Abstract
In recent decade microglia have been found to have a central role in the development of chronic neuropathic pain after injury to the peripheral nervous system. It is widely accepted that peripheral nerve injury triggers microglial activation in the spinal cord, which contributes to heightened pain sensation and eventually chronic pain states. The contribution of microglia to chronic pain arising after injury to the central nervous system, such as spinal cord injury (SCI), has been less studied, but there is evidence supporting microglial contribution to central neuropathic pain. In this systematic review, we focused on post-SCI microglial activation and how it is linked to emergence and maintenance of chronic neuropathic pain arising after SCI. We found that the number of studies using animal SCI models addressing microglial activity is still small, compared with the ones using peripheral nerve injury models. We have collected 20 studies for full inclusion in this review. Many mechanisms and cellular interactions are yet to be fully understood, although several studies report an increase of density and activity of microglia in the spinal cord, both in the vicinity of the injury and in the spared spinal tissue, as well as in the brain. Changes in microglial activity come with several molecular changes, including expression of receptors and activation of signalling pathways. As with peripheral neuropathic pain, microglia seem to be important players and might become a therapeutic target in the future.
-
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
-
Research funding: None declared.
-
Conflict of interest statement: The authors declare they have no conflicts of interests.
References
Aceves, M., Terminel, M.N., Okoreeh, A., Aceves, A.R., Gong, Y.M., Polanco, A., Sohrabji, F., and Hook, M.A. (2019). Morphine increases macrophages at the lesion site following spinal cord injury: protective effects of minocycline. Brain Behav. Immun. 79: 125–138, https://doi.org/10.1016/j.bbi.2019.01.023.Search in Google Scholar PubMed
Alizadeh, A., Dyck, S.M., and Karimi-Abdolrezaee, S. (2019). Traumatic spinal cord injury: an overview of pathophysiology, models and acute injury mechanisms. Front. Neurol. 10: 282, https://doi.org/10.3389/fneur.2019.00282.Search in Google Scholar PubMed PubMed Central
Barbin, G., Aigrot, M.S., Charles, P., Foucher, A., Grumet, M., Schachner, M., Zalc, B., and Lubetzki, C. (2004). Axonal cell-adhesion molecule L1 in CNS myelination. Neuron Glia Biol. 1: 65–72, https://doi.org/10.1017/s1740925x04000092.Search in Google Scholar PubMed
Batti, L., Sundukova, M., Murana, E., Pimpinella, S., De Castro Reis, F., Pagani, F., Wang, H., Pellegrino, E., Perlas, E., Di Angelantonio, S., et al.. (2016). TMEM16F regulates spinal microglial function in neuropathic pain states. Cell Rep. 15: 2608–2615, https://doi.org/10.1016/j.celrep.2016.05.039.Search in Google Scholar PubMed PubMed Central
Braaf, S., Lennox, A., Nunn, A., and Gabbe, B. (2017). Social activity and relationship changes experienced by people with bowel and bladder dysfunction following spinal cord injury. Spinal Cord 55: 679–686, https://doi.org/10.1038/sc.2017.19.Search in Google Scholar PubMed
Bradley, A., Ramírez-Solis, R., Zheng, H., Hasty, P., and Davis, A. (1992). Genetic manipulation of the mouse via gene targeting in embryonic stem cells. Ciba Found. Symp. 165: 256–269, discussion 269-276, https://doi.org/10.1002/9780470514221.ch15.Search in Google Scholar PubMed
