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. 2014 Nov 5;30(6):887–902. doi: 10.1007/s12264-014-1477-5

Post-stroke pain hypersensitivity induced by experimental thalamic hemorrhage in rats is region-specific and demonstrates limited efficacy of gabapentin

Fei Yang 1, Han Fu 1,2, Yun-Fei Lu 1, Xiao-Liang Wang 1,2, Yan Yang 3, Fan Yang 3, Yao-Qing Yu 1,2, Wei Sun 1,2, Jia-Shuang Wang 4, Michael Costigan 5,6, Jun Chen 1,2,3,✉
PMCID: PMC4357321  NIHMSID: NIHMS666823  PMID: 25370442

Abstract

Intractable central post-stroke pain (CPSP) is one of the most common sequelae of stroke, but has been inadequately studied to date. In this study, we first determined the relationship between the lesion site and changes in mechanical or thermal pain sensitivity in a rat CPSP model with experimental thalamic hemorrhage produced by unilateral intra-thalamic collagenase IV (ITC) injection. Then, we evaluated the efficacy of gabapentin (GBP), an anticonvulsant that binds the voltage-gated Ca2+ channel α2δ and a commonly used anti-neuropathic pain medication. Histological case-by-case analysis showed that only lesions confined to the medial lemniscus and the ventroposterior lateral/medial nuclei of the thalamus and/or the posterior thalamic nucleus resulted in bilateral mechanical pain hypersensitivity. All of the animals displaying CPSP also had impaired motor coordination, while control rats with intra-thalamic saline developed no central pain or motor deficits. GBP had a dose-related anti-allodynic effect after a single administration (1, 10, or 100 mg/kg) on day 7 post-ITC, with significant effects lasting at least 5 h for the higher doses. However, repeated treatment, once a day for two weeks, resulted in complete loss of effectiveness (drug tolerance) at 10 mg/kg, while effectiveness remained at 100 mg/kg, although the time period of efficacious analgesia was reduced. In addition, GBP did not change the basal pain sensitivity and the motor impairment caused by the ITC lesion, suggesting selective action of GBP on the somatosensory system.

Keywords: central post-stroke pain, intracerebral hemorrhage, intra-thalamic collagenase injection, mechanical pain hypersensitivity, gabapentinoids, anti-allodynic effect

Footnotes

These authors contributed equally to this work.

References

  • [1].O’Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, et al. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet. 2010;376:112–123. doi: 10.1016/S0140-6736(10)60834-3. [DOI] [PubMed] [Google Scholar]
  • [2].Jia Q, Liu LP, Wang YJ. Stroke in China. Clin Exp Pharmacol Physiol. 2010;37:259–264. doi: 10.1111/j.1440-1681.2009.05290.x. [DOI] [PubMed] [Google Scholar]
  • [3].Liu M, Wu B, Wang WZ, Lee LM, Zhang SH, Kong LZ. Stroke in China: epidemiology, prevention, and management strategies. Lancet Neurol. 2007;6:456–464. doi: 10.1016/S1474-4422(07)70004-2. [DOI] [PubMed] [Google Scholar]
  • [4].Tsai CF, Thomas B, Sudlow CL. Epidemiology of stroke and its subtypes in Chinese vs white populations: a systematic review. Neurology. 2013;81:264–272. doi: 10.1212/WNL.0b013e31829bfde3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Henry JL. Central poststroke pain: An animal model. In: Henry JL, Panju A, Yashpal K, editors. Central Neuropathic Pain: Focus on Poststroke Pain. Seattle: IASP Press; 2007. [Google Scholar]
