Antinociceptive effects of chronic administration of uncompetitive NMDA receptor antagonists in a rat model of diabetic neuropathic pain

Abstract

Diabetic neuropathic pain remains an unmet clinical problem and is poorly relieved by conventional analgesics. N-methyl-d-aspartate (NMDA) receptors play an important role in central sensitization in neuropathic pain. Although NMDA antagonists are highly effective in reducing neuropathic pain, these agents cause severe side effects at therapeutic doses, which limit their clinical uses. Neramexane and memantine are uncompetitive NMDA antagonists with minimal side effects at therapeutic doses. Here we determined the antinociceptive effect of chronic administration of neramexane and compared its effect with that of memantine and gabapentin in a rat model of diabetic neuropathic pain. Mechanical hyperalgesia was measured with a noxious pressure stimulus, and tactile allodynia was assessed with von Frey filaments in diabetic rats induced by streptozotocin. Compared with vehicle-treated rats, treatment with neramexane (12.3, 24.6, and 49.2 mg/kg/day) for 2 weeks via an osmotic minipump produced dose-dependent and sustained effects on mechanical hyperalgesia and allodynia. Administration of memantine (20 mg/kg/day) or gabapentin (50 mg/kg/day) for 2 weeks also produced significant and persistent antinociceptive effects on mechanical hyperalgesia and allodynia. The magnitude of the antinociceptive effect produced by the intermediate and high doses of neramexane was comparable to that of gabapentin and memantine. The plasma level achieved by neramexane at 12.3, 24.6, and 49.2 mg/kg/day was 0.26 ± 0.04, 0.50 ± 0.05, and 1.21 ± 0.16 μM, respectively. These data suggest that neramexane at therapeutically relevant doses attenuates diabetic neuropathic pain. Our study provides valuable information about the therapeutic potential of chronic administration of neramexane and memantine for painful diabetic neuropathy.

Introduction

Diabetic neuropathy is one of the most common causes of chronic neuropathic pain. The neuropathic pain symptoms are often intractable because they are poorly relieved by conventional analgesics (Brown and Asbury, 1984, Chen and Pan, 2003, Clark and Lee, 1995). Pain associated with diabetic neuropathy can occur spontaneously or as a result of exposure to mildly painful stimuli (hyperalgesia) or to stimuli not normally perceived as painful (allodynia). In addition to the changes of primary afferent nerves, central sensitization plays an important role (Chen and Pan, 2002, Daulhac et al., 2006, Khan et al., 2002, Wang et al., 2007). Although the cellular and molecular mechanisms underlying chronic pain in diabetic neuropathy are not fully known, increased glutamatergic input and N-methyl-d-aspartate (NMDA) receptor activity contribute importantly to central sensitization in painful diabetic neuropathy (Chen and Pan, 2002, Wang et al., 2007). Persistent over-stimulation of NMDA receptors is essential for the long-term plastic changes in the spinal dorsal horn and the development of diabetic neuropathic pain (Calcutt and Chaplan, 1997, Daulhac et al., 2006, Tomiyama et al., 2005). The NMDA receptor antagonists, such as ketamine and dextromethorphan, are effective in reducing various types of neuropathic pain symptoms in patients (Correll et al., 2004, Eide et al., 1995, Max et al., 1995, Sang et al., 2002). However, these agents also cause severe side effects at therapeutic doses including hallucinations, dysphoria, and impairment of cognitive and motor function, which limit their clinical uses (Cvrcek, 2008, Max et al., 1995, Sang et al., 2002). Thus, development of new NMDA antagonists with a reduced side-effect profile is much needed.

Neramexane and memantine are uncompetitive NMDA receptor antagonists with moderate affinity, strong voltage-dependency, and rapid unblocking kinetics, which could explain their minimal side effects at the doses within the therapeutic range (Danysz et al., 2002, Johnson and Kotermanski, 2006, Parsons et al., 1999a, Parsons et al., 1999b, Rogawski and Wenk, 2003). Both drugs are presently used clinically to treat Alzheimer's disease (Danysz et al., 2002). It has been shown that acute administration of memantine has a potent inhibitory effect on the hypersensitivity of spinal dorsal neurons in animal models of neuropathic pain (Carlton et al., 1998, Suzuki et al., 2001). Although neramexane is well tolerated in patients, its therapeutic actions on diabetic neuropathic pain are uncertain.

To determine the therapeutic effect of analgesics on chronic pain in animals, it is important to evaluate the actions of the agents administered at a constant rate for a prolonged period of time. This will allow for the assessment of how drug effects, at a clinically relevant dosage, change over time in the presence of ongoing pain. Therefore, the first aim of the present study was to investigate the dose-response effect of systemic chronic administration of neramexane on mechanical allodynia and hyperalgesia in a rat model of diabetic neuropathic pain. The anticonvulsant, gabapentin, has been effectively used to treat patients with chronic pain caused by diabetic neuropathy and postherpetic neuralgia (Backonja et al., 1998, Rowbotham et al., 1998) and is commonly used as a comparator in animal studies in which the efficacy of new compounds is evaluated for the treatment of chronic pain. The second aim of this study was to compare the antinociceptive effect of neramexane on diabetic neuropathic pain with that produced by memantine and gabapentin.