Brown, E.V., Falnikar, A., Heinsinger, N., Cheng, L., Andrews, C.E., DeMarco, M., and Lepore, A.C. (2021). Cervical spinal cord injury-induced neuropathic pain in male mice is associated with a persistent pro-inflammatory macrophage/microglial response in the superficial dorsal horn. Exp. Neurol. 343, https://doi.org/10.1016/j.expneurol.2021.113757.Search in Google Scholar PubMed PubMed Central
Cheriyan, T., Ryan, D.J., Weinreb, J.H., Cheriyan, J., Paul, J.C., Lafage, V., Kirsch, T., and Errico, T.J. (2014). Spinal cord injury models: a review. Spinal Cord 52: 588–595, https://doi.org/10.1038/sc.2014.91.Search in Google Scholar PubMed
Chincholkar, M. (2018). Analgesic mechanisms of gabapentinoids and effects in experimental pain models: a narrative review. Br. J. Anaesth. 120: 1315–1334, https://doi.org/10.1016/j.bja.2018.02.066.Search in Google Scholar PubMed
Choi, D.C., Lee, J.Y., Lim, E.J., Baik, H.H., Oh, T.H., and Yune, T.Y. (2012). Inhibition of ROS-induced p38MAPK and ERK activation in microglia by acupuncture relieves neuropathic pain after spinal cord injury in rats. Exp. Neurol. 236: 268–282, https://doi.org/10.1016/j.expneurol.2012.05.014.Search in Google Scholar PubMed
Cregg, J.M., DePaul, M.A., Filous, A.R., Lang, B.T., Tran, A., and Silver, J. (2014). Functional regeneration beyond the glial scar. Exp. Neurol. 253: 197–207, https://doi.org/10.1016/j.expneurol.2013.12.024.Search in Google Scholar PubMed PubMed Central
Crone, S.A., Quinlan, K.A., Zagoraiou, L., Droho, S., Restrepo, C.E., Lundfald, L., Endo, T., Setlak, J., Jessell, T.M., Kiehn, O., et al.. (2008). Genetic ablation of V2a ipsilateral interneurons disrupts left-right locomotor coordination in mammalian spinal cord. Neuron 60: 70–83, https://doi.org/10.1016/j.neuron.2008.08.009.Search in Google Scholar PubMed
Crown, E.D., Gwak, Y.S., Ye, Z., Yu Tan, H., Johnson, K.M., Xu, G.Y., McAdoo, D.J., and Hulsebosch, C.E. (2012). Calcium/calmodulin dependent kinase II contributes to persistent central neuropathic pain following spinal cord injury. Pain 153: 710–721, https://doi.org/10.1016/j.pain.2011.12.013.Search in Google Scholar PubMed PubMed Central
David, B.T. and Steward, O. (2010). Deficits in bladder function following spinal cord injury vary depending on the level of the injury. Exp. Neurol. 226: 128–135, https://doi.org/10.1016/j.expneurol.2010.08.014.Search in Google Scholar PubMed PubMed Central
Dijkers, M., Bryce, T., and Zanca, J. (2009). Prevalence of chronic pain after traumatic spinal cord injury: a systematic review. J. Rehabil. Res. Dev. 46: 13–29, https://doi.org/10.1682/jrrd.2008.04.0053.Search in Google Scholar
Donnelly, C.R., Andriessen, A.S., Chen, G., Wang, K., Jiang, C., Maixner, W., and Ji, R.R. (2020). Central nervous system targets: glial cell mechanisms in chronic pain. Neurotherapeutics 17: 846–860, https://doi.org/10.1007/s13311-020-00905-7.Search in Google Scholar PubMed PubMed Central
Finnerup, N.B. (2013). Pain in patients with spinal cord injury. Pain 154: S71–S76, https://doi.org/10.1016/j.pain.2012.12.007.Search in Google Scholar PubMed
Finnerup, N.B., Attal, N., Haroutounian, S., McNicol, E., Baron, R., Dworkin, R.H., Gilron, I., Haanpää, M., Hansson, P., Jensen, T.S., et al.. (2015). Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 14: 162–173, https://doi.org/10.1016/j.jvs.2015.08.010.Search in Google Scholar
Garraway, S.M., Woller, S.A., Huie, J.R., Hartman, J.J., Hook, M.A., Miranda, R.C., Huang, Y.J., Ferguson, A.R., and Grau, J.W. (2014). Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: role of tumor necrosis factor alpha and apoptosis. Pain 155: 2344–2359, https://doi.org/10.1016/j.pain.2014.08.034.Search in Google Scholar PubMed PubMed Central
