NMDA Antagonists and Neuropathic Pain - Multiple Drug Targets and Multiple Uses

Abstract

NMDA (N-methyl-D-aspartate) receptors are one class of ionotropic receptor for the ubiquitous excitatory neurotransmitter L-glutamate. The receptor is made up of four protein subunits combined from a larger library of proteins, which gives this receptor a great deal of variability. This explains the large number of modulatory sites, a variety of sites at which antagonists can interact, and therefore a number of potential drug targets. Sensitivity of the NMDA ion channel to ambient levels of Mg++ gives it a voltage dependence that suits a function of responding to intense synaptic activation; the ability of the channel to admit Ca++ tends to trigger long-term processes. The receptor is thereby involved in long-term physiological processes such as learning and memory as well as in pathological processes such as neuropathic pain. Separating these functions therapeutically with NMDA antagonists has been a major difficulty, and has not yet been achieved with currently-available agents. This review summarises the preclinical rationale, based on animal models, and the clinical evidence on the use of NMDA antagonists in pain states. It also summarises the details of the receptor so as to explain the rationale for targeting either specific sites on the receptor, or exploiting anatomical differences in subtype expression, so as to provide the beneficial effects of NMDA receptor block with an improved side effect profile. In particular, agents that are selective for receptors that include the NR2B subunit preclinically have a substantially better profile for treating neuropathic pain than do current NMDA antagonists; some emerging clinical evidence supports this view.

Pharmacological dissection of the paradoxical pain induced by a thermal grill

“…The selective effects of low doses of ketamine on paradoxical pain suggests that the thermal grill illusion of pain may share some mechanisms with pathological pain (inflammatory or neuropathic), particularly mechanical and thermal hyperalgesia/allodynia, which respond preferentially to NMDA antagonists both in animals and humans (Eide et al, 1994;Fundytus, 2001;Jorum et al, 2003;Chizh and Headley, 2005). This is consistent with the interpretation of the thermal grill effect according to the thermosensory disinhibition theory, which suggests that this phenomenon is related to the pathological mechanisms of spontaneous pain and/or cold allodynia frequently associated with central neurological lesion (Craig et al, 1994;Craig, 1998Craig, , 2003.…”

Targeting the NMDA Receptor Subunit NR2B for the Treatment of Neuropathic Pain

“…77 For example, in clinical studies ketamine was effective in relieving pain intensity, wind-up, and allodynia in a number of pathological pain syndromes, including postherpetic neuralgia, spinal cord injury-induced central neuropathic pain, and peripheral neuropathy. 78,79 High doses of dextromethorphan showed statistically significant effects in diabetic neuropathy patients (although the reported effects may be underestimated, given the log-linear nature of the Gracely pain intensity scale), but had no effect in postherpetic neuralgia.…”

“…84,85 After the identification of ifenprodil, a second generation of compounds was developed, such as Ro 25-6981 and CI-1041, which have demonstrated efficacy in a number of animal pain models, apparently with superior adverse effect profiles, relative to earlier analogues. 5,77 One compound, traxoprodil (CP-101,606) has progressed to phase II clinical trials. A preliminary report indicates that intravenous administration of the compound is effective in patients suffering from central pain such as spinal cord injury, but show no typical psychotomimetic effects.…”

Liposome reconstitution and modulation of recombinant N -methyl- d -aspartate receptor channels by membrane stretch

“…he ionotropic, glutamate-activated N-methyl-D-aspartate (NMDA) receptors are ligand-gated cation channels that play an important role in both physiological and pathological processes, including long-term potentiation and synaptic plasticity (1,2), neuronal excitotoxicity, and cognitive deficits attributable to aging and pain (3)(4)(5)(6)(7)(8). NMDA receptors are formed by heterooligomers of various NR1 and NR2 subunits (9).…”