Abstract
Central sensitization is one form of long-term plasticity in the central nervous system.
Sustained activation of primary sensory fibers supplying dorsal horn can induce long-lasting
increases in the discharge amplitude of primary afferent synapses. This is similar
to the long-term potentiation that occurs in many other CNS regions. Drugs that limit
the short-duration wind-up component of central sensitization include sodium channel
blockers, NMDA antagonists, fast-acting opioids and the calcium-channel ligands gabapentin
and pregabalin (S-3-(aminomethyl)-5-methylhexanoic acid). Pregabalin, like gabapentin,
binds selectively to the CaVα2δ auxiliary subunit of presynaptic voltage-gated calcium channels. The conformational
changes induced by this binding inhibit abnormally intense neuronal activity by reducing
the synaptic release of glutamate and other neurotransmitters. Recent identification
in animal models of increased CaVα2δ protein expression in chronic pain, allodynia, and hyperalgesia have drawn additional
interest to drugs that bind the CaVα2δ site. Experimental studies with animal models and healthy human volunteers have
shown that pregabalin reduces nociceptive responses, particularly in conditions involving
central sensitization. Since these actions occur with relatively modest effects on
physiological and cognitive functions, pregabalin may be an important consideration
in the pharmacotherapy of otherwise difficult-to-treat pain syndromes.
Perspective
This focus article discusses how the central nervous system plasticity phenomenon,
central sensitization, is established in the induction and maintenance of chronic
pain, allodynia, and hyperalgesia. In addition, it explores the neurophysiologic actions
of the calcium-channel ligands gabapentin and pregabalin in limiting pathological
manifestations of central sensitization.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The Journal of PainAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The anti-allodynic effects of amitriptyline, gabapentin, and lidocaine in a rat model of neuropathic pain.Anesth Analg. 1998; 87: 1360-1366
- Effects of gabapentin on experimental somatic pain and temporal summation.Reg Anesth Pain Med. 2007; 32: 382-388
- A 14-week, randomized, double-blinded, placebo-controlled monotherapy trial of pregabalin in patients with fibromyalgia.J Pain. 2008; 9: 792-805
- Gabapentin relieves mechanical, warm and cold allodynia in a rat model of peripheral neuropathy.Neurosci Lett. 2004; 368: 341-344
- CHF3381, a novel antinociceptive agent, attenuates capsaicin-induced pain in rats.Eur J Pharmacol. 2005; 519: 231-236
- Pregabalin-mediated anti-allodynia in neuropathic pain correlates with impaired alpha-2-delta 1 trafficking to presynaptic terminals.Scotland, Presented at 12th World Congress on Pain, GlasgowAugust 12-17, 2008
- The increased trafficking of the calcium channel subunit α2δ-1 to presynaptic terminals in neuropathic pain is inhibited by the α2δ ligand pregabalin.J Neurosci. 2009; 29: 4076-4088
- Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain.Pain. 2008; 139: 358-366
- Surgically induced osteoarthritis in the rat results in the development of both osteoarthritis-like joint pain and secondary hyperalgesia.Osteoarthritis Cartilage. 2006; 14: 1041-1048
- The insula: a multidimensional integration site for pain.Pain. 2007; 128: 1-2
- Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain.J Neurosci. 2002; 22: 5129-5136
Buvanedran A, Reuben SS, Kroin JS: Perioperative pregabalin reduces neuropathic pain at 6 months after total knee arthroplasty [presentation A595]. Presented at 2008 Annual Meeting of the American Society of Anesthesiologists, Orlando, FL, October 18-22, 2008
- Effect of systemic and intrathecal gabapentin on allodynia in a new rat model of postherpetic neuralgia.Brain Res. 2005; 1042: 108-113
- Stereospecific effect of pregabalin on ectopic afferent discharges and neuropathic pain induced by sciatic nerve ligation in rats.Anesthesiology. 2001; 95: 1473-1479
- Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical hyperalgesia model in human volunteers.Br J Anaesth. 2007; 98: 246-254
