Intrathecal Injection of JWH-015 Attenuates Bone Cancer Pain Via Time-Dependent Modification of Pro-inflammatory Cytokines Expression and Astrocytes Activity in Spinal Cord

Cannabinoid receptor type 2 (CB2) agonists display potential analgesic effects in acute and neuropathic pain. However, its complex cellular and molecular mechanisms in bone cancer pain remain unclear. And less relevant reports concerned its time-dependent effects on the long-lasting modifications of behavior, spinal inflammatory cytokines levels, astrocytes activity induced by bone cancer pain. A rat model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells was utilized. Pain behaviors at different time points were assessed by ambulatory pain scores and paw withdrawal mechanical threshold (PWMT). Pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-18, and tumor necrosis factor alpha (TNF-α), were quantitated by Western blots. Glial activity was assessed by immunohistochemistry. Intra-tibia inoculation of Walker 256 mammary gland carcinoma cells induced progressive bone cancer pain; a long-term up-regulation of IL-1β, IL-6, IL-18, and TNF-α; and the activation of glia in spinal cord. Activation of microglia was first evident on day 4 after surgery and reached to a peak on day 7 while activation of astrocytes was on day 10. A single intrathecal injection of JWH-015 attenuated bone cancer induced spontaneous pain and mechanical allodynia, reduced the expression of pro-inflammatory cytokines, and inhibited the activity of astrocytes. All the modifications were transient and peaked at 24 h after JWH-015 administration. Furthermore, the protective effects of JWH-015 were reversed in the presence of CB2-selective antagonist AM630. Overall, our results provided evidences for the persistent participation of inflammation reaction in the progression of bone cancer pain, and demonstrated that JWH-015 reduced the expression of IL-1β, IL-6, IL-18, and TNF-α and inhibited astrocytes activation in a time-dependent manner, thereby displaying an analgesic effect.

This is a preview of subscription content, access via your institution.

Access optionsBuy single article

Instant access to the full article PDF.

39,95 €

Price includes VAT (India)

dataLayer.push({"ecommerce":{"currency":"EUR","impressions":[{"name":"Intrathecal Injection of JWH-015 Attenuates Bone Cancer Pain Via Time-Dependent Modification of Pro-inflammatory Cytokines Expression and Astrocytes Activity in Spinal Cord","id":"1573-2576","price":39.95,"brand":"Springer US","category":"Biomedicine","variant":"ppv-article","quantity":1}]}});

Rent this article via DeepDyve.

function deepDyveResponse(data) { if (data.status === 'ok') { [].slice.call(document.querySelectorAll('.c-box.buybox__rent-article')).forEach(function (article) { article.style.display = 'flex' var link = article.querySelector('.deepdyve-link') if (link) { link.setAttribute('href', data.url) } }) } } var script = document.createElement('script') script.src = '//www.deepdyve.com/rental-link?docId=10.1007/s10753-015-0168-3&journal=1573-2576&fieldName=journal_doi&affiliateId=springer&format=jsonp&callback=deepDyveResponse' document.body.appendChild(script)

