N-Methyl-?-Aspartate (NMDA) Receptors, Mu and Kappa Opioid Tolerance, and Perspectives on New Analgesic Drug Development
NeuropsychopharmacologyPublished 1 December 1995
Kathryn Elliott
Citations131
SJR quartileQ1
SJR score2.94
SNIP1.99
Generate an AI Snapshot to get a quick, structured summary of this paper.
Study Snapshot
ObjectiveStudy objective
MethodsResearch methodology
PopulationPopulation studied
Sample sizeSample sizes
OutcomesStudy outcomes here
ResultsStudy results comes here
LimitationsResearch study limitations comes here
A concise AI-generated summary of the paper will appear here once you click Generate AI Snapshot.
TL;DR
A strategy, which utilizes efficacy as an NMDA receptor antagonist and clinical safety, provides the basis for a discussion of the clinical potential of dextromethorphan, ketamine, and felbamate as modulators of opioid tolerance in pain patients or opioid addicts.
Abstract
This laboratory perspective reviews the pharmagologic approaches that have been used in preclinical animal models to demonstrate the ability of competitive (LY274614) and noncompetitive (MK801 and dextromethorphan) N-methyl-D-aspartate (NMDA) receptor antagonists to attenuate or reverse the development of morphine tolerance. We provide additional data to support previous observations that these NMDA antagonists modulate morphine (mu) opioid tolerance but do not affect U50488H (kappa 1) opioid tolerance. A strategy, which utilizes efficacy as an NMDA receptor antagonist and clinical safety, provides the basis for a discussion of the clinical potential of dextromethorphan, ketamine, and felbamate as modulators of opioid tolerance in pain patients or opioid addicts. The potential use of NMDA receptor antagonists and nitric oxide synthase (NOS) inhibitors in neuropathic pain is also discussed.
Keywords
MedicineNeuroscience
New England Journal of MedicineExcitatory Amino Acids as a Final Common Pathway for Neurologic Disorders
2,662 Citations1994Franklin H. Epstein, Stuart A. Lipton +1 more
In many neurologic disorders, injury to neurons may be caused at least in part by overstimulation of receptors for excitatory amino acids, including glutamate and aspartate.
PainThe induction and maintenance of central sensitization is dependent on N -methyl-d-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states
1,982 Citations1991Clifford J. Woolf, Steve Thompson
Results indicate that NMDA receptors are involved in the induction and maintenance of the central sensitization produced by high threshold primary afferent inputs and have a bearing both on the potential role of NMDA antagonists for pre‐emptive analgesia and for treating established pain states.
Trends in Pharmacological SciencesExcitatory amino acid neurotoxicity and neurodegenerative disease
1,774 Citations1990Brian S. Meldrum, John Garthwaite
In vivo and in vitro studies of the cytotoxicity of amino acids are reviewed and the contribution of such toxicity to acute and chronic neurodegenerative disorders is summarized.
SciencePathological Changes Induced in Cerebrocortical Neurons by Phencyclidine and Related Drugs
1,251 Citations1989John W. Olney, Joann Labruyere +1 more
These findings raise new questions regarding the safety of these agents in the clinical management of neurodegenerative diseases and reinforce concerns about the potential risks associated with illicit use of PCP.
ScienceInhibition of Morphine Tolerance and Dependence by the NMDA Receptor Antagonist MK-801
1,219 Citations1991Keith A. Trujillo, Huda Akil
The present studies suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.
ScienceRegulation of Gene Expression in Hippocampal Neurons by Distinct Calcium Signaling Pathways
1,164 Citations1993Hilmar Bading, David D. Ginty +1 more
Results indicate that Ca2+, depending on its mode of entry into neurons, can activate two distinct signaling pathways, and differential signal processing may provide a mechanism by which Ca2+ controls diverse cellular functions.
ScienceNMDA Antagonist Neurotoxicity: Mechanism and Prevention
850 Citations1991John W. Olney, Joann Labruyere +4 more
It is shown that the morphological damage can be prevented by certain anticholinergic drugs or by diazepam and barbiturates, which act at the gamma-aminobutyric acid (GABA) receptor-channel complex and are known to suppress the psychotomimetic symptoms caused by ketamine, thereby enhancing their utility as neuroprotective drugs.
PainRelief of post-herpetic neuralgia with the Symbol receptor antagonist ketamine: A double-blind, cross-over comparison with morphine and placebo
493 Citations1994Per Kristian Eide, Ellen Jørum +3 more
The hypothesis that the Symbol (NMDA) receptors are involved in the control of post‐herpetic neuralgia including allodynia and wind‐up‐like pain and the NMDA receptors also may play a role in the modulation of thermal perception is supported.