- Effect of gabapentin and lamotrigine on mechanical allodynia-like behaviour in a rat model of trigeminal neuropathic pain.Pain. 2001; 93: 147-153
- Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): A 6-month, double-blind, placebo-controlled trial with pregabalin.Pain. 2008; 136: 419-431
- Pregabalin 1008-105 Study Group. Pregabalin for the treatment of fibromyalgia syndrome: Results of a randomized, double-blind, placebo-controlled trial.Arthritis Rheum. 2005; 52: 1264-1273
- Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation.Neuropharmacology. 1987; 26: 1235-1238
- Pregabalin (CI-1008) inhibits the trinitrobenzene sulfonic acid-induced chronic colonic allodynia in the rat.J Pharmacol Exp Ther. 2002; 302: 1013-1022
- Gabapentin suppresses cutaneous hyperalgesia following heat-capsaicin sensitization.Anesthesiology. 2002; 97: 102-107
- Preferential action of gabapentin and pregabalin at P/Q-type voltage-sensitive calcium channels: Inhibition of K+-evoked [3H]-norepinephrine release from rat neocortical slices.Synapse. 2002; 45: 171-190
- Inhibition of K+-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin.Neurosci Lett. 2000; 280: 107-110
- Ca2+ channel α2δ ligands: Novel modulators of neurotransmission.Trends Pharmacol Sci. 2007; 28: 75-82
- Combined application of excitatory amino acids and substance P produces long-lasting changes in responses of primate spinothalamic tract neurons.Brain Res Brain Res Rev. 1993; 18: 227-246
- Pharmacological characterisation of the spared nerve injury model of neuropathic pain.Pain. 2002; 98: 151-161
- Incorporating synaptic time-dependent plasticity and dynamic synapse into a computational model of wind-up.Neural Netw. 2008; 21: 241-249
- Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C.Pain. 2003; 105: 133-141
- Identification of the α2-δ-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin.Proc Natl Acad Sci U S A. 2006; 103: 17537-17542
- Evaluation of gabapentin and S-(+)-3-isobutylgaba in a rat model of postoperative pain.J Pharmacol Exp Ther. 1997; 282: 1242-1246
- Gabapentin and pregabalin, but not morphine and amitriptyline, block both static and dynamic components of mechanical allodynia induced by streptozocin in the rat.Pain. 1999; 80: 391-398
- Gabapentin (neurontin) and S-(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents.Br J Pharmacol. 1997; 121: 1513-1522
- Inhibition of neuronal Ca2+ influx by gabapentin and pregabalin in the human neocortex.Neuropharmacology. 2002; 42: 229-236
- Inhibition of neuronal Ca2+ influx by gabapentin and subsequent reduction of neurotransmitter release from rat neocortical slices.Br J Pharmacol. 2000; 130: 900-906
- Comparative activity of the anti-convulsants oxcarbazepine, carbamazepine, lamotrigine and gabapentin in a model of neuropathic pain in the rat and guinea-pig.Pain. 2003; 105: 355-362
- Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens.Pain. 2005; 115: 254-263
- Transient allodynia pain models in mice for early assessment of analgesic activity.Br J Pharmacol. 2008; 153: 769-774
- Gabapentin reverses the allodynia produced by the administration of anti-GD2 ganglioside, an immunotherapeutic drug.Anesth Analg. 1998; 86: 111-116
- Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia.Anesthesiology. 2004; 101: 1400-1408
- Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia.Arthritis Rheum. 2002; 46: 1333-1343
- Antiallodynic effect of pregabalin in rat models of sympathetically maintained and sympathetic independent neuropathic pain.Yonsei Med J. 2007; 48: 41-47
- Repeated administration of systemic gabapentin alleviates allodynia-like behaviors in spinally injured rats.Neurosci Lett. 2000; 280: 211-214
- Gabapentin activates spinal noradrenergic activity in rats and humans and reduces hypersensitivity after surgery.Anesthesiology. 2007; 106: 557-562
- Long-term potentiation and depression of synaptic transmission in rat posterior cingulate cortex.Brain Res. 1995; 670: 181-196
- Pharmacological disruption of calcium channel trafficking by the α2δ ligand gabapentin.Proc Natl Acad Sci U S A. 2008; 105: 3628-3633
- Fibromyalgia–from syndrome to disease. Overview of pathogenetic mechanisms.J Rehabil Med. 2003; 41: 89-94