  • [6].Henry JL, Lalloo C, Yashpal K. Central poststroke pain: an abstruse outcome. Pain Res Manag. 2008;13:41–49. doi: 10.1155/2008/754260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Jensen TS, Finnerup NB. Central pain. In: McMahon SB, Koltzenburg M, Tracey I, Turk DC, editors. Wall and Melzack’s Textbook of Pain. 6th edition. Philadelphia: Elsevier Saunders (Printed in China); 2013. [Google Scholar]
  • [8].Jensen TS, Lenz FA. Central post-stroke pain: a challenge for the scientist and the clinician. Pain. 1995;61:161–164. doi: 10.1016/0304-3959(94)00227-6. [DOI] [PubMed] [Google Scholar]
  • [9].Kim JS. Post-stroke pain. Expert Rev Neurother. 2009;9:711–721. doi: 10.1586/ern.09.19. [DOI] [PubMed] [Google Scholar]
  • [10].Klit H, Finnerup NB, Jensen TS. Central post-stroke pain: clinical characteristics, pathophysiology, and management. Lancet Neurol. 2009;8:857–868. doi: 10.1016/S1474-4422(09)70176-0. [DOI] [PubMed] [Google Scholar]
  • [11].Kumar B, Kalita J, Kumar G, Misra UK. Central poststroke pain: a review of pathophysiology and treatment. Anesth Analg. 2009;108:1645–1657. doi: 10.1213/ane.0b013e31819d644c. [DOI] [PubMed] [Google Scholar]
  • [12].Kumar G, Soni CR. Central post-stroke pain: current evidence. J Neurol Sci. 2009;284:10–17. doi: 10.1016/j.jns.2009.04.030. [DOI] [PubMed] [Google Scholar]
  • [13].Andersen G, Vestergaard K, Ingeman-Nielsen M, Jensen TS. Incidence of central post-stroke pain. Pain. 1995;61:187–193. doi: 10.1016/0304-3959(94)00144-4. [DOI] [PubMed] [Google Scholar]
  • [14].Bowsher D. Stroke and central poststroke pain in an elderly population. J Pain. 2001;2:258–261. doi: 10.1054/jpai.2001.24549. [DOI] [PubMed] [Google Scholar]
  • [15].Jonsson AC, Lindgren I, Hallstrom B, Norrving B, Lindgren A. Prevalence and intensity of pain after stroke: a population based study focusing on patients’ perspectives. J Neurol Neurosurg Psychiatry. 2006;77:590–595. doi: 10.1136/jnnp.2005.079145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Kong KH, Woon VC, Yang SY. Prevalence of chronic pain and its impact on health-related quality of life in stroke survivors. Arch Phys Med Rehabil. 2004;85:35–40. doi: 10.1016/S0003-9993(03)00369-1. [DOI] [PubMed] [Google Scholar]
  • [17].Raffaeli W, Minella CE, Magnani F, Sarti D. Population-based study of central post-stroke pain in Rimini district, Italy. J Pain Res. 2013;6:705–711. doi: 10.2147/JPR.S46553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Bogousslavsky J, Regli F, Uske A. Thalamic infarcts: clinical syndromes, etiology, and prognosis. Neurology. 1988;38:837–848. doi: 10.1212/WNL.38.6.837. [DOI] [PubMed] [Google Scholar]
  • [19].Chung CS, Caplan LR, Han W, Pessin MS, Lee KH, Kim JM. Thalamic haemorrhage. Brain. 1996;119:1873–1886. doi: 10.1093/brain/119.6.1873. [DOI] [PubMed] [Google Scholar]
  • [20].Kumral E, Kocaer T, Ertubey NO, Kumral K. Thalamic hemorrhage: A prospective study of 100 patients. Stroke. 1995;26:964–970. doi: 10.1161/01.STR.26.6.964. [DOI] [PubMed] [Google Scholar]
  • [21].Nasreddine ZS, Saver JL. Pain after thalamic stroke: right diencephalic predominance and clinical features in 180 patients. Neurology. 1997;48:1196–1199. doi: 10.1212/WNL.48.5.1196. [DOI] [PubMed] [Google Scholar]
  • [22].Paciaroni M, Bogousslavsky J. Pure sensory syndromes in thalamic stroke. Eur Neurol. 1998;39:211–217. doi: 10.1159/000007936. [DOI] [PubMed] [Google Scholar]
  • [23].Wessel K, Vieregge P, Kessler C, Kompf D. Thalamic stroke: correlation of clinical symptoms, somatosensory evoked potentials, and CT findings. Acta Neurol Scand. 1994;90:167–173. doi: 10.1111/j.1600-0404.1994.tb02700.x. [DOI] [PubMed] [Google Scholar]