Learn more about Institutional subscriptions

.sprcom-buybox-articleSidebar{box-shadow: 0px 0px 5px rgba(51,51,51,0.101);display: flex;flex-wrap: wrap;font-family: -apple-system, BlinkMacSystemFont, 'Segoe UI', Roboto, Oxygen-Sans, Ubuntu, Cantarell, 'Helvetica Neue', sans-serif;text-align: center; } .sprcom-buybox-articleSidebar *{box-sizing: border-box;line-height: calc(100% + 4px);margin: 0px; } .sprcom-buybox-articleSidebar > *{display: flex;flex-basis: 240px;flex-direction: column;flex-grow: 1;flex-shrink: 1;margin: 0.5px; } .sprcom-buybox-articleSidebar > *{box-shadow: 0 0 0 1px rgba(204,204,204,0.494); } .sprcom-buybox-articleSidebar .c-box__body{display: flex;flex-direction: column-reverse;flex-grow: 1;justify-content: space-between;padding: 6%; } .sprcom-buybox-articleSidebar .c-box__body .buybox__buy{display: flex;flex-direction: column-reverse; } .sprcom-buybox-articleSidebar p{color: #333;font-size: 15px; } .sprcom-buybox-articleSidebar .buybox__price{font-size: 24px;font-weight: 500;line-height: calc(100% + 8px);margin: 20px 0;order: 1; } .sprcom-buybox-articleSidebar form{order: 1; } .sprcom-buybox-articleSidebar .buybox__price-info{margin-bottom: 20px; } .sprcom-buybox-articleSidebar .c-box__heading{background-color: #f0f0f0;color: #333;font-family: -apple-system, BlinkMacSystemFont, 'Segoe UI', Roboto, Oxygen-Sans, Ubuntu, Cantarell, 'Helvetica Neue', sans-serif;font-size: 16px;margin: 0px;padding: 10px 12px;text-align: center; } .sprcom-buybox-articleSidebar .c-box__button{background-color: #3365A4;border: 1px solid transparent;border-radius: 2px;color: #fff;cursor: pointer;display: inline-block;font-family: inherit;font-size: 16px;max-width: 222px;padding: 10px 12px;text-decoration: none;width: 100%; } .sprcom-buybox-articleSidebar h3{clip: rect(1px, 1px, 1px, 1px);height: 1px;overflow: hidden;position: absolute;width: 1px; } .sprcom-buybox-articleSidebar h2{flex-basis: 100%;margin-bottom: 16px;text-align: left; } .sprcom-buybox-articleSidebar .buybox__institutional-sub, .buybox__rent-article .c-box__body{flex-direction: row; } .sprcom-buybox-articleSidebar .buybox__institutional-sub, .buybox__rent-article .buybox__info{text-align: left; } .sprcom-buybox-articleSidebar .buybox__institutional-sub{background-color: #f0f0f0; } .sprcom-buybox-articleSidebar .visually-hidden{clip: rect(1px, 1px, 1px, 1px);height: 1px;overflow: hidden;position: absolute;width: 1px; } .sprcom-buybox-articleSidebar style{display: none; } ;(function () { var timestamp = Date.now() document.write('') var head = document.getElementsByTagName("head")[0] var script = document.createElement("script") script.type = "text/javascript" script.src = "https://buy.springer.com/assets/js/buybox-bundle-abe5f44a67.js" script.id = "ecommerce-scripts-" + timestamp head.appendChild(script) var buybox = document.querySelector("[data-id=id_"+ timestamp +"]").parentNode ;[].slice.call(buybox.querySelectorAll(".buying-option")).forEach(init) function init(buyingOption, index) { var form = buyingOption.querySelector("form") if (form) { var formAction = form.getAttribute("action") document.querySelector("#ecommerce-scripts-" + timestamp).addEventListener("load", bindModal(form, formAction, timestamp, index), false) } } function bindModal(form, formAction, timestamp, index) { var weHasBrowserSupport = window.fetch && Array.from return function() { console.log("ecommerce-scripts loaded, attempting to init modal …") var Buybox = EcommScripts ? EcommScripts.Buybox : null var Modal = EcommScripts ? EcommScripts.Modal : null if (weHasBrowserSupport && Buybox && Modal) { var modalID = "ecomm-modal_" + timestamp + "_" + index var modal = new Modal(modalID) modal.domEl.addEventListener("close", close) function close() { form.querySelector("button[type=submit]").focus() } var cartURL = "/cart" var cartModalURL = "/cart?messageOnly=1" form.setAttribute( "action", formAction.replace(cartURL, cartModalURL) ) var formSubmit = Buybox.interceptFormSubmit( Buybox.fetchFormAction(window.fetch), Buybox.triggerModalAfterAddToCartSuccess(modal), function() { form.removeEventListener("submit", formSubmit, false) form.setAttribute( "action", formAction.replace(cartModalURL, cartURL) ) form.submit() } ) form.addEventListener("submit", formSubmit, false) document.body.appendChild(modal.domEl) } else { console.log("binding failed:", weHasBrowserSupport, EcommScripts) } } } })() Fig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6 AbbreviationsCB1 :