Garrido-Mesa, N., Zarzuelo, A., and Gálvez, J. (2013). Minocycline: far beyond an antibiotic. Br. J. Pharmacol. 169: 337–352, https://doi.org/10.1111/bph.12139.Search in Google Scholar PubMed PubMed Central
Griffin, M.R., O’Fallon, W.M., Opitz, J.L., and Kurland, L.T. (1985). Mortality, survival and prevalence: traumatic spinal cord injury in Olmsted County, Minnesota, 1935–1981. J. Chron. Dis. 38: 643–653, https://doi.org/10.1016/0021-9681(85)90018-9.Search in Google Scholar PubMed
Hargreaves, K., Dubner, R., Brown, F., Flores, C., and Joris, J. (1988). A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32: 77–88, https://doi.org/10.1016/0304-3959(88)90026-7.Search in Google Scholar PubMed
Higgins, J.P., Altman, D.G., Gotzsche, P.C., Juni, P., Moher, D., Oxman, A.D., Savovic, J., Schulz, K.F., Weeks, L., Sterne, J.A. (2011). The Cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343: d5928, https://doi.org/10.1136/bmj.d5928.Search in Google Scholar PubMed PubMed Central
Honjoh, K., Nakajima, H., Hirai, T., Watanabe, S., and Matsumine, A. (2019). Relationship of inflammatory cytokines from M1-type microglia/macrophages at the injured site and lumbar enlargement with neuropathic pain after spinal cord injury in the CCL21 knockout (plt) mouse. Front. Cell. Neurosci. 13, https://doi.org/10.3389/fncel.2019.00525.Search in Google Scholar PubMed PubMed Central
Hooijmans, C.R., Rovers, M.M., de Vries, R.B., Leenaars, M., Ritskes-Hoitinga, M., and Langendam, M.W. (2014). SYRCLE’s risk of bias tool for animal studies. BMC Med. Res. Methodol. 14: 43, https://doi.org/10.1186/1471-2288-14-43.Search in Google Scholar PubMed PubMed Central
Hu, F., Feng, A.P., Liu, X.X., Zhang, S., Xu, J.T., Wang, X., Zhong, X.L., He, M.W., and Chen, H.X. (2015a). Lipoxin A4 inhibits lipopolysaccharide-induced production of inflammatory cytokines in keratinocytes by up-regulating SOCS2 and down-regulating TRAF6. J. Huazhong Univ. Sci. Technol. Med. Sci. 35: 426–431, https://doi.org/10.1007/s11596-015-1448-8.Search in Google Scholar PubMed
Hu, F., Liu, X.X., Wang, X., Alashkar, M., Zhang, S., Xu, J.T., Zhong, X.L., He, M.W., Feng, A.P., and Chen, H.X. (2015b). Lipoxin A4 inhibits proliferation and inflammatory cytokine/chemokine production of human epidermal keratinocytes associated with the ERK1/2 and NF-κB pathways. J. Dermatol. Sci. 78: 181–188, https://doi.org/10.1016/j.jdermsci.2015.03.009.Search in Google Scholar PubMed
James, S.L., Theadom, A., Ellenbogen, R.G., Bannick, M.S., Montjoy-Venning, W., Lucchesi, L.R., Abbasi, N., Abdulkader, R., Abraha, H.N., Adsuar, J.C., et al.. (2019). Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18: 56–87, https://doi.org/10.1016/s1474-4422(18)30415-0.Search in Google Scholar
Kataria, H., Lutz, D., Chaudhary, H., Schachner, M., and Loers, G. (2016). Small molecule agonists of cell adhesion molecule L1 mimic L1 functions in vivo. Mol. Neurobiol. 53: 4461–4483, https://doi.org/10.1007/s12035-015-9352-6.Search in Google Scholar PubMed
Kilkenny, C., Browne, W., Cuthill, I.C., Emerson, M., and Altman, D.G. (2010). Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br. J. Pharmacol. 160: 1577–1579, https://doi.org/10.1002/jgm.1473.Search in Google Scholar PubMed
Kraus, J.F., Franti, C.E., Riggins, R.S., Richards, D., and Borhani, N.O. (1975). Incidence of traumatic spinal cord lesions. J. Chronic. Dis. 28: 471–492, https://doi.org/10.1016/0021-9681(75)90057-0.Search in Google Scholar PubMed
