Modulation of formalin-induced behaviors and edema by local and systemic administration of dextromethorphan, memantine and ketamine

Abstract

The present study examined the effects of local peripheral and systemic administration of three clinically used excitatory amino acid receptor antagonists (dextromethorphan, memantine, ketamine) on pain behaviors and edema produced by formalin (1.5% and 5%) in rats. Peripheral administration of dextromethorphan produced a locally mediated suppression of flinching behaviors induced by 1.5% and 5% formalin, but biting/licking behaviors were not affected. Memantine and ketamine had no effect on either of these behaviors. All three agents augmented edema produced by 1.5% and 5% formalin. When administered alone, dextromethorphan, memantine and ketamine produced an intrinsic paw swelling response, and this was blocked by the biogenic amine receptor antagonists mepyramine, phentolamine, methysergide and ketanserin. Following systemic administration, all three agents suppressed biting/licking behaviors, had no effect on flinching behaviors, and suppressed paw swelling induced by 5% formalin to varying degrees. These results provide evidence for a peripherally mediated antinociceptive action of dextromethorphan in the rat formalin test, but this may not necessarily be due to block of excitatory amino acid receptors as it is not observed with memantine or ketamine. All three agents produce a peripherally mediated paw swelling, which is likely due to blockade of biogenic amine reuptake. Systemic administration of all three agents produces antinociceptive and anti-inflammatory actions that may be due to block of excitatory amino acid receptors in the spinal cord.

Introduction

For some time, the spinal cord has been recognized as a target for excitatory amino acid receptor antagonists in producing analgesia in inflammatory and neuropathic pain states Dickenson, 1994, Price et al., 1994. More recently, it has been appreciated that peripheral excitatory amino acid receptors can regulate inflammatory pain. Thus, the local peripheral administration of agonists for such receptors can produce hyperalgesia and allodynia Jackson et al., 1995, Zhou et al., 1996, Lawland et al., 1997, while local administration of antagonists produces antihyperalgesic and analgesic actions Jackson et al., 1995, Davidson et al., 1997, Lawland et al., 1997, Davidson and Carlton, 1998. Excitatory amino acid receptors are present on sensory axons (Coggeshall and Carlton, 1998) and sympathetic postganglionic efferents (Coggeshall and Carlton, 1999), and these are upregulated following inflammation Carlton and Coggeshall, 1999, Coggeshall and Carlton, 1999. Such observations have led to the suggestion that peripheral excitatory amino acid receptors may represent a novel target for analgesic therapies by localized or topical administration of excitatory amino acid receptor antagonists (Carlton, 2001).

In the present study, we have examined the effects of peripheral administration of three clinically used N-methyl-d-aspartate (NMDA) receptor antagonists (dextromethorphan, memantine, ketamine) on pain behaviors produced by two different concentrations of formalin (1.5% and 5%). The formalin test is widely used as a model of acute inflammatory pain. Formalin injection activates peripheral sensory nerves Puig and Sorkin, 1995, McCall et al., 1996 and produces pain behaviors that involve ongoing peripheral activity and peripheral and central sensitization Tjølsen et al., 1992, Coderre et al., 1993b, Dallel et al., 1995. The formalin test generally uses concentrations ranging from 0.5% to 5%, and while pain behaviors are dose-related over this range Coderre et al., 1993a, Abbott et al., 1995, different mechanisms are involved at low and high concentrations. Thus, at low concentrations (<2%), there is a predominant activity of capsaicin-sensitive neurogenic components, while at a high concentration (5%), there is the additional involvement of more complex inflammatory elements (Damas and Liégois, 1999). Only the high concentration of formalin (5%) activates microglia in the spinal cord and produces a long-term hyperalgesia (Fu et al., 2000), and drugs that inhibit prostaglandin synthesis have a selective effect at 5% formalin (Yashpal and Coderre, 1998). It was demonstrated recently that 5% formalin, but not 2% formalin, releases glutamate from the rat spinal cord (Okuda et al., 2001). Five-percent formalin also releases glutamate locally in the rat hindpaw, but data for a lower concentration were not reported (Omote et al., 1998). If peripheral release of glutamate is also selective for a high concentration of formalin, then local peripheral administration of NMDA receptor antagonists could exert a selective action at high, but not low, formalin concentrations. On the other hand, dextromethorphan, memantine and ketamine all exert multiple pharmacological actions in addition to blocking NMDA receptors (see Discussion), and other mechanisms might have a selective expression at lower formalin concentrations where neurogenic mechanisms are predominantly involved and there is little concern for ceiling effects or behavioral asymptotes (cf. Abbott et al., 1995) obscuring drug actions. Dextromethorphan (Bern and Peck, 1992), memantine (Parsons et al., 1999) and ketamine (Reich and Silvay, 1989) are currently in clinical use, and these agents represent the first line of NMDA receptor antagonists that might be used for local peripheral application (e.g. as topical analgesics) to control pain. Each of these agents produces analgesia following systemic and spinal administration in various preclinical and clinical paradigms (Fisher et al., 2000), but their peripheral effects have received limited attention.

The local injection of formalin also produces an inflammatory response resulting in paw swelling Wheeler-Aceto et al., 1990, Damas and Liégois, 1999. Spinal administration of excitatory amino acid receptor antagonists can regulate peripheral inflammatory responses (Sluka and Westlund, 1993), but there is little data on a peripheral contribution of glutamate to this process. Given that glutamate can stimulate sensory afferent nerves (Du et al., 2001), it could potentially contribute to inflammation by recruiting a neurogenic mechanism. We therefore also determined the effects of dextromethorphan, memantine and ketamine on edema produced by formalin at 1.5% and 5% formalin. When an increase in edema was observed, intrinsic effects of these agents on paw volume, and potential mechanisms involved, were examined.