Cannabinoid receptor type 1

CB2 :

Cannabinoid receptor type 2

IL:

Interleukin

TNF-α:

Tumor necrosis factor alpha

PWMT:

Paw withdrawal mechanical threshold

CNS:

Central nervous system

DMSO:

Dimethyl sulfoxide

PBS:

Phosphate buffered saline

GFAP:

Glial fibrillary acidic protein

SD:

Standard deviation

CCR:

Chemokine receptor

COX:

Cyclo-oxygen-ase

NMDA:

N-methyl-d-aspartic acid receptor

References

Hernandez, B.Y., M.D. Green, K.D. Cassel, A.M. Pobutsky, V. Vu, and L.R. Wilkens. 2010. Preview of Hawaii cancer facts and Figures 2010. Hawaii Medical Journal 69: 223–224.

PubMed Central PubMed Google Scholar

Coleman, R.E. 2006. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research 12: 6243s–6249s.

Article Google Scholar

DeNardo, D.G., M. Johansson, and L.M. Coussens. 2008. Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Reviews 27: 11–18.

CAS Article PubMed Google Scholar

Luger, N.M., D.B. Mach, M.A. Sevcik, and P.W. Mantyh. 2005. Bone cancer pain: from model to mechanism to therapy. Journal of Pain and Symptom Management 29: S32–S46.

CAS Article PubMed Google Scholar

O’Connor, J.P., and T. Lysz. 2008. Celecoxib, NSAIDs and the skeleton. Drugs of Today 44: 693–709.

Article PubMed Google Scholar

Davis, M.P. 2014. Cannabinoids in pain management: CB1, CB2 and non-classic receptor ligands. Expert Opinion on Investigational Drugs 23: 1123–1140.

CAS Article PubMed Google Scholar

Gilron, I., and A.H. Dickenson. 2014. Emerging drugs for neuropathic pain. Expert Opinion on Emerging Drugs 19: 329–341.

CAS Article PubMed Google Scholar

Devane, W.A., F.A. Dysarz 3rd, M.R. Johnson, L.S. Melvin, and A.C. Howlett. 1988. Determination and characterization of a cannabinoid receptor in rat brain. Molecular Pharmacology 34: 605–613.

CAS PubMed Google Scholar

Tsou, K., S. Brown, M.C. Sanudo-Pena, K. Mackie, and J.M. Walker. 1998. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83: 393–411.

CAS Article PubMed Google Scholar

Gaffuri, A.L., D. Ladarre, and Z. Lenkei. 2012. Type-1 cannabinoid receptor signaling in neuronal development. Pharmacology 90: 19–39.

CAS Article PubMed Google Scholar

Harvey-Girard, E., A.C. Giassi, W. Ellis, and L. Maler. 2013. Expression of the cannabinoid CB1 receptor in the gymnotiform fish brain and its implications for the organization of the teleost pallium. The Journal of Comparative Neurology 521: 949–975.

CAS Article PubMed Google Scholar

Klein, T.W., C. Newton, K. Larsen, L. Lu, I. Perkins, L. Nong, and H. Friedman. 2003. The cannabinoid system and immune modulation. Journal of Leukocyte Biology 74: 486–496.

CAS Article PubMed Google Scholar

Solas, M., P.T. Francis, R. Franco, and M.J. Ramirez. 2013. CB2 receptor and amyloid pathology in frontal cortex of Alzheimer’s disease patients. Neurobiology of Aging 34: 805–808.

CAS Article PubMed Google Scholar

Moreno-Martet, M., F. Espejo-Porras, J. Fernandez-Ruiz, and E. de Lago. 2014. Changes in endocannabinoid receptors and enzymes in the spinal cord of SOD1(G93A) transgenic mice and evaluation of a Sativex((R)) -like combination of phytocannabinoids: interest for future therapies in amyotrophic lateral sclerosis. CNS Neuroscience & Therapeutics 20: 809–815.