Li, Y., Ritzel, R.M., He, J., Cao, T., Sabirzhanov, B., Li, H., Liu, S., Wu, L.J., and Wu, J. (2021). The voltage-gated proton channel Hv1 plays a detrimental role in contusion spinal cord injury via extracellular acidosis-mediated neuroinflammation. Brain Behav. Immun. 91: 267–283, https://doi.org/10.1016/j.bbi.2020.10.005.Search in Google Scholar PubMed PubMed Central
Li, Y., Ritzel, R.M., Khan, N., Cao, T., He, J., Lei, Z., Matyas, J.J., Sabirzhanov, B., Liu, S., Li, H., et al.. (2020). Delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice. Theranostics 10: 11376–11403, https://doi.org/10.7150/thno.49199.Search in Google Scholar PubMed PubMed Central
Li, Z., Wu, F., Xu, D., Zhi, Z., and Xu, G. (2019). Inhibition of TREM1 reduces inflammation and oxidative stress after spinal cord injury (SCI) associated with HO-1 expressions. Biomed. Pharmacother. 109: 2014–2021, https://doi.org/10.1016/j.biopha.2018.08.159.Search in Google Scholar PubMed
Lo, J., Chan, L., and Flynn, S. (2021). A systematic review of the incidence, prevalence, costs, and activity and work limitations of amputation, osteoarthritis, rheumatoid arthritis, back pain, multiple sclerosis, spinal cord injury, stroke, and traumatic brain injury in the United States: a 2019 update. Arch. Phys. Med. Rehabil. 102: 115–131, https://doi.org/10.1016/j.apmr.2020.04.001.Search in Google Scholar PubMed PubMed Central
Loggia, M., Disorders, N.I.o.N., Stroke and Hospital, M.G. (2017). Evaluating the role of neuroinflammation in low back pain, Available at: https://ClinicalTrials.gov/show/NCT03106740.Search in Google Scholar
Manville, R.W. and Abbott, G.W. (2018). Gabapentin is a potent activator of KCNQ3 and KCNQ5 potassium channels. Mol. Pharmacol. 94: 1155–1163, https://doi.org/10.1124/mol.118.112953.Search in Google Scholar PubMed PubMed Central
Martini, A.C., Berta, T., Forner, S., Chen, G., Bento, A.F., Ji, R.R., and Rae, G.A. (2016). Lipoxin A4 inhibits microglial activation and reduces neuroinflammation and neuropathic pain after spinal cord hemisection. J. Neuroinflammation 13: 75, https://doi.org/10.1186/s12974-016-0540-8.Search in Google Scholar PubMed PubMed Central
Masri, R. and Keller, A. (2012). Chronic pain following spinal cord injury. Adv. Exp. Med. Biol. 760: 74–88.10.1007/978-1-4614-4090-1_5Search in Google Scholar PubMed PubMed Central
Matejuk, A. and Ransohoff, R.M. (2020). Crosstalk between astrocytes and microglia: an overview. Front. Immunol. 11: 1416, https://doi.org/10.3389/fimmu.2020.01416.Search in Google Scholar PubMed PubMed Central
Morgado, C., Pereira-Terra, P., Cruz, C., and Tavares, I. (2011). Minocycline completely reverses mechanical hyperalgesia in diabetic rats through microglia-induced changes in the expression of the potassium chloride co-transporter 2 (KCC2) at the spinal cord. Diabetes Obes. Metabol. 13: 150–159, https://doi.org/10.1111/j.1463-1326.2010.01333.x.Search in Google Scholar PubMed
Nakajima, H., Honjoh, K., Watanabe, S., Kubota, A., and Matsumine, A. (2020). Distribution and polarization of microglia and macrophages at injured sites and the lumbar enlargement after spinal cord injury. Neurosci. Lett. 737, https://doi.org/10.1016/j.neulet.2020.135152.Search in Google Scholar PubMed
Naseri, K., Saghaei, E., Abbaszadeh, F., Afhami, M., Haeri, A., Rahimi, F., and Jorjani, M. (2013). Role of microglia and astrocyte in central pain syndrome following electrolytic lesion at the spinothalamic tract in rats. J. Mol. Neurosci. 49: 470–479, https://doi.org/10.1007/s12031-012-9840-3.Search in Google Scholar PubMed
