Local Peripheral Effects of β-Caryophyllene through CB₂ Receptors in Neuropathic Pain in Mice

Hikari Kuwahata, Soh Katsuyama, Takaaki Komatsu, Hitoshi Nakamura, Maria Tiziana Corasaniti, Giacinto Bagetta, Shinobu Sakurada, Tsukasa Sakurada, Kazuo Takahama

Department of Clinical Pharmaceutics, Tohoku Pharmaceutical University, Sendai, Japan.
Department of Environmental and Molecular Health and Sciences, Graduated School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Department of Pharmacobiological Sciences, University of Magna Gracia of Catanzaro, Catanzaro, Italy.
Department of Pharmacobiology, and University Consortium for Adaptive Disorders and Headach (UCADH), Section of Neuropharmacology of Normal and Pathological Neuronal Plasticity, University of Calabria, Arcavacata di Rende, Italy.
Department of Pharmacology, Daiichi College of Pharmaceutical Sciences, Fukuoka, Japan.
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, Sendai, Japan..

DOI: 10.4236/pp.2012.34053                

Abstract

β-Caryophyllene (BCP) is known as a common constitute of the essential oils of numerous food plants and primary component in Cannabis. In this study, we investigated the effect of local intraplantar (i.pl.) injection of BCP on mechanical hypersensitivity induced by partial sciatic nerve ligation (PSNL) in mice. Relative to sham operation controls, mice with the PSNL displayed a maximum level of hyperresponsiveness to von Frey metallic filament on post-operative day 7. PSNL-induced allodynia was seen in the ipsilateral side of nerve ligation, but not in the contralateral side. The i.pl. injection of BCP into the ipsilateral hindpaw to PSNL attenuated mechanical allodynia in a dose-dependent manner. BCP injection into the contralateral hindpaw did not produce anti-allodynic effects, suggesting a local peripheral anti-allodynic effect of BCP. Anti-allodynic effects induced by i.pl. injection of BCP were prevented by pretreatment with the cannabinoid (CB₂) receptor antagonist AM630, but not by the CB₁ receptor antagonist AM251. These data suggest that i.pl. injection of BCP could produce anti-allodynia by activating peripheral CB₂ receptors, but not CB₁ receptors in a mouse model of neuropathic pain. Taken together, these results suggest that peripheral CB₂ receptors may contribute to the effectiveness of BCP in the treatment of neuropathic pain disorders.

Keywords

β-Caryophyllene (BCP); Neuropathic Pain; Partial Sciatic Nerve Ligation (PSNL); Peripheral Cannabinoid (CB) Receptor

