Alleviation of capsaicin-induced mechanical allodynia by Arbutus andrachne L. methanolic leaf extract in male rats

Sahar Jaffal, Sawsan Oran, Mohammad Alsalem



Sahar Jaffal


Sawsan Oran

Mohammad Alsalem



Pain is one of the major health problems that impose huge social and economic burdens all over the world. Mechanical allodynia is a symptom of pain defined as a painful sensation resulting from innocuous stimuli such as touch. Currently available drugs have several side effects urging the need for new natural sources that alleviate mechanical allodynia. This study investigated the effect of Arbutus andrachne L. (a medicinal plant growing in Jordan) on capsaicin (Caps)-induced mechanical allodynia in male rats and the mechanism that underlie its effect. Caps injection decreased paw withdrawal threshold (PWT) significantly compared to control group. Mechanical allodynia was detected 30, 90 and 150 min after Caps injection to the plantar surface of the left hind paw of rats. The intraplantar (ipl) injection of 100 µg (but not 50 or 200 µg) of A. andrachne extract, ipsilaterally, prior to Caps injection increased PWT at all-time points similar to the anti-nociceptive effect in the positive group that was treated with 2.5% diclofenac sodium prior to Caps injection. The ipsilateral pre-treatment with the antagonists of transient receptor potential vanilloid-1 (TRPV1), cannabinoid receptor 1 (CB1) and peroxisome proliferator-activated receptor alpha (PPARα) reversed the activity of the leaf extract in contrast to the antagonists of PPARγ and α2-adrenergic receptors. In all groups, no effect was detected on the contralateral hind paw of animals at any time point. In conclusion, A. andrachne can be exploited as an anti-nociceptive agent.



Arbutus andrachne, TRPV1, mechanical allodynia, PPAR, CB1, α2-adrenergic

Full Text:



Abbas, M. A. (2020). Modulation of TRPV1 channel function by natural products in the treatment of pain. Chemico-Biological Interactions. 330, 109178.

Ahluwalia, J., Urban, L., Bevan, S. & Nagy, I. (2003). Anandamide regulates neuropeptide release from capsaicin-sensitive primary sensory neurons by activating both the cannabinoid 1 receptor and the vanilloid receptor 1 in vitro. European Journal of Neuroscience. 17, 2611−2618.

Al-Eisawi, D. M. (1998). Field guide to wild flowers of Jordan and neighbouring countries. D.M.H, Amman, Jordan.

Alsalem, M., Altarifi, A., Haddad, M., Azab, B., Kalbouneh, H., Imraish, A., Saleh, T., & El-Salem, K. (2020). Analgesic effects and impairment in locomotor activity induced by cannabinoid/Opioid combinations in rat models of chronic pain. Brain Sciences. 10(8), 523.

Alsalem, M., Altarifi, A., Kalbouneh, H., Al- Zer, H., Azab, B. & El- Salem, K. (2016). Role of PPARα and PPARγ in Mediating the Analgesic Properties of Ibuprofen in vivo and the Effects of Dual PPARα/γ Activation in Inflammatory Pain Model in the Rat. International Journal of Pharmacology. 12, 812-820.

Alsalem, M., Haddad, M., Aldossary, S., Kalbouneh, H., Azab, B., Dweik, A., Imraish, A. & El-Salem, K. (2019). Effects of dual peroxisome proliferator-activated receptors α and γ activation in two rat models of neuropathic pain. PPAR Research. 2019, 1-9.

Ambrosino, P., Soldovieri, M.V., De Maria, M., Russo, C. & Taglialatela, M. (2014). Functional and biochemical interaction between PPARα receptors and TRPV1 channels: Potential role in PPARα agonists-mediated analgesia. Pharmacological Research. 87, 113-122.

An, S. S., Kim, Y. O., Park, C. H., Lin, H. and Yoon, M. H. (2014). Antiallodynic effect of intrathecal epigallocatechin-3-gallate due to suppression of reactive oxygen species. Korean Journal of Anesthesiology. 67(2), 123.

Andersen, M. E. (1981). Saturable metabolism and its relationship to toxicity. Critical Reviews in Toxicology. 9(2), 105-150.

Azevedo, M. I., Pereira, A. F., Nogueira, R. B., Rolim, F. E., Brito, G. A., Wong, D. V., Lima-Júnior, R. C., De Albuquerque Ribeiro, R. and Vale, M. L. (2013), The antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin-induced chronic painful peripheral neuropathy. Molecular Pain, 9, 53.