Percie du Sert, N., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., Dirnagl, U., Emerson, M., et al.. (2020a). Reporting animal research: explanation and elaboration for the ARRIVE guidelines 2.0. PLOS Biol. 18: e3000411, https://doi.org/10.1371/journal.pbio.3000411.Search in Google Scholar PubMed PubMed Central
Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., Dirnagl, U., et al.. (2020b). The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol. 18: e3000410, https://doi.org/10.1111/bph.15193.Search in Google Scholar PubMed PubMed Central
Pezet, S. and McMahon, S.B. (2006). Neurotrophins: mediators and modulators of pain. Annu. Rev. Neurosci. 29: 507–538, https://doi.org/10.1146/annurev.neuro.29.051605.112929.Search in Google Scholar PubMed
Ramer, L.M., Ramer, M.S., and Steeves, J.D. (2005). Setting the stage for functional repair of spinal cord injuries: a cast of thousands. Spinal Cord 43: 134–161, https://doi.org/10.1038/sj.sc.3101715.Search in Google Scholar PubMed
Rossetto, O., Pirazzini, M., Fabris, F., and Montecucco, C. (2021). Botulinum neurotoxins: mechanism of action. Handb. Exp. Pharmacol. 263: 35–47, https://doi.org/10.1007/164_2020_355.Search in Google Scholar PubMed
Sabirzhanov, B., Li, Y., Coll-Miro, M., Matyas, J.J., He, J., Kumar, A., Ward, N., Yu, J., Faden, A.I., and Wu, J. (2019a). Inhibition of NOX2 signaling limits pain-related behavior and improves motor function in male mice after spinal cord injury: participation of IL-10/miR-155 pathways. Brain Behav. Immun. 80: 73–87, https://doi.org/10.1016/j.bbi.2019.02.024.Search in Google Scholar PubMed PubMed Central
Sabirzhanov, B., Matyas, J., Coll-Miro, M., Yu, L.L., Faden, A.I., Stoica, B.A., and Wu, J. (2019b). Inhibition of microRNA-711 limits angiopoietin-1 and Akt changes, tissue damage, and motor dysfunction after contusive spinal cord injury in mice. Cell Death Dis. 10: 839, https://doi.org/10.1038/s41419-019-2079-y.Search in Google Scholar PubMed PubMed Central
Schafer, D.P., Lehrman, E.K., and Stevens, B. (2013). The “quad-partite” synapse: microglia-synapse interactions in the developing and mature CNS. Glia 61: 24–36, https://doi.org/10.1002/glia.22389.Search in Google Scholar PubMed PubMed Central
Sekhon, L.H.S. and Fehlings, M.G. (2001). Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine 26: S2–S12, https://doi.org/10.1097/00007632-200112151-00002.Search in Google Scholar PubMed
Sekiguchi, A., Kanno, H., Ozawa, H., Yamaya, S., and Itoi, E. (2011). Rapamycin promotes autophagy and reduces neural tissue damage and locomotor impairment after spinal cord injury in mice. J. Neurotrauma 29: 946–956, https://doi.org/10.1089/neu.2011.1919.Search in Google Scholar PubMed
Siddall, P.J., McClelland, J.M., Rutkowski, S.B., and Cousins, M.J. (2003). A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury. Pain 103: 249–257, https://doi.org/10.1016/s0304-3959(02)00452-9.Search in Google Scholar PubMed
Stover, S.L. and Fine, P.R. (1987). The epidemiology and economics of spinal cord injury. Paraplegia 25: 225–228, https://doi.org/10.1038/sc.1987.40.Search in Google Scholar PubMed
Takeura, N., Nakajima, H., Watanabe, S., Honjoh, K., Takahashi, A., and Matsumine, A. (2019). Role of macrophages and activated microglia in neuropathic pain associated with chronic progressive spinal cord compression. Sci. Rep. 9, https://doi.org/10.1038/s41598-019-52234-1.Search in Google Scholar PubMed PubMed Central
Tavares, I., Costa-Pereira, J.T., and Martins, I. (2021). Monoaminergic and opioidergic modulation of brainstem circuits: new insights into the clinical challenges of pain treatment? Front Pain Res 2: 696515, https://doi.org/10.3389/fpain.2021.696515.Search in Google Scholar PubMed PubMed Central