British Journal of Pharmacology<scp>l</scp>‐N<sup>G</sup>‐nitro arginine methyl ester exhibits antinociceptive activity in the mouse
474 Citations1991Philip K. Moore, Ademola O. Oluyomi +3 more
The results suggest that l‐NAME produces an opioid‐independent and long‐lasting antinociception in the mouse most probably by a direct effect within the central nervous system.
NeuronSustained potentiation of NMDA receptor-mediated glutamate responses through activation of protein kinase C by a μ opioid
444 Citations1991Li Chen, Li-Yen Mae Huang Marine
Intracellularly applied protein kinase C (PKC) mimics the effect of D AGO, and a specific PKC inhibitor interrupts the sustained potentiation produced by DAGO, suggesting that PKC plays a key role in mediating the action of mu opioid peptides.
NeuroscienceNitric oxide mediates the thermal hyperalgesia produced in a model of neuropathic pain in the rat
380 Citations1992Stephen T. Meller, P.S. Pechman +2 more
Results suggest that a sustained production of nitric oxide and subsequent activation of soluble guanylate cyclase in the lumbar spinal cord mediate the thermal hyperalgesia produced in a model of neuropathic pain in the rat.
PainThe Symbol receptor antagonist dextromethorphan selectively reduces temporal summation of second pain in man
368 Citations1994Donald D. Price, Jianren Mao +2 more
Oral doses of dextromethorphan were given on a double‐blind basis to normal volunteer human subjects, providing evidence that DM selectively reduces temporal summation of second pain, as has been shown for wind‐up.
Neuroscience LettersInvolvement of nitric oxide in spinally mediated hyperalgesia in the mouse
313 Citations1992Kelley F. Kitto, Jane E. Haley +1 more
PainThe NMDA-receptor antagonist CPP abolishes neurogenic ‘wind-up pain’ after intrathecal administration in humans
303 Citations1992Jens D. Kristensen, B. A. Svensson +1 more
Early experiences with i.t. administration of NMDA-receptor antagonists to humans indicate that the NMDA -receptor system plays an important role in neurogenic pain and that antagonizing this system may be a useful way to obtain better pain control although psychotomimetic side effects due to rostral spread might be a problem.
Brain ResearchExcitatory amino acid antagonists (kynurenic acid and MK-801) attenuate the development of morphine tolerance in the rat
299 Citations1991Przemysław Marek, Shamgar Ben‐Eliyahu +2 more
Control experiments showed that at the same doses neither acute nor chronic administration of these antagonists affected morphine analgesia itself in a manner that can explain these findings.
NeuropharmacologyElectrophysiological evidence for a role of nitric oxide in prolonged chemical nociception in the rat
293 Citations1992Jane E. Haley, Anthony H. Dickenson +1 more
Nitric oxide may be involved, in a complex way, in nociceptive events both in the periphery and within the spinal cord during acute electrically-evoked and prolonged chemically-Evoked nocICEptive stimulation in rats anaesthetised with halothane.
Brain ResearchIntrathecal MK-801 and local nerve anesthesia synergistically reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy
285 Citations1992Jianren Mao, Donald D. Price +3 more
PainThe NMDA Receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids
278 Citations1994Kathryn Elliott, Nobuko Minami +3 more
The results suggest that mu‐opioid tolerance but not kappa1‐ or kappa3‐opIOid tolerance involves the mediation of NMDA receptors and the nitric oxide system.
Proceedings of the National Academy of SciencesBlockade of tolerance to morphine but not to kappa opioids by a nitric oxide synthase inhibitor.
275 Citations1993Yuri Kolesnikov, Chaim G. Pick +2 more
No2Arg does not prevent tolerance to analgesia mediated by the kappa 1 agonist trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolindinyl)cyclohexyl]- benzene-acetamide (U50,488H), indicating a selective action of NO in the mechanisms of mu tolerance and dependence.
SciencePotentiation of Opiate Analgesia and Apparent Reversal of Morphine Tolerance by Proglumide
264 Citations1984L.R. Watkins, B. Kinscheck I +1 more
Proglumide potentiated analgesia produced by morphine and endogenous opiates and seemed to reverse tolerance in rats, suggesting that endogenous cholecystokinin systems oppose the action of opiates.
Brain ResearchIntrathecal treatment with dextrorphan or ketamine potently reduces pain-related behaviors in a rat model of peripheral mononeuropathy
239 Citations1993Jianren Mao, Donald D. Price +4 more
The therapeutic effects of dextrorphan and ketamine, two non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, on neuropathic pain-related behaviors were examined in rats with peripheral mononeuropathy induced by loose ligation of the common sciatic nerve, and a new therapeutic utility of these 'old' compounds is suggested.
Journal of Pharmacology and Experimental TherapeuticsAttenuation and reversal of morphine tolerance by the competitive N-methyl-D-aspartate receptor antagonist, LY274614.