CAS Article Google Scholar

Lanciego, J.L., P. Barroso-Chinea, A.J. Rico, L. Conte-Perales, L. Callen, E. Roda, V. Gomez-Bautista, I.P. Lopez, C. Lluis, J.L. Labandeira-Garcia, and R. Franco. 2011. Expression of the mRNA coding the cannabinoid receptor 2 in the pallidal complex of Macaca fascicularis. Journal of Psychopharmacology 25: 97–104.

CAS Article PubMed Google Scholar

Gong, J.P., E.S. Onaivi, H. Ishiguro, Q.R. Liu, P.A. Tagliaferro, A. Brusco, and G.R. Uhl. 2006. Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Research 1071: 10–23.

CAS Article PubMed Google Scholar

Onaivi, E.S., H. Ishiguro, J.P. Gong, S. Patel, A. Perchuk, P.A. Meozzi, L. Myers, Z. Mora, P. Tagliaferro, E. Gardner, A. Brusco, B.E. Akinshola, Q.R. Liu, B. Hope, S. Iwasaki, T. Arinami, L. Teasenfitz, and G.R. Uhl. 2006. Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Annals of the New York Academy of Sciences 1074: 514–536.

CAS Article PubMed Google Scholar

Rahn, E.J., and A.G. Hohmann. 2009. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics 6: 713–737.

CAS Article Google Scholar

Fernandez-Ruiz, J. 2009. The endocannabinoid system as a target for the treatment of motor dysfunction. British Journal of Pharmacology 156: 1029–1040.

PubMed Central CAS Article PubMed Google Scholar

Marrs, W.R., J.L. Blankman, E.A. Horne, A. Thomazeau, Y.H. Lin, J. Coy, A.L. Bodor, G.G. Muccioli, S.S. Hu, G. Woodruff, S. Fung, M. Lafourcade, J.P. Alexander, J.Z. Long, W. Li, C. Xu, T. Moller, K. Mackie, O.J. Manzoni, B.F. Cravatt, and N. Stella. 2010. The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nature Neuroscience 13: 951–957.

PubMed Central CAS Article PubMed Google Scholar

Pertwee, R.G., A.C. Howlett, M.E. Abood, S.P. Alexander, V. Di Marzo, M.R. Elphick, P.J. Greasley, H.S. Hansen, G. Kunos, K. Mackie, R. Mechoulam, and R.A. Ross. 2010. International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: Beyond CB(1) and CB(2). Pharmacological Reviews 62: 588–631.

PubMed Central CAS Article PubMed Google Scholar

Atwood, B.K., and K. Mackie. 2010. CB2: a cannabinoid receptor with an identity crisis. British Journal of Pharmacology 160: 467–479.

PubMed Central CAS Article PubMed Google Scholar

Watkins, L.R., E.D. Milligan, and S.F. Maier. 2001. Glial activation: a driving force for pathological pain. Trends in Neurosciences 24: 450–455.

CAS Article PubMed Google Scholar

Guo, W., H. Wang, M. Watanabe, K. Shimizu, S. Zou, S.C. LaGraize, F. Wei, R. Dubner, and K. Ren. 2007. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. Journal of Neuroscience : the Official Journal of the Society for Neuroscience 27: 6006–6018.

CAS Article Google Scholar

Sun, Y.E., L. Peng, X. Sun, J. Bo, D. Yang, Y. Zheng, C. Liu, B. Zhu, Z. Ma, and X. Gu. 2012. Intrathecal injection of spironolactone attenuates radicular pain by inhibition of spinal microglia activation in a rat model. PLoS One 7: e39897.