  • [24].Henry JL, Panju A, Yashpal K, editors. Central Neuropathic Pain: Focus on Poststroke Pain. Seattle: IASP Press; 2007. [Google Scholar]
  • [25].Dworkin RH, O’Connor AB, Audette J, Baron R, Gourlay GK, Haanpaa ML, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010;85:S3–S14. doi: 10.4065/mcp.2009.0649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132:237–251. doi: 10.1016/j.pain.2007.08.033. [DOI] [PubMed] [Google Scholar]
  • [27].Haanpaa M, Attal N, Backonja M, Baron R, Bennett M, Bouhassira D, et al. NeuPSIG guidelines on neuropathic pain assessment. Pain. 2011;152:14–27. doi: 10.1016/j.pain.2010.07.031. [DOI] [PubMed] [Google Scholar]
  • [28].O’Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med. 2009;122:S22–S32. doi: 10.1016/j.amjmed.2009.04.007. [DOI] [PubMed] [Google Scholar]
  • [29].Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010;150:573–581. doi: 10.1016/j.pain.2010.06.019. [DOI] [PubMed] [Google Scholar]
  • [30].Finnerup NB, Gottrup H, Jensen TS. Anticonvulsants in central pain. Expert Opin Pharmacother. 2002;3:1411–1420. doi: 10.1517/14656566.3.10.1411. [DOI] [PubMed] [Google Scholar]
  • [31].Kim JS, Bashford G, Murphy TK, Martin A, Dror V, Cheung R. Safety and efficacy of pregabalin in patients with central poststroke pain. Pain. 2011;152:1018–1023. doi: 10.1016/j.pain.2010.12.023. [DOI] [PubMed] [Google Scholar]
  • [32].Castel A, Helie P, Beaudry F, Vachon P. Bilateral central pain sensitization in rats following a unilateral thalamic lesion may be treated with high doses of ketamine. BMC Vet Res. 2013;9:59. doi: 10.1186/1746-6148-9-59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Hanada T, Kurihara T, Tokudome M, Tokimura H, Arita K, Miyata A. Development and pharmacological verification of a new mouse model of central post-stroke pain. Neurosci Res. 2014;78:72–80. doi: 10.1016/j.neures.2013.09.005. [DOI] [PubMed] [Google Scholar]
  • [34].Wasserman JK, Koeberle PD. Development and characterization of a hemorrhagic rat model of central poststroke pain. Neuroscience. 2009;161:173–183. doi: 10.1016/j.neuroscience.2009.03.042. [DOI] [PubMed] [Google Scholar]
  • [35].Castel A, Vachon P. Gabapentin reverses central pain sensitization following a collagenase-induced intrathalamic hemorrhage in rats. J Pain Res. 2013;17:5–12. doi: 10.2147/JPR.S55201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [36].Amr YM. Multi-day low dose ketamine infusion as adjuvant to oral gabapentin in spinal cord injury related chronic pain: a prospective, randomized, double blind trial. Pain Physician. 2010;13:245–249. [PubMed] [Google Scholar]
  • [37].To TP, Lim TC, Hill ST, Frauman AG, Cooper N, Kirsa SW, Brown DJ. Gabapentin for neuropathic pain following spinal cord injury. Spinal Cord. 2002;40:282–285. doi: 10.1038/sj.sc.3101300. [DOI] [PubMed] [Google Scholar]
  • [38].Vranken JH, Dijkgraaf MG, Kruis MR, Van der Vegt MH, Hollmann MW, Heesen M. Pregabalin in patients with central neuropathic pain: a randomized, double-blind, placebocontrolled trial of a flexible-dose regimen. Pain. 2008;136:150–157. doi: 10.1016/j.pain.2007.06.033. [DOI] [PubMed] [Google Scholar]
  • [39].Finnerup NB. A review of central neuropathic pain states. Curr Opin Anaesthesiol. 2008;21:586–589. doi: 10.1097/ACO.0b013e32830a4c11. [DOI] [PubMed] [Google Scholar]
  • [40].Siniscalchi A, Gallelli L, De Sarro G, Malferrari G, Santangelo E. Antiepileptic drugs for central post-stroke pain management. Pharmacol Res. 2012;65:171–175. doi: 10.1016/j.phrs.2011.09.003. [DOI] [PubMed] [Google Scholar]