215 Citations1993Paul J. Tiseo, Charles E. Inturrisi
The demonstration that LY274614 can prevent and reverse the development of morphine tolerance without reducing the analgesic response suggests that the adaptive system involved in the development and maintenance of tolerance requires a functional N-methyl-D-aspartate receptor.
PainDextromethorphan for the treatment of neuropathic pain: a double-blind randomised controlled crossover trial with integral n-of-1 design
183 Citations1994Henry J McQuay, Dawn Carroll +5 more
There were no significant differences between DM and placebo on any of the clinic assessment outcome measures, and two patients had significantly better analgesia on more than one outcome measure on within‐patient testing.
Brain ResearchDextrorphan and dextromethorphan attenuate glutamate neurotoxicity
161 Citations1987Dennis W. Choi
Thedextrorotatory morphinan opioid, dextrorphan, was found at 10-100 microM concentrations to attenuate both morphological and chemical evidence of glutamate neurotoxicity in murine neocortical cell cultures; a similar effect was found with its methyl ester derivative, deXTromethorphan.
Journal of Pharmacology and Experimental TherapeuticsEvidence for anticonvulsant and neuroprotectant action of felbamate mediated by strychnine-insensitive glycine receptors.
159 Citations1993R. Tyler McCabe, Claude G. Wasterlain +3 more
The data presented in this report strongly indicate a mechanism of action for felbamate through strychnine-insensitive glycine receptor interaction as a novel anticonvulsant for the treatment of generalized tonic-clonic and complex partial seizures.
European Journal of PharmacologyDifferential effects of dextrorphan and levorphanol on the excitation of rat spinal neurons by amino acids
154 Citations1985John Church, David Lodge +1 more
This observation supports the proposal that the NMA-blocking activity of a variety of drugs with psychotomimetic properties is subserved by actions at phencyclidine (PCP)/sigma opiate receptors.
PainComparison of ketamine and pethidine in experimental and postoperative pain
146 Citations1989A Maurset, Lasse A. Skoglund +2 more
The results are in accordance with the hypothesis that the analgesic effect of ketamine is mediated by a non‐opioid mechanism, possibly involving PCP‐receptor‐mediated blockade of the NMDA‐recept‐operated ion channel.
Neuroscience LettersStudies on the spinal interaction of morphine and the NMDA antagonist MK-801 on the hyperesthesia observed in a rat model of sciatic mononeuropathy
144 Citations1992Tatsuo Yamamoto, Tony L. Yaksh
The results suggest that NMDA antagonism does not alter the thermal sensitivity in the normal paw, selectively abolishes the hypersensitivity of the hypersthetic paw and has a simple additive interaction with the antinociceptive effects of morphine in the hyperesthetic paw.
European Journal of PharmacologyDextromethorphan blocks N-methyl-D-aspartate-induced currents and voltage-operated inward currents in cultured cortical neurons
143 Citations1993Rainer Netzer, Pascal Pflimlin +1 more
The results suggest that the neuroprotective effect of dextromethorphan, previously found to occur in a concentration range of 10-100 microM, may be due to a complete blockade of the NMDA receptor channel and a partial inhibition of voltage-dependent Ca2+ and Na+ channels.
PainKetamine hydrochloride in the treatment of phantom limb pain
142 Citations1993Catherine Stannard, Gwenda E. Porter
Three cases are described in which phantom limb pain was successfully treated with ketamine hydrochloride and possible mechanisms for this observation are suggested.
EpilepsiaA Neuropharmacological Evaluation of Felbamate as a Novel Anticonvulsant
142 Citations1992H. Steve White, Harold H. Wolf +3 more
The results support the concept that FBM is a relatively nontoxic agent with a unique profile of anticonvulsant action, a broad margin of safety, and a clinical potential that includes at least generalized tonic‐clonic and complex partial seizures.
PainDextromethorphan attenuates and reverses analgesic tolerance to morphine
134 Citations1994Kathryn Elliott, Alexandra Hynansky +1 more
It is demonstrated that dextromethorphan, an NMDA receptor antagonist can modulate morphine (mu‐receptor)‐mediated tolerance and reversal of morphine tolerance with the almost complete return of the morphine ED50 value to the control (opioid naive) value.
European Journal of PharmacologyDextromethorphan inhibits NMDA-induced convulsions
124 Citations1988John W. Ferkany, Susan A. Borosky +2 more
The results are consistent with the interpretation that dextromethorphan elicits some of its pharmacological responses via an interaction with receptors for excitatory amino acids.
Journal of Pharmacology and Experimental TherapeuticsModulation of morphine tolerance by the competitive N-methyl-D-aspartate receptor antagonist LY274614: assessment of opioid receptor changes.
91 Citations1994Paul J. Tiseo, Juei‐Tang Cheng +2 more
Results demonstrate that the competitive NMDA receptor antagonist LY274614 can both attenuate and reverse the development of morphine tolerance.