PubMed Central CAS Article PubMed Google Scholar

Sun, Y., W. Zhang, Y. Liu, X. Liu, Z. Ma, and X. Gu. 2014. Intrathecal injection of JWH015 attenuates remifentanil-induced postoperative hyperalgesia by inhibiting activation of spinal glia in a rat model. Anesthesia and Analgesia 118: 841–853.

CAS Article PubMed Google Scholar

Bossu, P., A. Ciaramella, F. Salani, D. Vanni, I. Palladino, C. Caltagirone, and G. Scapigliati. 2010. Interleukin-18, from neuroinflammation to Alzheimer’s disease. Current Pharmaceutical Design 16: 4213–4224.

CAS Article PubMed Google Scholar

Sutinen, E.M., T. Pirttila, G. Anderson, A. Salminen, and J.O. Ojala. 2012. Pro-inflammatory interleukin-18 increases Alzheimer’s disease-associated amyloid-beta production in human neuron-like cells. Journal of Neuroinflammation 9: 199.

PubMed Central CAS Article PubMed Google Scholar

Bossu, P., D. Cutuli, I. Palladino, P. Caporali, F. Angelucci, D. Laricchiuta, F. Gelfo, P. De Bartolo, C. Caltagirone, and L. Petrosini. 2012. A single intraperitoneal injection of endotoxin in rats induces long-lasting modifications in behavior and brain protein levels of TNF-alpha and IL-18. Journal of Neuroinflammation 9: 101.

PubMed Central CAS Article PubMed Google Scholar

Karavelioglu, E., Y. Gonul, S. Kokulu, O. Hazman, F. Bozkurt, A. Kocak, and O. Eser. 2014. Anti-inflammatory and antiapoptotic effect of interleukine-18 binding protein on the spinal cord ischemia-reperfusion injury. Inflammation 37: 917–923.

CAS Article PubMed Google Scholar

Miyoshi, K., K. Obata, T. Kondo, H. Okamura, and K. Noguchi. 2008. Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. Journal of Neuroscience : the Official Journal of the Society for Neuroscience 28: 12775–12787.

CAS Article Google Scholar

Zimmermann, M. 1983. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16: 109–110.

CAS Article PubMed Google Scholar

Mao-Ying, Q.L., J. Zhao, Z.Q. Dong, J. Wang, J. Yu, M.F. Yan, Y.Q. Zhang, G.C. Wu, and Y.Q. Wang. 2006. A rat model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells. Biochemical and Biophysical Research Communications 345: 1292–1298.

CAS Article PubMed Google Scholar

Medhurst, S.J., K. Walker, M. Bowes, B.L. Kidd, M. Glatt, M. Muller, M. Hattenberger, J. Vaxelaire, T. O’Reilly, G. Wotherspoon, J. Winter, J. Green, and L. Urban. 2002. A rat model of bone cancer pain. Pain 96: 129–140.

CAS Article PubMed Google Scholar

Mestre, C., T. Pelissier, J. Fialip, G. Wilcox, and A. Eschalier. 1994. A method to perform direct transcutaneous intrathecal injection in rats. Journal of Pharmacological and Toxicological Methods 32: 197–200.

CAS Article PubMed Google Scholar

Dixon, W.J. 1980. Efficient analysis of experimental observations. Annual Review of Pharmacology and Toxicology 20: 441–462.

CAS Article PubMed Google Scholar

Ji, R.R., Y. Kawasaki, Z.Y. Zhuang, Y.R. Wen, and I. Decosterd. 2006. Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. Neuron Glia Biology 2: 259–269.

PubMed Central Article PubMed Google Scholar

Rubens, R.D. 1998. Bone metastases—the clinical problem. European Journal of Cancer 34: 210–213.

CAS Article PubMed Google Scholar

Solomayer, E.F., I.J. Diel, G.C. Meyberg, C. Gollan, and G. Bastert. 2000. Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Research and Treatment 59: 271–278.

CAS Article PubMed Google Scholar

Romero-Sandoval, A., N. Nutile-McMenemy, and J.A. DeLeo. 2008. Spinal microglial and perivascular cell cannabinoid receptor type 2 activation reduces behavioral hypersensitivity without tolerance after peripheral nerve injury. Anesthesiology 108: 722–734.