- The health status burden of people with fibromyalgia: A review of studies that assessed health status with the SF-36 or the SF-12.Int J Clin Pract. 2008; 62: 115-126
- The effect of novel anti-epileptic drugs in rat experimental models of acute and chronic pain.Eur J Pharmacol. 1997; 324: 153-160
- Gabapentin and pregabalin can interact synergistically with naproxen to produce antihyperalgesia.Anesthesiology. 2002; 97: 1263-1273
- Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans.Proc Natl Acad Sci U S A. 2005; 102: 18195-18200
- Central sensitization and LTP: Do pain and memory share similar mechanisms?.Trends Neurosci. 2003; 26: 696-705
- Efficacy of duloxetine, a potent and balanced serotonergic and noradrenergic reuptake inhibitor, in inflammatory and acute pain models in rodents.J Pharmacol Exp Ther. 2005; 312: 726-732
- Systemic gabapentin and S(+)-3-isobutyl-γ-aminobutyric acid block secondary hyperalgesia.Brain Res. 1998; 810: 93-99
- Suppression by gabapentin of pain-related mechano-responses in mice given orthotopic tumor inoculation.Biol Pharm Bull. 2003; 26: 550-552
- Comparison of antiepileptic drugs tiagabine, lamotrigine, and gabapentin in mouse models of acute, prolonged, and chronic nociception.J Pharmacol Exp Ther. 2002; 302: 1168-1175
- Calcium channel α2δ1 subunit mediates spinal hyperexcitability in pain modulation.Pain. 2006; 125: 20-34
- Behavioral and pharmacological description of oxaliplatin-induced painful neuropathy in rat.Pain. 2007; 128: 225-234
- Injury type-specific calcium channel α2δ-1 subunit up-regulation in rat neuropathic pain models correlates with antiallodynic effects of gabapentin.J Pharmacol Exp Ther. 2002; 303: 1199-1205
- Upregulation of dorsal root ganglion α2δ calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats.J Neurosci. 2001; 21: 1868-1875
- Pregabalin: A review of its use in fibromyalgia.Drugs. 2008; 68: 2205-2223
- Gabapentin inhibits the substance P-facilitated K+-evoked release of [3H]glutamate from rat caudial trigeminal nucleus slices.Pain. 2001; 93: 191-196
- A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia.J Rheumatol. 2008; 35: 502-514
- [3H] pregabalin binding is increased in ipsilateral dorsal horn following chronic constriction injury.Neurosci Lett. 2007; 417: 187-192
- Alternative splicing of the Ca2+ channel ß4 subunit confers specificity for gabapentin inhibition of Cav2.1 trafficking.Mol Pharmacol. 2008; 74: 904-912
- Pregabalin reduces the release of synaptic vesicles from cultured hippocampal neurons.Mol Pharmacol. 2006; 70: 467-476
- Rats with chronic post-ischemia pain exhibit an analgesic sensitivity profile similar to human patients with complex regional pain syndrome–type I.Eur J Pharmacol. 2008; 583: 97-102
- Vincristine-induced allodynia in the rat.Pain. 2001; 93: 69-76
- Characterization of the effects of gabapentin and 3-isobutyl-gamma-aminobutyric acid on substance P-induced thermal hyperalgesia.Anesthesiology. 1998; 88: 196-205
- Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain.Exp Neurol. 2005; 193: 85-100
- Chronic pain and medullary descending facilitation.Trends Neurosci. 2002; 25: 319-325
- Psychological and neural mechanisms of the affective dimension of pain.Science. 2000; 288: 1769-1772
- An isobolographic analysis of the effects of N-methyl-D-aspartate and NK1 tachykinin receptor antagonists on inflammatory hyperalgesia in the rat.Br J Pharmacol. 1996; 117: 196-202
- Pharmacological characterisation of the rat brachial plexus avulsion model of neuropathic pain.Brain Res. 2004; 1018: 159-170
- Pregabalin for the treatment of painful diabetic peripheral neuropathy: A double-blind, placebo-controlled trial.Pain. 2004; 110: 628-638
- Pharmacological differences between static and dynamic allodynia in mice with herpetic or postherpetic pain.J Pharmacol Sci. 2008; 108: 266-273
- Multiple dose gabapentin attenuates cutaneous pain and central sensitisation but not muscle pain in healthy volunteers.Pain. 2006; 125: 158-164
- Pregabalin in central neuropathic pain associated with spinal cord injury: A placebo-controlled trial.Neurology. 2006; 67: 1792-1800
- Pregabalin for postherpetic neuralgia: Placebo-controlled trial of fixed and flexible dosing regimens on allodynia and time to onset of pain relief.J Pain. 2008; 9: 1006-1017
