Clonidine potentiates the neuropathic pain-relieving action of MK-801 while preventing its neurotoxic and hyperactivity side effects

doi:10.1016/S0006-8993(97)01247-X

Brain Research

Volume 781, Issues 1–2, 19 January 1998, Pages 202-211

https://doi.org/10.1016/S0006-8993(97)01247-X Get rights and content

Abstract

Antagonists of NMDA glutamate receptors have been shown to alleviate neuropathic pain in rats and humans. However, NMDA antagonists can cause significant side effects ranging from behavioral disturbances to injury of neurons in the posterior cingulate/retrosplenial (PC/RS) cortex. We have found that alpha-2 adrenergic agonists prevent the PC/RS neurotoxic side effects of NMDA antagonists. In the present study of adult female rats subjected to sciatic nerve ligation (Bennett neuropathic pain model) and tested for paw withdrawal latency (PWL) following a thermal stimulus, we evaluated the ability of the NMDA antagonist, MK-801, to alleviate neuropathic pain either by itself or when administered together with the alpha-2 adrenergic agonist, clonidine. We found that MK-801, at a dose (0.05 mg/kg s.c.) that is known to cause mild hyperactivity but is subthreshold for producing PC/RS neurotoxic changes, relieved the neuropathic pain state associated with sciatic nerve ligation. However, the relief at this dose was very transient, and no neuropathic pain-relieving effect was observed at a lower dose (0.025 mg/kg s.c.) of MK-801. Clonidine, at a dose (0.05 mg/kg s.c.) that prevents the cerebrocortical neurotoxic effects of MK-801, decreased sensitivity to the thermal stimulus equally under all conditions (ligated, sham ligated, unoperated), but did not specifically relieve neuropathic pain in the ligated limb. Combining this dose of clonidine with an ineffective dose (0.025 mg/kg s.c.) of MK-801 provided specific, complete and long lasting (up to 4 h) relief from neuropathic pain. Rats receiving this drug combination did not display hyperactivity or any other behavioral disturbance typically associated with MK-801 treatment, nor show neurotoxic changes in cerebrocortical neurons. In separate experiments on normal unoperated rats, we found that clonidine (0.05 mg/kg s.c.) counteracted the hyperactivity induced by MK-801 (0.05 mg/kg s.c.) and returned activity levels to a normal range. These findings signify that clonidine, which does not specifically relieve neuropathic pain, can potentiate the neuropathic pain-relieving action of MK-801, while also protecting against neurotoxicity and hyperactivity side effects of MK-801. The potentiation is of a sufficient magnitude that it permits cutting the MK-801 dose requirement in half, thereby achieving prolonged neuropathic pain relief while doubling the margin of safety against any type of side effect that might be mediated by blockade of NMDA receptors.

Introduction

A number of recent studies implicate glutamate (Glu) as a transmitter in nociceptive pathways in the spinal cord and suggest that hyperactivation of NMDA (N-methyl-d-aspartate) Glu receptors on small interneurons (wide dynamic range neurons) in the dorsal horn of the spinal cord is crucial for the mediation of certain types of chronic pain, including neuropathic pain 1, 2, 17, 26, 32. The neuropathic pain syndrome consists of chronic pain, dysesthesia, hyperalgesia and allodynia [12]. It is largely unresponsive to analgesic medications, including opiates. However, both animal and preliminary human studies have shown NMDA antagonists to be beneficial in alleviating symptoms of neuropathic pain 4, 6, 7, 9, 17, 20, 21, 26.

A significant obstacle to the therapeutic use of NMDA antagonists in the management of chronic pain is their potentially serious side effects; they are known to induce psychotomimetic reactions in adult humans 8, 10, 18, 25and induce behavioral disturbances such as learning and memory impairments, sensorimotor disturbances, stereotypical behaviors, and hyperactivity 26, 27, 31and pathomorphological changes in neurons of the posterior cingulate/retrosplenial (PC/RS) cortex of the adult rat 3, 13, 22, 23. On a more optimistic note, it has been found that several classes of drugs, when administered together with NMDA antagonists, can prevent their neurotoxic side effects 23, 24. Of particular interest is the recent finding [11]that alpha-2 adrenergic agonists, including clonidine, can prevent the neurotoxic side effects of NMDA antagonists. Relevance of this finding to the management of chronic pain is suggested by the following observations: (1) Transdermal clonidine may confer some therapeutic benefit in the management of diabetic neuropathic pain [33]; (2) Intrathecal administration of either clonidine or the potent NMDA antagonist, MK-801, to rats reduces the tactile hyperesthesia associated with spinal nerve ligation, and intrathecal co-application of clonidine plus MK-801 provides a greater anti-hyperesthetic effect than either agent by itself [19].

To explore further the potential advantage of combined treatment with an NMDA antagonist and alpha-2 adrenergic agonist, we undertook the present experiments in which clonidine and MK-801 were administered systemically to rats and tested for their ability, individually or in combination, to reduce the hyperesthetic response to thermal stimulation in a rat sciatic nerve ligation model of neuropathic pain [5]. In addition, a separate set of experiments was conducted on normal unoperated rats to assess the effects of clonidine on increased locomotor activity induced by MK-801.

Section snippets

Chemicals and animals

Experiments were performed on adult female Sprague–Dawley rats (weight 290–320 g). The noncompetitive NMDA antagonist MK-801 (dizocilpine) was purchased from Research Biochemicals, Natick, MA, and clonidine, an alpha-2 adrenergic agonist, from Sigma Chemical, St. Louis, MO.

Sciatic nerve ligation

In order to induce the hyperesthetic state in rats, a loose ligation of the sciatic nerve was performed [5]. Rats were maintained in a surgical plane of anesthesia with isoflurane (delivered by vaporizer through a nose cone)

General health of the operated animals

The animals subjected to sciatic nerve ligation maintained a normal weight following surgery and had a normal appearance except that they demonstrated a definite limp and the toes of the hind paw on the operated side were held in a ventroflexed posture. In addition, the affected hind paw was held close to the body reflecting an apparent reluctance to place it on the floor. As previously described by Bennett and Xie [5], a significant degree of hyperesthesia was elicitable approximately 7–10

Discussion

Here we show that an NMDA antagonist, MK-801, at a dose (0.05 mg/kg s.c.) that induces mild hyperactivity but is subthreshold for producing cerebrocortical neurotoxic changes, relieves the hyperalgesic state associated with sciatic nerve ligation. However, the analgesic effect at this dose was very transient, and no analgesic effect was observed at a lower dose (0.025 mg/kg s.c.) of MK-801. Clonidine, at a dose (0.05 mg/kg s.c.) that prevents the cerebrocortical neurotoxic effects of MK-801 [11]

Acknowledgements

This work was partially supported by NIH grants AG 11355, DA 05072 and RSA MH38894 (JWO). Portions of the present work were presented at the 1996 Society for Neuroscience Meetings.

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Research reportClonidine potentiates the neuropathic pain-relieving action of MK-801 while preventing its neurotoxic and hyperactivity side effects

Abstract

Introduction

Section snippets

Chemicals and animals

Sciatic nerve ligation

General health of the operated animals

Discussion

Acknowledgements

Pain

Pain

Pain

Brain Res.

Brain Res.

Neurosci. Lett.

Neuropsychopharmacology

Exp. Neurol.

Pain

Pain

Brain Res.

Neuropsychopharmacology

Pain

Neurosci. Lett.

Pain

Pain

Research report
Clonidine potentiates the neuropathic pain-relieving action of MK-801 while preventing its neurotoxic and hyperactivity side effects