PubMed Central CAS Article PubMed Google Scholar

Martin Fontelles, M.I., and C. Goicoechea Garcia. 2008. Role of cannabinoids in the management of neuropathic pain. CNS Drugs 22: 645–653.

CAS Article PubMed Google Scholar

Elikkottil, J., P. Gupta, and K. Gupta. 2009. The analgesic potential of cannabinoids. Journal of Opioid Management 5: 341–357.

PubMed Google Scholar

Karst, M., S. Wippermann, and J. Ahrens. 2010. Role of cannabinoids in the treatment of pain and (painful) spasticity. Drugs 70: 2409–2438.

CAS Article PubMed Google Scholar

Thaler, A., A. Gupta, and S.P. Cohen. 2011. Cannabinoids for pain management. Advances in Psychosomatic Medicine 30: 125–138.

Article PubMed Google Scholar

Lombard, C., M. Nagarkatti, and P. Nagarkatti. 2007. CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: potential role for CB2-selective ligands as immunosuppressive agents. Clinical Immunology 122: 259–270.

PubMed Central CAS Article PubMed Google Scholar

Preet, A., Z. Qamri, M.W. Nasser, A. Prasad, K. Shilo, X. Zou, J.E. Groopman, and R.K. Ganju. 2011. Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis. Cancer Prevention Research 4: 65–75.

PubMed Central CAS Article PubMed Google Scholar

Gu, X., F. Mei, Y. Liu, R. Zhang, J. Zhang, and Z. Ma. 2011. Intrathecal administration of the cannabinoid 2 receptor agonist JWH015 can attenuate cancer pain and decrease mRNA expression of the 2B subunit of N-methyl-D-aspartic acid. Anesthesia and Analgesia 113: 405–411.

CAS Article PubMed Google Scholar

Austin, P.J., and G. Moalem-Taylor. 2010. The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. Journal of Neuroimmunology 229: 26–50.

CAS Article PubMed Google Scholar

Kawasaki, Y., L. Zhang, J.K. Cheng, and R.R. Ji. 2008. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. Journal of Neuroscience : the Official Journal of the Society for Neuroscience 28: 5189–5194.

CAS Article Google Scholar

Liou, J.T., F.C. Liu, C.C. Mao, Y.S. Lai, and Y.J. Day. 2011. Inflammation confers dual effects on nociceptive processing in chronic neuropathic pain model. Anesthesiology 114: 660–672.

Article PubMed Google Scholar

Raghavendra, V., F. Tanga, and J.A. DeLeo. 2003. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. The Journal of Pharmacology and Experimental Therapeutics 306: 624–630.

CAS Article PubMed Google Scholar

Sung, B., G. Lim, and J. Mao. 2003. Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. Journal of Neuroscience : the Official Journal of the Society for Neuroscience 23: 2899–2910.

CAS Google Scholar

Ji, R.R., and M.R. Suter. 2007. p38 MAPK, microglial signaling, and neuropathic pain. Molecular Pain 3: 33.

PubMed Central Article PubMed Google Scholar

Meunier, A., A. Latremoliere, E. Dominguez, A. Mauborgne, S. Philippe, M. Hamon, J. Mallet, J.J. Benoliel, and M. Pohl. 2007. Lentiviral-mediated targeted NF-kappaB blockade in dorsal spinal cord glia attenuates sciatic nerve injury-induced neuropathic pain in the rat. Molecular Therapy : the Journal of the American Society of Gene Therapy 15: 687–697.

CAS Google Scholar

Ledeboer, A., M. Gamanos, W. Lai, D. Martin, S.F. Maier, L.R. Watkins, and N. Quan. 2005. Involvement of spinal cord nuclear factor kappaB activation in rat models of proinflammatory cytokine-mediated pain facilitation. The European Journal of Neuroscience 22: 1977–1986.