  • [41].Ren LY, Lu ZM, Liu MG, Yu YQ, Li Z, Shang GW, et al. Distinct roles of the anterior cingulate cortex in spinal and supraspinal bee venom-induced pain behaviors. Neuroscience. 2008;153:268–278. doi: 10.1016/j.neuroscience.2008.01.067. [DOI] [PubMed] [Google Scholar]
  • [42].Back SK, Won SY, Hong SK, Na HS. Gabapentin relieves mechanical, warm and cold allodynia in a rat model of peripheral neuropathy. Neurosci Lett. 2004;368:341–344. doi: 10.1016/j.neulet.2004.07.091. [DOI] [PubMed] [Google Scholar]
  • [43].Chen SR, Pan HL. Effect of systemic and intrathecal gabapentin on allodynia in a new rat model of postherpetic neuralgia. Brain Res. 2005;1042:108–113. doi: 10.1016/j.brainres.2005.02.024. [DOI] [PubMed] [Google Scholar]
  • [44].Coetzee JF, Mosher RA, Kohake LE, Cull CA, Kelly LL, Mueting SL, et al. Pharmacokinetics of oral gabapentin alone or co-administered with meloxicam in ruminant beef calves. Vet J. 2011;190:98–102. doi: 10.1016/j.tvjl.2010.08.008. [DOI] [PubMed] [Google Scholar]
  • [45].Pan HL, Eisenach JC, Chen SR. Gabapentin suppresses ectopic nerve discharges and reverses allodynia in neuropathic rats. J Pharmacol Exp Ther. 1999;288:1026–1030. [PubMed] [Google Scholar]
  • [46].Chen J, Luo C, Li H, Chen H. Primary hyperalgesia to mechanical and heat stimuli following subcutaneous bee venom injection into the plantar surface of hindpaw in the conscious rat: a comparative study with the formalin test. Pain. 1999;83:67–76. doi: 10.1016/S0304-3959(99)00075-5. [DOI] [PubMed] [Google Scholar]
  • [47].Cao FL, Shang GW, Wang Y, Yang F, Li CL, Chen J. Antinociceptive effects of intragastric DL-tetrahydropalmatine on visceral and somatic persistent nociception and pain hypersensitivity in rats. Pharmacol Biochem Behav. 2011;100:199–204. doi: 10.1016/j.pbb.2011.08.016. [DOI] [PubMed] [Google Scholar]
  • [48].Yu HY, Liu MG, Liu DN, Shang GW, Wang Y, Qi C, et al. Antinociceptive effects of systemic paeoniflorin on bee venom-induced various ‘phenotypes’ of nociception and hypersensitivity. Pharmacol Biochem Behav. 2007;88:131–140. doi: 10.1016/j.pbb.2007.07.013. [DOI] [PubMed] [Google Scholar]
  • [49].Jones EG. The Thalamus. New York: Plenum; 1985. [Google Scholar]
  • [50].Cruccu G, Sommer C, Anand P, Attal N, Baron R, Garcia-Larrea L, et al. EFNS guidelines on neuropathic pain assessment: revised 2009. Eur J Neurol. 2010;17:101–118. doi: 10.1111/j.1468-1331.2010.02969.x. [DOI] [PubMed] [Google Scholar]
  • [51].Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al. Neuropathic pain: Redefinition and a grading system for clinical and research purposes. Neurology. 2008;70:1630–1635. doi: 10.1212/01.wnl.0000282763.29778.59. [DOI] [PubMed] [Google Scholar]
  • [52].Kim JH, Greenspan JD, Coghill RC, Ohara S, Lenz FA. Lesions limited to the human thalamic principal somatosensory nucleus (ventral caudal) are associated with loss of cold sensations and central pain. The Journal of neuroscience. 2007;27:4995–5004. doi: 10.1523/JNEUROSCI.0716-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [53].Krause T, Brunecker P, Pittl S, Taskin B, Laubisch D, Winter B, et al. Thalamic sensory strokes with and without pain: differences in lesion patterns in the ventral posterior thalamus. J Neurol Neurosurg Psychiatry. 2012;83:776–784. doi: 10.1136/jnnp-2011-301936. [DOI] [PubMed] [Google Scholar]
