The intrathecal effect of 0.1 to 10 μg of RP-67,580 (3aR,7aR)-7,7-diphenyl-2[1-imino-2(2-methoxyphenyl)-ethyl]perhydroisoindol-4-onehydro chloride, CP-96,345 (2S,3S)-cis-(2(diphenylmethyl)-N-[(2-methoxyphenyl) methyl]-1-azabicyclo[2.2.2]octan-3-amine), SR-140,333 (S)-(1-{2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl}-4-phenyl-1-azonia-bicyclo[2.2.2.]octane,chloride), all neurokinin (NK)1-receptor antagonists, SR-48,968 (S)-N-methyl-N[4-(4-acetylamino-4-[phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl]benzamide, a tachykinin NK2 receptor antagonist and SR-142,801 (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N-methyl acetamide, a tachykinin NK3 receptor antagonist, and of their respective inactive enantiomers on thresholds of vocalization due to a mechanical stimulus in mononeuropathic (sciatic nerve ligature) and diabetic rats, was examined. The tachykinin NK1 and the NK2 receptor antagonists were antinociceptive in both models, with a higher effect of the former in diabetic rats. The tachykinin NK3 receptor antagonist was weakly effective in diabetic rats only. This indicates a differential involvement of the tachykinins according to the model of neuropathic pain, suggesting a potential role for tachykinin receptor antagonists in the treatment of neuropathic pain.

Introduction

Patients suffering from neuropathic disorders frequently complain of pain. Classical reference pain treatments such as tricyclic antidepressants are not always sufficiently effective or well tolerated (Onghena and Van Houdenhove, 1993; McQuay et al., 1996) and consequently improved treatments are required. Development of new therapies requires a fuller understanding of the pathophysiological mechanisms of neuropathic pain.

Tachykinins, substance P, neurokinin A and neurokinin B are important in sensory processing in the dorsal horn of the spinal cord (Helke et al., 1990) where they activate tachykinin NK1, NK2 and NK3 receptors, respectively (Helke et al., 1990; Nakanishi, 1991). Behavioural experiments using chemical (Nagahisa et al., 1992; Yamamoto and Yaksh, 1992; Sakurada et al., 1995; Holzer-Petsch and Rordorf-Nikolic, 1995) as well as thermal stimuli (Santucci et al., 1993) clearly demonstrate the pronociceptive role of tachykinin NK1 and NK2 receptor agonists. In addition, electrophysiological recordings of neuronal activity indicate the involvement of substance P and neurokinin A in the responses of spinothalamic tract neurons (Dougherty et al., 1994) and provide evidence for a role of these tachykinins in mediating nociceptive inputs in the dorsal horn (Fleetwood-Walker et al., 1990; Munro et al., 1993). Molecular biology has also revealed that chemical activation of nociceptors upregulates the expression of tachykinin NK1 and NK3 receptor mRNA in the dorsal root ganglia (McCarson and Krause, 1994). However, the lack of effect of tachykinin NK1 receptor antagonists in acute pain models suggests that at least substance P may only be involved in conditions of persistent pain (Henry, 1993).

To date, little has been published concerning the role of tachykinin in nociceptive processing in chronic pain syndromes. Donaldson et al. (1992)have reported that monoarthritis increases the expression of preprotachykinin mRNA in the dorsal root ganglia of the rat. Using a model of neuropathic pain, Marchand et al. (1994)have shown that tachykinin expression is initially increased and later decreased in dorsal root ganglia neurons. RP-67,580, a non-peptide tachykinin NK1 receptor antagonist, has been shown to possess antinociceptive properties in a model of chronic painful diabetes, suggesting the involvement of substance P in the hyperalgesia resulting from this metabolic dysfunction (Courteix et al., 1993a). The recent development of some non-peptide tachykinin receptor antagonists and the availability of animal models of chronic pain have provided new research tools to investigate the role of tachykinins in persistent nociception, particularly when this is due to neurogenic changes.

The present experiments were undertaken to compare the spinal antinociceptive properties of tachykinin NK1 and NK2 receptor antagonists in two models of neurogenic pain, sciatic nerve ligature (Bennett and Xie, 1988) and streptozocin-induced diabetes (Courteix et al., 1993b), and in normal rats. These two models of neurogenic pain were chosen to determine whether there were differences in tachykinin involvement according to the etiology of the neuropathy (compressive or metabolic), an observation which could help to discriminate between neuropathic pain syndromes. To clarify the role played by neurokinin B at the NK3 receptor site, the effect of a non-peptide tachykinin NK3 receptor antagonist was also tested.

Section snippets

Animals

Male Sprague–Dawley rats (Charles River, France), initially weighing 200–250 g, were housed four or five per cage under standard laboratory conditions and allowed food and water ad libitum.

As some suffering might result from these experiments, the I.A.S.P. Committee for Research and Ethical Issues Guidelines (Zimmermann, 1983) were followed. Great care was taken, particularly with regard to housing conditions, to avoid or minimize discomfort to the animals.

Induction of mononeuropathy

The rats were anaesthetized with

Results

Diabetes significantly reduced the vocalization thresholds 3 weeks after streptozocin injection (mean values: 247±15 g before induction vs. 141±10 g after induction). Two weeks after nerve ligation, the vocalization thresholds (mean values: 257±11 g before surgery) were significantly lower (mean values: 107±6 g).

Discussion

The results obtained show an antinociceptive effect of the tachykinin NK1 receptor antagonist, RP-67,580, in mononeuropathic rats and confirm its activity in diabetic rats, as previously reported by Courteix et al. (1993b). Two other tachykinin NK1 receptor antagonists, CP-96,345 and SR-140,333, were also antinociceptive in diabetic and mononeuropathic rats (Snider et al., 1991; McLean et al., 1991; Rouissi et al., 1991; Emonds-Alt et al., 1993). All these compounds were shown to be ineffective

Acknowledgements

The authors would like to acknowledge the pharmaceutical companies: Pfizer; Rhône-Poulenc Rorer and Sanofi, for their generous gifts of the tachykinin receptor antagonists.

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