Article PubMed Google Scholar

Vincenzi, F., M. Targa, C. Corciulo, M.A. Tabrizi, S. Merighi, S. Gessi, G. Saponaro, P.G. Baraldi, P.A. Borea, and K. Varani. 2013. Antinociceptive effects of the selective CB2 agonist MT178 in inflammatory and chronic rodent pain models. Pain 154: 864–873.

CAS Article PubMed Google Scholar

Abbadie, C., J.A. Lindia, A.M. Cumiskey, L.B. Peterson, J.S. Mudgett, E.K. Bayne, J.A. DeMartino, D.E. MacIntyre, and M.J. Forrest. 2003. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proceedings of the National Academy of Sciences of the United States of America 100: 7947–7952.

PubMed Central CAS Article PubMed Google Scholar

Guo, W., K. Miyoshi, R. Dubner, M. Gu, M. Li, J. Liu, J. Yang, S. Zou, K. Ren, K. Noguchi, and F. Wei. 2014. Spinal 5-HT3 receptors mediate descending facilitation and contribute to behavioral hypersensitivity via a reciprocal neuron-glial signaling cascade. Molecular Pain 10: 35.

PubMed Central Article PubMed Google Scholar

Gu, X., J. Zhang, Z. Ma, J. Wang, X. Zhou, Y. Jin, X. Xia, Q. Gao, and F. Mei. 2010. The role of N-methyl-D-aspartate receptor subunit NR2B in spinal cord in cancer pain. European Journal of Pain 14: 496–502.

CAS Article PubMed Google Scholar

Cui, J.H., J. Ju, and M.H. Yoon. 2013. Pharmacology of cannabinoid receptor agonists and a cyclooxygenase-2 inhibitor in rat bone tumor pain. Pharmacology 92: 150–157.

CAS Article PubMed Google Scholar

Download references

Acknowledgments

This research was supported by the National Natural Science Foundation of China (81070892, 81171047, 81171048, and 81371207) and a grant from the Department of Health of Jiangsu Province of China (XK201140, RC2011006).

Conflict of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

All of the authors read and approved the final manuscript. CEL made substantial contributions to the experiments. YL was mainly involved in the pain behavioral tests and the spinal astrocyte activity assay. BS and YZ performed the surgical procedure, administration of drugs, and Western blotting studies. YES and BLH were responsible for statistical analyses. All of these individuals participated in drafting the manuscript. XPG and ZLM conceived the idea, designed the study, and helped to revise the manuscript.

Author informationAuthor notesAuthors and Affiliations

Department of Anesthesiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu Province, China

Cui’e Lu, Yue Liu, Bei Sun, Yu’e Sun, Bailing Hou, Yu Zhang, Zhengliang Ma & Xiaoping Gu

AuthorsCui’e LuView author publications

You can also search for this author in PubMed Google Scholar

Yue LiuView author publications

You can also search for this author in PubMed Google Scholar

Bei SunView author publications

You can also search for this author in PubMed Google Scholar

Yu’e SunView author publications

You can also search for this author in PubMed Google Scholar

Bailing HouView author publications

You can also search for this author in PubMed Google Scholar

Yu ZhangView author publications

You can also search for this author in PubMed Google Scholar

Zhengliang MaView author publications

You can also search for this author in PubMed Google Scholar

Xiaoping GuView author publications

You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhengliang Ma or Xiaoping Gu.

Additional information

Cui’e Lu, Yue Liu, Bei Sun and Yu’e Sun contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this articleCite this article

Lu, C., Liu, Y., Sun, B. et al. Intrathecal Injection of JWH-015 Attenuates Bone Cancer Pain Via Time-Dependent Modification of Pro-inflammatory Cytokines Expression and Astrocytes Activity in Spinal Cord. Inflammation 38, 1880–1890 (2015). https://doi.org/10.1007/s10753-015-0168-3

Download citation

Published: 21 April 2015

Issue Date: October 2015

DOI: https://doi.org/10.1007/s10753-015-0168-3