Targeting N-methyl-D-aspartate Receptors for Treatment of Neuropathic Pain

Hong-Yi Zhou; Shao-Rui Chen; Hui-Lin Pan

Disclosures

Expert Rev Clin Pharmacol. 2011;4(3):379-388. 

In This Article

Abstract and Introduction

Abstract

Neuropathic pain remains a major clinical problem and a therapeutic challenge because existing analgesics are often ineffective and can cause serious side effects. Increased N-methyl-D-aspartate receptor (NMDAR) activity contributes to central sensitization in certain types of neuropathic pain. NMDAR antagonists can reduce hyperalgesia and allodynia in animal models of neuropathic pain induced by nerve injury and diabetic neuropathy. Clinically used NMDAR antagonists, such as ketamine and dextromethorphan, are generally effective in patients with neuropathic pain, such as complex regional pain syndrome and painful diabetic neuropathy. However, patients with postherpetic neuralgia respond poorly to NMDAR antagonists. Recent studies on identifying NMDAR-interacting proteins and molecular mechanisms of increased NMDAR activity in neuropathic pain could facilitate the development of new drugs to attenuate abnormal NMDAR activity with minimal impairment of the physiological function of NMDARs. Combining NMDAR antagonists with other analgesics could also lead to better management of neuropathic pain without causing serious side effects.

Introduction

Chronic pain, such as neuropathic pain caused by peripheral nerve injury and diabetic neuropathy, can result in prolonged suffering and reduced quality of life. Pain can occur spontaneously or as a result of exposure to mildly painful stimuli (hyperalgesia) or stimuli not normally perceived as painful (allodynia). However, the treatment of chronic pain remains a major challenge, with only approximately 50% of patients receiving adequate pain relief.[1]

The glutamate N-methyl-D-aspartate receptors (NMDARs), especially those located in the dorsal horn of the spinal cord, are critically involved in nociceptive transmission and synaptic plasticity and have long been considered a target for the treatment of neuropathic pain. However, despite numerous preclinical studies demonstrating the efficacy of NMDAR antagonists in treating neuropathic pain, clinical studies suggest that NMDAR antagonists have limited effects in a subpopulation of patients with chronic neuropathic pain. Here, we review the current literature about the function and regulation of NMDARs and the therapeutic effects of NMDAR antagonists on chronic neuropathic pain.

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