Taylor, C.P. and Harris, E.W. (2020). Analgesia with gabapentin and pregabalin may involve N-Methyl-d-Aspartate receptors, neurexins, and thrombospondins. J. Pharmacol. Exp. Ther. 374: 161–174, https://doi.org/10.1124/jpet.120.266056.Search in Google Scholar PubMed
Tenorio, G., Kulkarni, A., and Kerr, B.J. (2013). Resident glial cell activation in response to perispinal inflammation leads to acute changes in nociceptive sensitivity: implications for the generation of neuropathic pain. Pain 154: 71–81, https://doi.org/10.1016/j.pain.2012.09.008.Search in Google Scholar PubMed
Thakkar, B. and Acevedo, E.O. (2023). BDNF as a biomarker for neuropathic pain: consideration of mechanisms of action and associated measurement challenges. Brain Behav. 13: e2903, https://doi.org/10.1002/brb3.2903.Search in Google Scholar PubMed PubMed Central
Turcato, F., Almeida, C., Mota, C., Kusuda, R., Carvalho, A., Nascimento, G.C., Zanon, S., Leite-Panissi, C.R., and Lucas, G. (2019). Dynamic expression of glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 in the mouse spinal cord dorsal horn under pathological pain states. Neurol. Res. 41: 633–643, https://doi.org/10.1080/01616412.2019.1603804.Search in Google Scholar PubMed
Widerström-Noga, E. (2017). Neuropathic pain and spinal cord injury: phenotypes and pharmacological management. Drugs 77: 967–984, https://doi.org/10.1007/s40265-017-0747-8.Search in Google Scholar PubMed
World Health Organization and International Spinal Cord Society (2013). International perspectives on spinal cord injury. World Health Organization, Geneva, Switzerland.Search in Google Scholar
Wu, J., Raver, C., Piao, C., Keller, A., and Faden, A.I. (2013). Cell cycle activation contributes to increased neuronal activity in the posterior thalamic nucleus and associated chronic hyperesthesia after rat spinal cord contusion. Neurotherapeutics 10: 520–538, https://doi.org/10.1007/s13311-013-0198-1.Search in Google Scholar PubMed PubMed Central
Wu, J., Stoica, B.A., Luo, T., Sabirzhanov, B., Zhao, Z., Guanciale, K., Nayar, S.K., Foss, C.A., Pomper, M.G., and Faden, A.I. (2014). Isolated spinal cord contusion in rats induces chronic brain neuroinflammation, neurodegeneration,and cognitive impairment: involvement of cell cycle activation. Cell Cycle 13: 2446–2458, https://doi.org/10.4161/cc.29420.Search in Google Scholar PubMed PubMed Central
Yao, M., Li, G., Pu, P.M., Zhou, L.Y., Li, Z.Y., Liu, S.F., Sng, K.S., Zheng, Z., Song, Y.J., Zhu, K., et al.. (2022). Neuroinflammation and apoptosis after surgery for a rat model of double-level cervical cord compression. Neurochem. Int. 157, https://doi.org/10.1016/j.neuint.2022.105340.Search in Google Scholar PubMed
Yu, C.Z., Liu, Y.P., Liu, S., Yan, M., Hu, S.J., and Song, X.J. (2014). Systematic administration of B vitamins attenuates neuropathichyperalgesia and reduces spinal neuron injury following temporary spinal cord ischaemia in rats. Eur. J. Pain 18: 76–85, https://doi.org/10.1002/j.1532-2149.2013.00390.x.Search in Google Scholar PubMed
Yu, D., Thakor, D.K., Han, I., Ropper, A.E., Haragopal, H., Sidman, R.L., Zafonte, R., Schachter, S.C., and Teng, Y.D. (2013). Alleviation of chronic pain following rat spinal cord compression injury with multimodal actions of huperzine A. Proc. Natl. Acad. Sci. U. S. A. 110: E746–E755, https://doi.org/10.1073/pnas.1300083110.Search in Google Scholar PubMed PubMed Central
© 2023 Walter de Gruyter GmbH, Berlin/Boston