Benarroch, E. E. (2016). Dorsal horn circuitry: Complexity and implications for mechanisms of neuropathic pain. Neurology. 86(11), 1060-1069.

Bhat, R. A., Lingaraju, M. C., Pathak, N. N., Kalra, J., Kumar, D., Kumar, D. and Tandan, S. K. (2016). Effect of ursolic acid in attenuating chronic constriction injury-induced neuropathic pain in rats. Fundamental and Clinical Pharmacology. 30(6), 517–528.

Brandt, M. R., Beyer, C.E. & Stahl, S.M. (2012). TRPV1 Antagonists and chronic pain: Beyond thermal perception. Pharmaceuticals. 5, 114-132.

Brooks, J. & Tracey, I. (2005). From nociception to pain perception, imaging the spinal and supraspinal pathways. Journal of Anatomy. 207(1), 19-33.

Caterina, M.J. (2014). TRP Channel Cannabinoid Receptors in Skin Sensation, Homeostasis, and Inflammation. ACS Chemical Neuroscience. 5(11), 1107–1116.

Caterina, M. J. & Julius, D. (2001). The vanilloid receptor: a molecular gateway to the pain pathway. Annual Review of Neuroscience. 24, 487−517.

Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T.A., Levine, J.D. & Julius, D. (1997). The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 389(6653), 816.

Dessaint, J., Yu, W., Krause, J.E. & Yue, L. (2004). Yohimbine inhibits firing activities of rat dorsal root ganglion neurons by blocking Na+ channels and vanilloid VR1 receptors. European Journal of Pharmacology. 485(1-3), 11-20.

Engel, M. A., Izydorczyk, I., Mueller-Tribbensee, S.M., Becker, C., Neurath, M.F. & Reeh, P.W. (2011). Inhibitory CB1 and activating/ desensitizing TRPV1-mediated cannabinoid actions on CGRP release in rodent skin. Neuropeptide. 45, 229−237.

Ferrier, J., Marchand F., Balayssac D. & Chu, H.U. (2016). Assessment of Mechanical Allodynia in Rats Using the Electronic Von Frey Test. Bio-protocol. 6(18).

Filippi, A., Caruntu, C., Gheorghe, R., Deftu, A., Amuzescu, B. & Ristoiu, V. (2016). Catecholamines reduce transient receptor potential vanilloid type 1 desensitization in cultured dorsal root ganglia neurons. Journal of Physiology and Pharmacology: an official journal of the Polish Physiological Society. 67(6), 843-850.

Gilchrist, H. D., Allard, B.L. & Simone, D.A. (1996). Enhanced withdrawal responses to heat and mechanical stimuli following intraplantar injection of capsaicin in rats. Pain. 67(1), 179-188.

Greenspon, C. M., Battell, E. E., Devonshire, I. M., Donaldson, L. F., Chapman, V. and Hathway, G. J. (2019). Lamina-specific population encoding of cutaneous signals in the spinal dorsal horn using multi-electrode arrays. The Journal of physiology. 597(2), 377–397.

Ibrahim, M. M., Porreca, F., Lai, J., Albrecht, P.J., Rice, F.L., Khodorova, A., Davar, G., Makriyannis, A., Vanderah, T.W., Mata, H.P. & Malan, T.P. (2005). CB2 Cannabinoid Receptor Activation Produces Antinociception by Stimulating Peripheral Release of Endogenous Opioids. Proceedings of the National Academy of Sciences of the United States of America. 102(8), 3093-3098.

Jaffal S. M., Oran S.A. & Alsalem M. (2020). Anti-nociceptive effect of Arbutus andrachne L. methanolic leaf extract mediated by CB1, TRPV1 and PPARs in mouse pain models. Inflammopharmacology. 37, 189-195.

Jaffal S.M., Oran S.A. & Alsalem M (2021). Anti-inflammatory and antipyretic potential of Arbutus andrachne L. methanolic leaf extract in rats. Asian Pacific Journal of Tropical Biomedicine. 11(11), 491-499.

Jara-Oseguera, A., Simon, S.A. & Rosenbaum, T. (2008). TRPV1: On the Road to Pain Relief. Current Molecular Pharmacology. 1(3), 255-269.

Kishore, L., Kaur, N. and Singh, R. (2018). Effect of Kaempferol isolated from seeds of Eruca sativa on changes of pain sensitivity in Streptozotocin-induced diabetic neuropathy. Inflammopharmacology. 26(4), 993-1003.

