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.

Increased Presynaptic and Postsynaptic α2-Adrenoceptor Activity in the Spinal Dorsal Horn in Painful Diabetic Neuropathy

“…Our data suggest that glutamate release from the primary afferents to spinal dorsal horn neurons is increased in diabetic neuropathic pain. The enhanced glutamate input probably contributes to the hyperexcitability of the dorsal horn neurons and the maintenance of diabetic neuropathic pain (Chen and Pan, 2002;Wang et al, 2007;Chen et al, 2009). Thus, effective reduction in glutamatergic input to spinal dorsal horn neurons represents an important therapeutic strategy for alleviating diabetic neuropathic pain.…”

“…Age-matched vehicle-injected rats were used as controls. The low dose of STZ was used to minimize the effects of STZ administration on the overall health of the animal (Chen and Pan, 2002;Chen et al, 2009). This model of neuropathic pain mimics the symptoms of neuropathy in diabetic patients, with alterations in pain sensitivity and poor responses to opioid administered systemically or intrathecally (Courteix et al, 1993;Malcangio and Tomlinson, 1998;Zurek et al, 2001;Chen and Pan, 2002).…”

Possible mechanism of protective effect of thalidomide in STZ-induced-neuropathic pain behavior in rats

“…Various mechanisms have been proposed to be involved in abnormal pain behavior and morphine tolerance such as activation of NMDA (Chen et al 2009), PKA (Smith and William 1999), PKC (Shukla et al 2006), receptor desensitization (Courteix et al 1998), increased oxidative stress (Obrosova et al 2007), cytokines (Johnston et al 2004) and NO level (Ahmed et al 2006).…”

Functional Plasticity of Group II Metabotropic Glutamate Receptors in Regulating Spinal Excitatory and Inhibitory Synaptic Input in Neuropathic Pain

“…The paw pressure test was used to quantify the mechanical nociceptive threshold of the hindpaw (mechanical hyperalgesia) Chen et al, 2009b). Nociceptive thresholds, expressed in grams, were measured with an analgesimeter (Ugo Basile, Varese, Italy).…”