  • [54].Montes C, Magnin M, Maarrawi J, Frot M, Convers P, Mauguiere F, et al. Thalamic thermo-algesic transmission: ventral posterior (VP) complex versus VMpo in the light of a thalamic infarct with central pain. Pain. 2005;113:223–232. doi: 10.1016/j.pain.2004.09.044. [DOI] [PubMed] [Google Scholar]
  • [55].Sprenger T, Seifert CL, Valet M, Andreou AP, Foerschler A, Zimmer C, et al. Assessing the risk of central post-stroke pain of thalamic origin by lesion mapping. Brain. 2012;135:2536–2545. doi: 10.1093/brain/aws153. [DOI] [PubMed] [Google Scholar]
  • [56].LaBuda CJ, Cutler TD, Dougherty PM, Fuchs PN. Mechanical and thermal hypersensitivity develops following kainate lesion of the ventral posterior lateral thalamus in rats. Neuroscience letters. 2000;290:79–83. doi: 10.1016/S0304-3940(00)01323-9. [DOI] [PubMed] [Google Scholar]
  • [57].Saade NE, Kafrouni AI, Saab CY, Atweh SF, Jabbur SJ. Chronic thalamotomy increases pain-related behavior in rats. Pain. 1999;83:401–409. doi: 10.1016/S0304-3959(99)00123-2. [DOI] [PubMed] [Google Scholar]
  • [58].Takami K, Fujita Hamabe W, Harada S, Tokuyama S. Aβ and Aδ but not C fibres are involved in stroke related pain and allodynia: an experimental study in mice. J Pharm Pharmacol. 2011;63:452–456. doi: 10.1111/j.2042-7158.2010.01231.x. [DOI] [PubMed] [Google Scholar]
  • [59].Tamiya S, Yoshida Y, Harada S, Nakamoto K, Tokuyama S. Establishment of a central post stroke pain model using global cerebral ischaemic mice. J Pharm Pharmacol. 2013;65:615–620. doi: 10.1111/jphp.12007. [DOI] [PubMed] [Google Scholar]
  • [60].Sun H, Ren K, Zhong CM, Ossipov MH, Malan TP, Lai J, et al. Nerve injury-induced tactile allodynia is mediated via ascending spinal dorsal column projections. Pain. 2001;90:105–111. doi: 10.1016/S0304-3959(00)00392-4. [DOI] [PubMed] [Google Scholar]
  • [61].Casey KL, Geisser M, Lorenz J, Morrow TJ, Paulson P, Minoshima S. Psychophysical and cerebral responses to heat stimulation in patients with central pain, painless central sensory loss, and in healthy persons. Pain. 2012;153:331–341. doi: 10.1016/j.pain.2011.10.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [62].Blomqvist A, Zhang ET, Craig AD. Cytoarchitectonic and immunohistochemical characterization of a specific pain and temperature relay, the posterior portion of the ventral medial nucleus, in the human thalamus. Brain. 2000;123:601–619. doi: 10.1093/brain/123.3.601. [DOI] [PubMed] [Google Scholar]
  • [63].Craig AD, Bushnell MC, Zhang ET, Blomqvist A. A thalamic nucleus specific for pain and temperature sensation. Nature. 1994;372:770–773. doi: 10.1038/372770a0. [DOI] [PubMed] [Google Scholar]
  • [64].Davies A, Hendrich J, Van Minh AT, Wratten J, Douglas L, Dolphin AC. Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels. Trends in pharmacological sciences. 2007;28:220–228. doi: 10.1016/j.tips.2007.03.005. [DOI] [PubMed] [Google Scholar]
  • [65].Klugbauer N, Marais E, Hofmann F. Calcium channel alpha2delta subunits: differential expression, function, and drug binding. J Bioenerg Biomembr. 2003;35:639–647. doi: 10.1023/B:JOBB.0000008028.41056.58. [DOI] [PubMed] [Google Scholar]
  • [66].Maneuf YP, Gonzalez MI, Sutton KS, Chung FZ, Pinnock RD, Lee K. Cellular and molecular action of the putative GABAmimetic, gabapentin. Cell Mol Life Sci. 2003;60:742–750. doi: 10.1007/s00018-003-2108-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [67].Bauer CS, Nieto-Rostro M, Rahman W, Tran-Van-Minh A, Ferron L, Douglas L, et al. The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. J Neurosci. 2009;29:4076–4088. doi: 10.1523/JNEUROSCI.0356-09.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [68].Bauer CS, Rahman W, Tran-van-Minh A, Lujan R, Dickenson AH, Dolphin AC. The anti-allodynic alpha(2)delta ligand pregabalin inhibits the trafficking of the calcium channel alpha(2)delta-1 subunit to presynaptic terminals in vivo. Biochem Soc Trans. 2010;38:525–528. doi: 10.1042/BST0380525. [DOI] [PubMed] [Google Scholar]