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	A. Di Sotto, M.G. Evandri, G. Mazzanti, “Antimutagenic and mutagenic activities of some terpenes in the bacterial reverse mutation assay,” Mutation Research, Vol. 653, No. 1-2, 2008, pp. 130-133.
[2]	J. Legault, A. Pichette, “Potentiating effect of beta-caryophyllene on anticancer activity of alpha-humulene, isocaryophyllene and paclitaxel,” Journal of Pharmacy and Pharmacolology, Vol. 59, No. 12 , 2007, pp.1643-1647.
[3]	A. C. Lourens, D. Reddy, K. H. Baser, A. M. Viljoen, S. F. Van Vuuren, “In vitro biological activity and essential oil composition of four indigenous South African Helichrysum species,” Journal of Ethnopharmacology, Vol. 95, No. 2-3, 2004, pp.253-258.
[4]	G. Singh, P. Marimuthu, C. S. De Heluani, C. A. Catalan, “Antioxidation and biocidal activities of Carum nigrum (seed) essential oil, oleoresin, their selected components,” Journal of Agricultural and Food Chemistry, Vol. 54, No. 1, 2006, pp.174-181.
[5]	I. Kubo, S. K. Chaudhuri, Y. Kubo, Y. Sanchez, T. Ogura, T. Saito, H. Ishikawa, H. Haraguchi, “Cytotoxic and antioxidation sesquiterpenoids from Heterotheca inuloides,” Planta Medica, Vol. 62, No. 5, 1996, pp. 427-430.
[6]	P. A. Cornwell, B. W. Barry, “Sesquiterpene components of volatile oils as skin penetration enhancers for the hydrophilic permeant 5-fluorouracil,” Journal of Pharmacy and Pharmacolology, Vol. 46, No. 6, 1994, pp.261-269.
[7]	H. Hendriks, T. Malingre, S. Battermann, R. Boss, “Mono-and Sesquiterpene hydrocarbons of essential oil of Cannabis sativa,” Phytochemistry, Vol. 14, No. 3, 1975, pp. 814-815.
[8]	R. B. Agarwal, V. D. Rangari, “Phytochemical investigation and evaluation of anti-inflammatory and anti-arthritic activities of essential oil of Strobilanthus ixiocephala Benth”, Indian Journal of Experimental Biology, Vol. 41, No. 8, 2003, pp.890-894.
[9]	D. Baricevic, S. Sosa, R. Della Loggia, A. Tubaro, B. Simonovska, A. Krasna, A. Zupancic, “Topical anti-inflammatory activity of Salvia officinalis L. leaves: the relevance of ursolic acid,” Journal of Ethnopharmacology, Vol. 75, No. 2, 2001, pp. 125-132.
[10]	S. Martin, E. Padilla, M. A. Ocete, J. Galvez, J. Jimenez, A. Zarzuelo, “Anti-inflammatory activity of the essential oil of Bupleurum fruticescens,” Planta Medica, Vol. 59, No. 6, 1993, pp. 533-536.
[11]	J. Y. Cho, H.-J. Chang, S.-K. Lee, H.-J. Kim, J.-K. Hwang, H. S. Chun, “Amelioration of dextran sulfate sodium-induced colitis in mice by oral administration of β-caryophyllene, a sesquiterpene,” Life Sciences,Vol. 80, No. 10, 2007, pp. 932-939.
[12]	J. Gertsch, M. Leonti, S. Raduner, I. Racz, J.-Z. Chen, X.-Q. Xie, K.-H. Altmann, M. Karsak, A. Zimmer, “Beta-caryophyllene is a dietary cannabinoid,” Proceeding of the National Academy of Sciences, Vol. 105, No. 26 , 2008, pp. 9099-9104.
[13]	A. Fox, A. Kesingland, C. Gentry, K. McNair, S. Patel, L. Urban, I. James, “The role of central and peripheral Cannabinoid 1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain,” Pain, Vol. 92, No. 1-2 , 2001, pp. 91-100.
[14]	U. Herzberg, E. Eliav, G. J. Bennett, I. J. Kopin, “The analgesic effects of R(+)-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain,” Neuroscience Letters, Vol. 221, No. 2-3, 1997, pp. 157-160.
[15]	T. P. Malan Jr, M. M. Ibrahim, H. Deng, Q. Liu, H. P. Mata, T. Vanderah, F. Porreca, A. Makriyannis, “ CB2 cannabinoid receptor-mediated peripheral antinociception,” Pain, Vol. 93, No. 3, 2001, pp. 239-245.