- Gabapentin, ineffective in normal rats, markedly reduces C-fibre evoked responses after inflammation.Neuroreport. 1997; 8: 587-590
- Cutaneous C-fiber pain abnormalities of fibromyalgia patients are specifically related to temporal summation.Pain. 2008; 139: 315-323
- Temporal summation of second pain and its maintenance are useful for characterizing widespread central sensitization of fibromyalgia patients.J Pain. 2007; 8: 893-901
- Mechanisms of disease: Pain in fibromyalgia syndrome.Nat Clin Pract Rheumatol. 2006; 2: 90-98
- Gabapentin inhibits calcium currents in isolated rat brain neurons.Neuropharmacology. 1998; 37: 83-91
- Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin.Pain. 2005; 117: 292-303
- Neurochemical evidence that supraspinally administered gabapentin activates the descending noradrenergic system after peripheral nerve injury.Eur J Pharmacol. 2007; 556: 69-74
- Pregabalin, S-(+)-3-isobutylgaba, activates the descending noradrenergic system to alleviate neuropathic pain in the mouse partial sciatic nerve ligation model.Neuropharmacology. 2007; 53: 842-853
- Activation of the neurokinin-1 receptor by substance P triggers the release of substance P from cultured adult rat dorsal root ganglion neurons.Mol Pain. 2007; 3: 42
- Pharmacologic investigation of the mechanism underlying cold allodynia using a new cold plate procedure in rats with chronic constriction injuries.Behav Pharmacol. 2008; 19: 85-90
- Pharmacology and mechanism of action of pregabalin: The calcium channel α2δ (alpha2-delta) subunit as a target for antiepileptic drug discovery.Epilepsy Res. 2007; 73: 137-150
- Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: A randomized, double-blind study.Eur J Pain. 2008; 12: 203-213
Tuchman M, Durso-DeCruz E, Murphy TK, Barrett JA: Central sensitization, chronic pain syndromes, and pregabalin [poster 293]. Presented at American Pain Society 27th Annual Scientific Meeting, Tampa, FL, May 8-10, 2008. Available at: http://www.ampainsoc.org/db2/abstract/view?poster_id=3877#293. Accessed December 9, 2008
- Gabapentin inhibits presynaptic Ca2+ influx and synaptic transmission in rat hippocampus and neocortex.Eur J Pharmacol. 2002; 449: 221-228
- Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: A 13-week, randomized trial.Curr Med Res Opin. 2006; 22: 375-384
- Effects of gabapentin in acute inflammatory pain in humans.Reg Anesth Pain Med. 2001; 26: 322-328
Wesche D, Bockbrader H: A pharmacokinetic comparison of pregabalin and gabapentin [poster 684]. Presented at American Pain Society 24th Annual Scientific Meeting, San Diego, CA, March 30-April 2, 2005. Available at: http://www.ampainsoc.org/db2/abstract/view?poster_id=2371#684. Accessed December 9, 2008
- Pharmacological characterisation of a rat model of incisional pain.Br J Pharmacol. 2004; 141: 85-91
- Long-term potentiation in spinothalamic neurons.Brain Res Brain Res Rev. 2002; 40: 202-214
- Evidence for a central component of post-injury pain hypersensitivity.Nature. 1983; 306: 686-688
- Neuronal plasticity: Increasing the gain in pain.Science. 2000; 288: 1765-1769
- Chemotherapy-evoked painful peripheral neuropathy: Analgesic effects of gabapentin and effects on expression of the alpha-2-delta type-1 calcium channel subunit.Neuroscience. 2007; 144: 714-720
- Noxious thermal and chemical stimulation induce increases in 3H-phorbol 12,13-dibutyrate binding in spinal cord dorsal horn as well as persistent pain and hyperalgesia, which is reduced by inhibition of protein kinase C.J Neurosci. 1995; 15: 3263-3272
- Fibromyalgia and overlapping disorders: The unifying concept of central sensitivity syndromes.Semin Arthritis Rheum. 2007; 36: 339-356
- A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging.Pain. 2005; 114: 397-407
Article info
Publication history
Published online: May 17, 2010
Footnotes
Several of the studies discussed in this paper were funded by Pfizer Inc. Editorial support for the development of this manuscript was provided by UBC Scientific Solutions and funded by Pfizer Inc.
Identification
Copyright
© 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.
