Ketamine Pain Mechanism
Pain is communicated from the brain to other parts of the body by the CNS (Central Nervous System) and nerve endings. (Mayer, Mao, Holt, Price, 7731-7736) The ligand-gated ion channels, also referred to as LGICs, or ionotropic receptors, are a group of intrinsic transmembrane ion channels that are opened in response to binding of a chemical messenger. (Collingridge, Singer, 290-296) (Dickenson, 307-309) (Dickenson, Chapman, Green, 633-638)
The ion channel is regulated by a neurotransmitter ligand that is very selective to one or more ions like potassium, sodium, calcium, and chloride.
(Kandel, Schwartz, Jessell, 178-180) Such receptors located at synapses converting the chemical signal to an electric signal in the post-synaptic cell. (Connolly, Wafford, 529-534) The NMDA receptor (N-methyl-D-aspartate) is such an ionotropic receptor for glutamate. (Dingledine, Borges, Bowie, Traynelis, 7-61) (Lodge, Johnson, 81-86) (Meller, 435-436) By X-ray crystallography, the NMDA receptors have an heterodimer subunits, which are involved in the binding of agonists and antagonists like Ketamine. (Hirota, Lambert, 441-444)
This channel complex contributes to excitatory synaptic transmission at sites throughout the brain and the spinal cord, and is modulated by a number of endogenous and exogenous compounds. (Rabben, Skljelbred, Oye, 1060-1066) NMDA receptors play a key role in a wide range of physiologic and pathologic processes. (Hoffman, Coppejans, Vercauteren, Adriemsen, 240-242) (Klepstadt, Maurset, Moberg, Oye, 513-518) (Coderre, Katz, Vaccarino, Melzack, 259-285) Ketamine is primarily a non-competitive antagonist, which opens in response to binding of glutamate. This NMDA receptor mediates the reduction of pain effects of ketamine at low doses. (Lofwall, Griffiths, Mintzer, 439-449)
Evidence for this is reinforced by the fact that naxolone, an opioid antagonist, does not reverse the analgesia. Studies also seem to indicate that ketamine is ‘use dependent’ meaning it only initiates its blocking action once a glutamate binds to the NMDA receptor. (Sorensen, Bengtsson, Ahlner, Henriksson, Ekselius et al., 1615-1621) At high level doses, ketamine has also been found to bind to opioid mu receptors and sigma receptors. Thus, loss of consciousness that occurs may be partially due to binding at the opioid mu and sigma receptors. (Lonnqvist, Norton, 617-621)
(Menigaux, Fletcher, Dupont, Guignard, Guirimand, et al. 129-135) (Koppert, Sittl, Scheuber, Alsheimer, Schmelz, 152-159) (Bushell, Endoh, Simen, Ren, Bindokas, 55-64)
Mayer DJ, Mao J, Holt J, Price DD. Cellular Mechanisms of Neuropathic Pain, Morphin Tolerance, and their Interactions. Proc. Natl Acac. Sci. USA. 1999, 96(14): 7731-7736.
Collingridge G, Singer W. Excitatory Amino Acid Receptors and Synaptic Plasticity. Trends Pharmacol Sci. 1990 11: 290-296.
Dickenson AH. A cure for wind-up: NMDA receptor antagonists as potential analgesics. Trends Pharmacol Sci 1990 11: 307-309
Dickenson AH, Chapman V and Green GM. The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord. Gen Pharmacol 1997 28: 633-638
Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th ed. McGraw-Hill: New York, (2000), pp.178-180
Connolly CN, Wafford KA. The Cys-Loop Superfamily of Ligand-Gated Ion Channels – the Impact of Receptor Structure on Function. Biochemical Society Transactions (2004) Vol. 32: 529-534.
Dingledine R, Borges K, Bowie D, Taynelis SF. The Glutamate Receptors Ion Channels. Pharmacology Reviews, 1999 51(1): 7-61
Lodge D and Johnson KM. Non-Competitive Excitatory Amino Acid Antagonists. Trends Pharmacol Sci 1990 11: 81-86
Meller ST. Ketamine: Relief from Chronic Pain through Actions at the NMDA Receptor? Pain 1996 68: 435-436
Hirota K, Lambert DG. Ketamine: Its Mechanism (s) of Action and its Unusual Clinical Uses. Br. J. Anesth. 1996, 77(4):441-444.
Rabben T, Skjelbred P, Oye I. Prolonged Analgesic Effects of Ketamine, an N-Methyl-D-Aspartate Receptor Inhibitor, in Patients with Chronic Pain. The Journal of Pharmacology and Experimental Pharmaceutics. 1999, 289(2):1060-1066.
Hoffmann V, Coppejans H, Vercauteren M and Adriaemsen H Successful Treatment of Postherpetic Neuralgia with Oral Ketamine. 1994 Clin J Pain 10: 240-242
Klepstad P, Maurset A, Moberg ER and Oye I Evidence for a Role for NMDA Receptors in Pain Perception. Eur J Pharmacol 1990 187: 513-518
Coderre TJ, Katz J, Vaccarino AL and Melzack R. Contribution of Central Neuroplasticity to Pathological Pain: A Review of Clinical and Experimental Evidence. 1993 Pain 52: 259-285.
Lofwall MR, Griffiths RR, Mintzer MZ. Cognitive and Subjective Acute Dose Effects of Intramuscular Ketamine in Healthy Adults. Ex. Clin. Psychopharmacol. (2006), 14(4):439-449
Sorensen J, Bengtsson A, Ahlner J, Henriksson KG, Ekselius L and Bengtsson M. Fibromyalgia. Are there different mechanisms in the processing of pain? A double Blind Crossover Comparison of analgesic Drugs. 1997 J Rheumatol 24: 1615-1621
Lonnqvist PA, Norton NS. Pediatric Day-Case Anesthesia and Pain Control. Curr. Opin. Anaest. (2006), 19(6): 617-621.
Menigaux C, Fletcher D, Dupont X, Guignard B, Guirimand F, Chauvin M. The Benefits of Intraoperative Small-Dose Ketamine on Postoperative Pain after Anterior Cruciate Ligament Repair. Anesth. Analg. 2000 90(1): 129-135
Koppert W, Sittl R, Scheuber K,Alsheimer M, Schmeltz M, Schuttler J. Differential Modulation of Remifentanil-Induced Analgesia and Post-Infusion Hyperalgesia by S-Ketamine and Clonidine in Humans. Anesthesiology. 2003, 99(1): 152-159.
Bushell T, Endoh T, Simen AA, Ren D, Bindokas VP, Miller RJ. Molecular Components of Tolerance to Opiates In Single Hippocampal Neurons. Mol. Pharmacol. 2002, 61(1): 55-64.