[16]	E. Palazzo, I. Marabese, V. de Novellis, P. Oliva, F. Rossi, L. Berrino, S. Maione, “Metabotropic and NMDA glutamate receptors partic-ipate in the cannabinoid-induced antinociception.” Neuro-pharmacology, Vol. 40, No. 3, 2001, pp. 319-326.
[17]	D. R. Sagar, S. Kelly, P. J. Mills, C. T. O’Shaughnessey, D. A. Ken-dall, V. Chapman, “Inhibitory effects of CB1 and CB2 receptor agonists on responses of DRG neurons and dorsal horn neurons in neuropathic rats,” European Journal of Neuroscience, Vol. 22, No. 2, 2005, pp.371-379.
[18]	C. Di Filippo, F. Rossi, S. Rossi, M. D’Amico, “Cannabinoid CB2 receptor reduces mouse myocardial ischemia-reperfusion injury: involvement of cytokine/chemokines and PMN,” Journal of Leukocyte Biology, Vol. 75, No. 3, 2004, pp. 453-459.
[19]	[19] S. Galiegue, S. Mary, J. Marchand, D. Dussossoy, D. Carriere, P. Carayon, M. Bouaboula, D. Shire, G. Le Fur, P. Casellas, “Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations,” European Journal of Biochemistry, Vol. 232, No. 1, 1995, pp. 54-61.
[20]	A. Hervera, R. Negrete, S. Leanez, J. Martin-Campos, O, Pol, “The role of nitric oxide in the local antiallodynic and antihyperal-gesic effects and expression of o-opioid and cannabinoid-2 receptors during neuropathic pain in mice,” Journal of Pharmacology and Experimental Therapeutics, Vol. 334, No. 3, 2010, pp. 887-896.
[21]	M. M. Ibrahim, M. L. Rude, N. J. Stagg, H. P. Mata, J. Lai, T. W. Vanderah, F. Porreca, N. E. Buckley, A. Makriyannis, T. P. Malan, “CB2 cannabinoid receptor mediation of antinociception,” Pain, Vol. 122, No. 1-2, 2006, pp. 36-42.
[22]	L. Hanus, A. Breuer, S. Tchilibon, S. Shiloah, D. Goldenberg, M. Horowitz, R.G. Pertwee, R.A. Ross, R. Mechoulam, E. Fride, “HU-308: a specific agonist of CB2 a peripheral cannabinoid receptor,” Proceedings of the National Academy of Sciences, Vol.96, No. 96,1999, pp. 14228-14233.
[23]	R. Payne, “Neuropathic pain syndromes, with special reference to causalgia and reflex sympathetic dystrophy,” Clinical Journal of Pain, Vol. 2, No. 1, 1986, pp. 59-73.
[24]	S. J. Elmes, M. D. Jhaveri, D. Smart, D. A. Kendall, V. Chapman,“Cannbinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in native rats and in rat models of inflammatory and neuropathic pain,” European Journal of Neuroscience, Vol. 20, No. 9, 2004, pp. 2311-2320.
[25]	M. M. Ibrahim, F. Porreca, J. Lai, P.J. Albrecht, F. L. Rice, A. Khodoroba, G. Davar, A. Makriyannis, T. W. Vanderah, H. P. Mata, T. P. Malan, “CB2 cannnabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids,” Proceedings of the National Academy of Sciences, Vol. 102, No. 102, 2005, pp. 3093-3098.
[26]	M.Zimmermann, “Ethical guidelines for investigations of experimental pain in conscious animals,” Pain, Vol. 16, No. 2, 1983, pp.109-110.
[27]	A. B. Malmberg, A. I. Basbaum, “Partial sciatic nerve injury in the mouse as a model of neuropathic pain: behavioral and neuroanatomical correlates,” Pain, Vol. 76, No. 3, 1998, pp. 215-222.
[28]	Z. Seltzer, R. Dubner, Y. Shir, “A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury,” Pain, Vol. 43, No. 2, 1990, 205-218.
[29]	A. T. Hama, J. Sagen, “Cannabinoid receptor – mediated antinociception with acetaminophen drug combinations in rats with neuropathic spinal cord injury pain,” Neuropharmacology, Vol. 58, No. 4-5, 2010, pp. 758-766.
[30]	R. A. Ross, H. C. Brockie, L. A. Stevenson, V. L.Murphy,F. Templeton, A. Makriyannis, R. G. Pertwee, “Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656 and Am630,” British Journal of Pharmacology, Vol. 126, No. 3, 1999, pp. 665-672.