  • [69].Dooley DJ, Taylor CP, Donevan S, Feltner D. Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission. Trends Pharmacol Sci. 2007;28:75–82. doi: 10.1016/j.tips.2006.12.006. [DOI] [PubMed] [Google Scholar]
  • [70].Hendrich J, Van Minh AT, Heblich F, Nieto-Rostro M, Watschinger K, Striessnig J, et al. Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin. Proc Natl Acad Sci U S A. 2008;105:3628–3633. doi: 10.1073/pnas.0708930105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [71].Li CY, Song YH, Higuera ES, Luo ZD. Spinal dorsal horn calcium channel alpha2delta-1 subunit upregulation contributes to peripheral nerve injury-induced tactile allodynia. J Neurosci. 2004;24:8494–8499. doi: 10.1523/JNEUROSCI.2982-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [72].Li CY, Zhang XL, Matthews EA, Li KW, Kurwa A, Boroujerdi A, et al. Calcium channel alpha2delta1 subunit mediates spinal hyperexcitability in pain modulation. Pain. 2006;125:20–34. doi: 10.1016/j.pain.2006.04.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [73].Luo ZD, Calcutt NA, Higuera ES, Valder CR, Song YH, Svensson CI, et al. Injury type-specific calcium channel alpha 2 delta-1 subunit up-regulation in rat neuropathic pain models correlates with antiallodynic effects of gabapentin. J Pharmacol Exp Ther. 2002;303:1199–1205. doi: 10.1124/jpet.102.041574. [DOI] [PubMed] [Google Scholar]
  • [74].Luo ZD, Chaplan SR, Higuera ES, Sorkin LS, Stauderman KA, Williams ME, et al. Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci. 2001;21:1868–1875. doi: 10.1523/JNEUROSCI.21-06-01868.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [75].Taylor CP. Mechanisms of analgesia by gabapentin and pregabalin—calcium channel alpha2-delta [Cavalpha2-delta] ligands. Pain. 2009;142:13–16. doi: 10.1016/j.pain.2008.11.019. [DOI] [PubMed] [Google Scholar]
  • [76].Erichsen HK, Blackburn-Munro G. Pharmacological characterisation of the spared nerve injury model of neuropathic pain. Pain. 2002;98:151–161. doi: 10.1016/S0304-3959(02)00039-8. [DOI] [PubMed] [Google Scholar]
  • [77].Gustafsson H, Flood K, Berge OG, Brodin E, Olgart L, Stiller CO. Gabapentin reverses mechanical allodynia induced by sciatic nerve ischemia and formalin-induced nociception in mice. Exp Neurol. 2003;182:427–434. doi: 10.1016/S0014-4886(03)00097-9. [DOI] [PubMed] [Google Scholar]
  • [78].Kukanich B, Cohen RL. Pharmacokinetics of oral gabapentin in greyhound dogs. Vet J. 2011;187:133–135. doi: 10.1016/j.tvjl.2009.09.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [79].Meregalli C, Ceresa C, Canta A, Carozzi VA, Chiorazzi A, Sala B, et al. CR4056, a new analgesic I2 ligand, is highly effective against bortezomib-induced painful neuropathy in rats. J Pain Res. 2012;5:151–167. doi: 10.2147/JPR.S32122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [80].Kusunose N, Koyanagi S, Hamamura K, Matsunaga N, Yoshida M, Uchida T, et al. Molecular basis for the dosing time-dependency of anti-allodynic effects of gabapentin in a mouse model of neuropathic pain. Mol Pain. 2010;6:83. doi: 10.1186/1744-8069-6-83. [DOI] [PMC free article] [PubMed] [Google Scholar]

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