NMDA receptors as targets for drug action in neuropathic pain

doi:10.1016/S0014-2999(01)01307-3

European Journal of Pharmacology

Volume 429, Issues 1–3, 19 October 2001, Pages 71-78

https://doi.org/10.1016/S0014-2999(01)01307-3 Get rights and content

Abstract

Hyperalgesia and allodynia following peripheral tissue or nerve injury are not only due to an increase in the sensitivity of primary afferent nociceptors at the site of injury but also depend on NMDA receptor-mediated central changes in synaptic excitability. Functional inhibition of NMDA receptors can be achieved through actions at different recognition sites such as the primary transmitter site (competitive), strychnine-insensitive glycine site (glycine_B), polyamine site (NR2B selective) and phencyclidine site located inside the cationic channel. Unfortunately, most agents which completely block NMDA receptors cause numerous side effects such as memory impairment, psychotomimetic effects, ataxia and motor incoordination. There is now, however, considerable evidence that moderate affinity channel blockers, glycine_B and NR2B selective antagonists show a much better profile in animal models than high affinity channel blockers and competitive NMDA receptor antagonists. These “therapeutically” safe NMDA receptor antagonists are also able to slow or prevent the development of opioid tolerance, indicating the utility of their combination with opioids in the treatment of chronic pain. The antinociceptive effects of NMDA receptor antagonists and opioids could be predicted to be synergistic and the presence of an NMDA receptor antagonist should block both the development of chronic pain states and inhibit the development of tolerance to the analgesic effects of morphine. Peripheral NMDA receptors offer a very attractive target for NMDA receptor antagonists that do not cross the blood brain barrier in inflammatory and visceral pain. Such agents might be predicted to be devoid of CNS side effects at doses producing powerful antinociception at peripheral NMDA receptors.

Section snippets

Glutamate in chronic pain

Despite intensive research on the neurobiological mechanisms of chronic pain, this therapeutic area remains one of the least satisfactorily covered by current drugs. Malfunctioning of glutamatergic neurotransmission has been implicated in a wide variety of neurological diseases such as acute stroke and trauma, chronic neurodegenerative diseases, epilepsy, schizophrenia and depression (see Parsons et al., 1998). Of particular relevance for this review is the involvement of glutamate in diseases

NMDA receptor antagonists

Functional inhibition of NMDA receptors can be achieved through actions at different recognition sites such as the primary transmitter site (competitive), strychnine-insensitive glycine site (glycine_B), polyamine site (NR2B selective) and phencyclidine site located inside the cationic channel (see Parsons et al., 1998). NMDA channel blockers act in an uncompetitive “use-dependent” manner, meaning that they only block the channel in the open state.

Unfortunately, antagonists which completely

Wind-up

More recent studies have addressed the issue whether it is possible to reproduce clinically the well characterized inhibition of wind-up seen with NMDA receptor antagonists in animal models. Dextromethorphan and ketamine, but not morphine significantly reduced both the area of secondary hyperalgesia and temporally summated ‘wind-up-like pain’ to repeated von Frey filament stimulation in healthy human volunteers with experimental first degree burn injury Ilkjaer et al., 1997, Mikkelsen et al.,

Opioid tolerance

It is believed that phenomena such as sensitisation, tolerance and drug-dependence might also involve synaptic plasticity. In fact, numerous studies indicate that NMDA receptor antagonists block sensitisation to amphetamine and cocaine as well as tolerance and dependence to ethanol and opioids in animal models Trujillo, 2000, Trujillo and Akil, 1991, Trujillo and Akil, 1995, Pasternak and Inturrisi, 1995, Mao, 1999. Recent studies indicate that the uncompetitive NMDA receptor antagonists

Peripheral NMDA receptors

Recent data indicate that peripheral NMDA receptors are also involved in inflammatory somatic and visceral pain. Peripheral glutamate receptors are associated with unmyelinated axons (Carlton et al., 1995) and the number of somatic sensory axons containing ionotropic glutamate receptors increases during peripheral sensitization due to inflammation Carlton and Coggeshall, 1999, Coggeshall and Carlton, 1999. Subcutaneous administration of formalin into the plantar surface of rat hindpaws causes

Conclusions

(1) NMDA receptor antagonists which completely block NMDA receptors cause numerous side effects such as memory impairment, psychotomimetic effects, ataxia and motor incoordination, and they also impair normal synaptic transmission—a two-edged sword.

(2) The challenge has therefore been to develop NMDA receptor antagonists that prevent the pathological activation of NMDA receptors but allow their physiological activation.

(3) There is now considerable evidence that moderate affinity channel

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ReviewNMDA receptors as targets for drug action in neuropathic pain

Abstract

Section snippets

Glutamate in chronic pain

NMDA receptor antagonists

Wind-up

Opioid tolerance

Peripheral NMDA receptors

Conclusions

Pain

Trends Neurosci.

Curr. Opin. Neurobiol.

J. Pain Symptom Manage.

Neurosci. Lett.

Neuropharmacology

Brain Res.

Neurosci. Lett.

Neurosci. Lett.

Brain Res.

Neurosci. Lett.

Pain

Trends Neurosci.

Brain Res.

Trends Pharmacol. Sci.

Gen. Pharmacol.

Neurosci. Lett.

Pain

Eur. J. Pharmacol.

Neurosci. Lett.

Neuropsychopharmacology

J. Physiol. (Paris)

Prog. Neurobiol.

Pain

Br. J. Anaesth.

Eur. J. Pharmacol.

Life Sci.

Biol. Psychiatry

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Cell

Brain Res. Rev.

Brain Res.

Pain

Gastroenterology

Neurosci. Lett.

Pain

Brain Res.

Neuropharmacology

Pharmacol. Biochem. Behav.

Neuropharmacology

Pain

Brain Res.

Pain

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Review
NMDA receptors as targets for drug action in neuropathic pain