[31]	R. Lan, Q. Liu, P. Fan, S. Lin, S. R. Fernando, D. McCallion, R. Pertwee, A. Makriyannis, “Structure-activity relationships of pirazole derivatives as cannabinoid receptor antagonists,” Journal of Medicinal Chemistry, Vol. 42, No. 4, 1999, pp. 769-776.
[32]	A. Quartilho, H. P. Mata, M. M. Ibrahim, T. W. Vanderah, F. Porreca, A. Makriyannis, T. P. Malan, “Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannnabinoid receptors,” Anesthesiology, Vol. 99, No. 4, 2003, pp. 955-960.
[33]	K. J. Valenzano, L. Tafesse, G. Lee, J. E. Harrison, J. M. Boulet, S. L.Gottshall, L. Mark, M. S. Pearson, W. Miller, S. Shan, L. Rabadi, Y. Rotshteyn, S. M. Chaffer, P. I. Turchin, D. A. Elsemore, M. Toth, L.Koetzner, G. T. Whiteside, “Pharmacological and pharmacokinetic characterization of cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy,” Neuropharmacology, Vol. 48, No. 5, 2005, pp. 658-672.
[34]	E. S. Fernandes, G. F. Passos, R. Medeiros, F. M. da Cunha, J. Ferreria, M. M. Campos, L. F. Pianowski, J. B. Calixto, “Anti-inflammatory effects of compounds alpha-humulene and (-)-transcaryophyllene isolated from the essential oil Cordia verbenacea,” European Journal of Phamacology, Vol. 569, No. 3, 2007, pp. 228-236.
[35]	R. Baron, “Mechanisms of disease: neuropathic pain – a clinical perspective,” Nature Clinical Practice Neurology, Vol. 2, No. 2, 2006, pp. 95-106.
[36]	K. Moriwaki, O. Yuge, H. Tanaka, H. Sasaki, H. Izumi, K. Kaneko, “Neuropathic pain and prolonged regional inflammation as two distinct symptomatological components in complex regional pain syndrome with patchy osteo-porosis-a pilot study,” Pain, Vol. 72, No. 1, 1997, pp. 277-282.
[37]	N. Clayton, F.H. Marshall, C. Bountra, C.T. O’Shaughnessy, “CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain,” Pain, Vol. 96, No. 8, 2002, pp. 253-260.
[38]	M. M. Ibrahim, H. Deng, A. Zvonok, D. A. Cockayne, J. Kwan, H. P.Mata, T. W. Vanderah, J. Lai, F. Porreca, A. Makriyannis, T. P. Malan, “Activation of CB2 cannna-binoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS,” Proceedings of the National Academy of Sciences, Vol. 100, No. 18, 2003, pp. 10529-10533.
[39]	A. G. Nackley, A. Makriyannis, A. G. Hohmann, “Selective activation of cannabinoid CB2 receptors suppresses spinal Fos protein expression and pain behavior in a rat model of inflammation,” Neuroscience, Vol. 119, No. 3, 2003, pp. 747-757.
[40]	L. Facci, R. Dal Toso, S. Romanello, A. Buriani, S.D. Skaper, A. Leon, “Mast cells ex-press a peripheral cannabinoid receptor with differential sensi-tivity to anandamide and palmitoylethanolamide,” Proceedings of the National Academy of Sciences, Vol. 92, No. 8, 1995, pp. 3376-3380.
[41]	S. Munro, K. L. Thomas, M. Abu-Sharr, “Molecular characterization of a peripheral receptor for canna-binoids,” Nature, Vol. 365, No. 2, 1993, pp. 61-65.
[42]	G. Griffin, S. R. Fernando, R. A. Ros, N. G. McKay, M. L. Ash-fold, D. Shire, J. W. Huffman, S. Yu, J. A. Kaintin, “Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminal,” European Journal of Phramacology, Vol. 339, No. 1, 1997, pp. 53-61.
[43]	R. G. Pertwee, “Evidence for the presence of CB1 cannabinoid receptors on peripheral neurons and for the existence of neuronal non-CB1 cannabinoid receptors,” Life Sciences, Vol. 65, No. 6-7, 1999, pp. 597-605.
[44]	J. S. Walczak, V. Pichette, F. Leblond, K. Desbiens, P. Beauileu, “Behavioral, pharmacological and molecular characterization of the saphenous nerve partial ligation: a new model of neuropathic pain,” Neuroscience, Vol. 132, No. 4, 2005, pp. 1093-1102.