Kuwahata, H., Komatsu, T., Katsuyama, S., Corasaniti, M. T., Bagetta, G., Sakurada, S., Sakurada, T. and Takahama, K. (2013). Peripherally injected linalool and bergamot essential oil attenuate mechanical allodynia via inhibiting spinal ERK phosphorylation. Pharmacology Biochemistry and Behavior. 103(4), 735–741.

Lee , H. G., Choi, J.I., Kim, Y.O., Yoon, M.H. (2013). The Role of alpha-2 Adrenoceptor Subtype in the Antiallodynic Effect of Intraplantar Dexmedetomidine in a Rat Spinal Nerve Ligation Model. Neuroscience Letter. 557, Pt B,118-122.

Litwack, G. (2013). Anandamide an Endogenous Cannabinoid. Academic Press, London, United Kingdom.

Liu, D., Zhou, Y., Tian, Y. and Ye, D. (2018). Quercetin, a bioflavonoid, attenuates mechanical allodynia in a rat model of cancer-induced bone pain via suppressing the PI3Kγ/Akt signaling pathway. The Journal of Pain. 19(3), S77.

Matsushita, Y., Manabe, M., Kitamura, N. & Shibuya, I. (2018). Adrenergic receptors inhibit TRPV1 activity in the dorsal root ganglion neurons of rats. PloS one. 13(1), e0191032.

Meotti F. C., Missau, F. C., Ferreira, J., Pizzolatti, M. G., Mizuzaki, C., Nogueira, C. W. and Santos, A. R. S. (2006). Anti-allodynic property of flavonoid myricitrin in models of persistent inflammatory and neuropathic pain in mice. Biochemical Pharmacology. 72(12), 1707–1713.

Nozadze, I., Tsiklauri, N., Gurtskaia, G. & Tsagareli, M.G. (2016). NSAIDs attenuate hyperalgesia induced by TRP channel activation. Data in Brief. 6, 668-673.

Oran, S.A. (2014). The status of medicinal plants in Jordan. Journal of Agricultural Science and Technology. 4, 461-467.

Oran, S. A. (2015). Flora of Bader Al-Jadida County, western high mountains of Amman city/Jordan. International Journal of Herbal Medicine. 3, 49-59.

O'Sullivan, S. (2016). An update on peroxisome proliferator-activated receptor (PPAR) activation by cannabinoids. British Journal of Pharmacology. 173, 1899-1910.

Pandey, A. & Tripathi, S.M. (2014). Concept of standardization, extraction and pre phytochemical screening strategies for herbal drug. Journal of Pharmacognosy and Phytochemistry. 2(5), 115-119.

Resham, K., Khare, P., Bishnoi, M. and Sharma, S. S. (2020). Neuroprotective effects of isoquercitrin in diabetic neuropathy via Wnt/β‐catenin signaling pathway inhibition. BioFactors. 46(3), 411–420.

Sagar, D. R., Smith, P.A., Millns, P.J., Smart, D., Kendall, D.A. & Chapman, V. (2004). TRPV1 and CB(1) receptor-mediated effects of the endovanilloid/endocannabinoid N-arachidonoyl-dopamine on primary afferent fibre and spinal cord neuronal responses in the rat. The European Journal of Neuroscience. 20, 175-184.

Shi, Q., Cai, X., Li, C., Wang, Z. and Lv, X. (2019). Conjugated linoleic acid attenuates neuropathic pain induced by sciatic nerve in mice. The Tropical Journal of Pharmaceutical Research.18(9),1895-1901.

Tenuta, M., Tundis, R., Xiao, J., Loizzo, M., Dugay, A. & Deguin, B. (2018). Arbutus species (Ericaceae) as source of valuable bioactive products. Critical Reviews in Food Science and Nutrition. 59, 1-18.

Tiwari, V., Kuhad, A. and Chopra, K. (2009). Tocotrienol ameliorates behavioral and biochemical alterations in the rat model of alcoholic neuropathy. Pain. 145(1), 129–135.

Trevisan, G., Rossato, M. F., Tonello, R., Hoffmeister, C., Klafke, J. Z., Rosa, F., Pinheiro, K. V., Pinheiro, F. V., Boligon, A. A., Athayde, M. L. & Ferreira, J. (2014). Gallic acid functions as a TRPA1 antagonist with relevant antinociceptive and antiedematogenic effects in mice. Naunyn-Schmiedeberg’s Archives of Pharmacology. 387(7), 679–689.


  • There are currently no refbacks.

Published by