Brain ResearchGenetic influences in opioid analgesic sensitivity in mice
78 Citations1991Chaim G. Pick, Jie Cheng +2 more
The results suggests that the genetic controls over mu and kappa analgesia operate independently and further illustrate the many difficulties in evaluating potential analgesics.
PainDextromethorphan suppresses both formalin-induced nociceptive behavior and the formalin-induced increase in spinal cord c- fos mRNA
76 Citations1995Kathryn Elliott, Marina Brodsky +3 more
The data indicate that dextromethorphan suppresses formalin nociceptive behavior and one of the biochemical consequences of formalinNociception, i.e., induction of c‐fos mRNA, as assessed with quantitative solution hybridization at 30 min postinjection.
European Journal of PharmacologyFelbamate reduces hypoxic-ischemic brain damage in vivo
72 Citations1992Claude G. Wasterlain, Lisa M. Adams +2 more
The neuroprotective effects of felbamate were tested in a model of incomplete cerebral ischemia and hypoxia in 7-day-old rat pups, and the number of necrotic neurons in the dentate gyrus was reduced over both DMSO and saline controls.
Acta NeuropathologicaThe nature and time course of neuronal vacuolation induced by the N-methyl-D-aspartate antagonist MK-801
68 Citations1994Roland N. Auer, K. C. Coulter
It is concluded that the vacuolation induced by NMDA antagonists is a reaction to aldehyde fixation of perturbed but living neurons, resulting in artifactual distortion of multiple intracellular compartments.
Life SciencesBlockade of mu and kappa1 opioid analgesic tolerance by NPC17742, a novel NMDA antagonist
59 Citations1993Yuri Kolesnikov, John W. Ferkany +1 more
The ability of NPC17742 to block tolerance to U50488H distinguishes this compound from other NMDA antagonist and raises the possibility of subclasses of NMDA antagonists.
Life SciencesOpiate tolerance-induced modulation of free intracellular calcium in synaptosomes
55 Citations1991Sandra P. Welch, Kirsten G. Olson
The data suggest that chronic exposure to morphine results in an alteration in either the number of the activation state of calcium channels in the membrane or changes in intracellular free calcium, which may be the final common pathway through which neurons adapt to the chronic Exposure to morphine.
NeuroreportL-NAME blocks responses to NMDA, substance P and noxious cutaneous stimuli in cat dorsal horn
52 Citations1993V. Radhakrishnan, J.L. Henry
The results suggest the possible involvement of nitric oxide in the mediation of the spinal effects of NMDA and substance P, and in the transmission of thermal and mechanical nociceptive imputs.
NeurologyDextromethorphan for treatment Of complex partial seizures
50 Citations1990Robert S. Fisher, Barbara J. Cysyk +6 more
StrokeSafety and tolerance of oral dextromethorphan in patients at risk for brain ischemia.
46 Citations1991Gregory W. Albers, Rodolfo E. Sáenz +2 more
No clinical evidence of toxicity attributable to dextromethorphan is documented in this preliminary study and patients with a history of recent stroke or transient ischemic attack are treated.
SynapseNMDA antagonists and clonidine block c‐fos expression during morphine withdrawal
43 Citations1995Kurt Rasmussen, Marina Brodsky +1 more
The results further delineate both the neuroanatomical pathways involved in morphine withdrawal and the locus of action of compounds that reduce morphine‐withdrawal symptoms.
Brain ResearchThe specific N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 blocks U-50,488, but not morphine antinociception
40 Citations1992Benjamin Kest, Przemysław Marek +1 more
The present results are the first to suggest a critical role for the NMDA receptor in opiate antinociception involving the kappa receptor.
Brain ResearchEvidence for the role of nitric oxide in κ-opiate tolerance in mice
40 Citations1993Sanjay N. Thorat, Poluru L. Reddy +1 more
A potential role for NO in the development of κ-opiate tolerance is suggested after concurrent treatment of NO synthase inhibitor and U-50,488H with l -NMMA.
Brain ResearchEffect of dizocilpine (MK-801) on analgesia and tolerance induced by U-50,488H, a κ-opioid receptor agonist, in the mouse
40 Citations1994Hemendra N. Bhargava, Sanjay N. Thorat
It is concluded that MK-801 in doses which do not affect U-50,488H-induced analgesia blocks the development of tolerance to its analgesic action in mice, and suggests that NMDA receptors play a crucial role in the developmentof tolerance to kappa-opioid agonist in mice.
NeuropharmacologyDextromethorphan and levorphanol on dorsal horn nociceptive neurones in the rat
38 Citations1991Anthony H. Dickenson, Ann F. Sullivan +2 more
Unlike levorphanol and other opiates, intrathecal administration of dextromethorphan blocked the C-fibre input and A beta response in parallel and was not reversed by naloxone.