Elsevier

European Journal of Pharmacology

Volume 451, Issue 3, 20 September 2002, Pages 279-286
European Journal of Pharmacology

Actions of intrathecal ω-conotoxins CVID, GVIA, MVIIA, and morphine in acute and neuropathic pain in the rat

https://doi.org/10.1016/S0014-2999(02)02247-1Get rights and content

Abstract

Agents which decrease conductance of N-type voltage-gated Ca2+ channels have been shown to attenuate measures of neuropathic pain in animal models and to provide symptom relief in humans. The ω-conotoxins have demonstrated efficacy but have a low therapeutic index. We have investigated the effects of a new ω-conotoxin, CVID (AM-336), and compared them with ω-conotoxin GVIA (SNX-124), ω-conotoxin MVIIA (SNX-111) and morphine in a spinal nerve ligation model of neuropathic pain in the rat. The ED50 (and 95% CI) for attenuation of tactile allodynia by intrathecal administration for ω-conotoxin CVID, GVIA, MVIIA and morphine was 0.36 (0.27–0.48), 0.12 (0.06–0.24), 0.32 (0.23–0.45) and 4.4 (2.9–6.5) μg/kg, respectively. Only morphine significantly prolonged acute tail flick responses (ED50 2.3 (1.1–4.9) μg/kg). Of the ω-conotoxins, ω-conotoxin CVID showed the highest ratio of efficacy to behavioural toxicity. These observations show that intrathecal ω-conotoxins are effective in attenuating tactile allodynia in the rat without significantly affecting acute nociceptive responses. ω-Conotoxin CVID had similar potency to ω-conotoxin MVIIA but showed less toxicity in the therapeutic range.

Introduction

Neuropathic pain manifesting as allodynia and hyperalgesia continues to be a significant problem in clinical medicine. The neurophysiological mechanisms underlying the pathogenesis of these conditions are complex and, despite considerable research, are still incompletely understood. Morphine has been shown to be moderately effective in the treatment of chronic neuropathic pain, but not all individuals are responsive and in animals, tolerance develops to continued exposure Levy et al., 1994, Malmberg and Yaksh, 1995. There is evidence that N-type voltage-gated Ca2+ channels (N-VGCCs) are involved in neurotransmitter release at a spinal cord level, and that blockade of these channels attenuates neuropathic pain responses (Chaplan et al., 1994b) and is less prone to the development of tolerance Malmberg and Yaksh, 1995, Omote et al., 1996. ω-Conotoxin GVIA (ω-conotoxin GVIA, also known as SNX-124) is a peptide derived from the venom of the marine snail Conus geographus which blocks N-type Ca2+ channels in a highly selective manner (Plummer et al., 1989). The potency in vivo of ω-conotoxin GVIA is greater than that of the related peptide from Conus magus, ω-conotoxin MVIIA (SNX-111) (Vega et al., 1995). ω-Conotoxin MVIIA has been shown to inhibit neuropathic pain responses using the spinal (intrathecal) route in animal studies (Bowersox et al., 1996), and it has also been used in clinical trials (Brose et al., 1997). Animal studies suggest that ω-conotoxin MVIIA has higher potency and induces less tolerance than morphine Bowersox et al., 1996, Malmberg and Yaksh, 1995. However, side effects have been reported with clinical use of ω-conotoxin MVIIA (Penn and Paice, 2000), so there is a need to investigate alternatives.

In this study, we compared the antinociceptive activity of intrathecal morphine, ω-conotoxin GVIA, and ω-conotoxin MVIIA with a new ω-conotoxin from Conus catus, CVID (AM-336) Lewis et al., 2000, Nielsen et al., 2000, in a rat model of neuropathic pain.

Section snippets

Materials and methods

Male Sprague–Dawley rats were housed in a facility with a 12-h day–night cycle and free access to food and water. They were caged in groups until after intrathecal catheter placement, when they were caged separately but adjacent to other animals. Animals were observed regularly throughout the treatment period and any showing signs of distress were removed from the study and humanely killed. The sequence of the study is shown in Table 1. All experiments were approved by the University of

Establishment of neuropathy

Following nerve ligation surgery, the tactile allodynia thresholds were significantly lower in the left (operated) hind paw compared with the right (P<0.001, repeated measures ANOVA, n=116). The mean (±S.E.) threshold for the left hind paw prior to agent administration was 3.0 (±0.2) g, compared with 12.5 (±0.4) for the right side (Fig. 1). There were no significant effects on tail-flick thermal latency following nerve ligation.

Sham surgery was performed in 20 animals. There was no significant

Discussion

This study demonstrates that the intrathecal administration of morphine and ω-conotoxins GVIA, MVIIA and CVID is effective in attenuating neuropathic pain in the rat. From the ED50 values calculated at 50% MPE, ω-conotoxin GVIA was three to four times more potent than ω-conotoxin MVIIA and ω-conotoxin CVID, and approximately 40 times more potent than morphine. Importantly, morphine but not the conotoxins, also prolonged tail-flick latency. Amongst the ω-conotoxins, CVID had the largest ratio of

Acknowledgements

We gratefully acknowledge the Australian and New Zealand College of Anaesthetists for a research grant which supported part of this project. Conotoxin compounds and a grant in aid were supplied by AMRAD (Burnley, Victoria, Australia). We thank Linda Cornthwaite-Duncan for her valuable assistance.

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