title: Repetitive Acupuncture Point Treatment with Diluted Bee Venom Relieves Mechanical Allodynia and Restores Intraepidermal Nerve Fiber Loss in Oxaliplatin-Induced Neuropathic Mice.
abstract: The chemotherapeutic agent, oxaliplatin, produces a robust painful neuropathy that results in the loss of intraepidermal nerve fibers (IENFs). We have previously reported that an acupuncture point (acupoint) injection of diluted bee venom (DBV) produces a temporary antiallodynic effect in oxaliplatin-induced neuropathic mice. Herein we show a significant long-lasting antinociceptive effect of repetitive DBV acupoint treatment on oxaliplatin-induced mechanical allodynia and a significant reduction in the loss of IENFs. DBV (0.1 mg/kg, subcutaneous) was administered once a day for 18 days beginning on day 15 after oxaliplatin injection. Immunohistochemistry for IENF was performed on the glabrous skin of the hind paw footpad using the pan-neuronal marker, protein gene product 9.5. A temporary increase in mechanical threshold was observed 60 minutes after a single DBV injection into the Zusanli acupoint, and this effect was enhanced over time with repetitive DBV treatments. The basal mechanical threshold before daily DBV injection also increased from day 7 after DBV injections, and peaked at day 14 after DBV treatment. Moreover, the oxaliplatin-induced loss of IENFs was significantly reduced in mice treated repetitively with DBV. Repetitive pretreatment with the α-2 adrenoceptor antagonist, yohimbine, (5 mg/kg, subcutaneous) completely prevented the antiallodynic effects and the increase in IENFs observed in mice treated repetitively with DBV.
  
  
  CONCLUSIONS
  We showed that repetitive acupoint stimulation with DBV gradually and significantly reduced oxaliplatin-induced mechanical allodynia and restored the loss of IENFs in neuropathic mice via an α-2 adrenoceptor mechanism. Collectively, results of this study suggest that repetitive acupoint treatment with DBV can be a potential strategy for the management of chemotherapy-induced neuropathy.
authors.affiliation: Department of Oral Physiology and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Ji-Hee
authors.initials: JH
authors.lastname: Yeo
authors.affiliation: Department of Brain and Cognitive Sciences College of Natural Sciences, Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seo-Yeon
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Department of Oral Physiology and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Soon-Keun
authors.initials: SK
authors.lastname: Kwon
authors.affiliation: Department of Oral Physiology and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Sol-Ji
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jang-Hern
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota.
authors.forename: Alvin J
authors.initials: AJ
authors.lastname: Beitz
authors.affiliation: Department of Oral Physiology and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea. Electronic address: dhroh@khu.ac.kr.
authors.forename: Dae-Hyun
authors.initials: DH
authors.lastname: Roh
mesh_terms: D015669:Acupuncture Points; D015670:Acupuncture Therapy / Q000379:methods*; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D001514:Bee Venoms / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004817:Epidermis / Q000187:drug effects / Q000294:innervation / Q000473:pathology; D005528:Foot / Q000294:innervation / Q000473:pathology; D006930:Hyperalgesia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000473:pathology*; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010146:Pain / Q000473:pathology / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D011897:Random Allocation; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D014110:Touch; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000700:Analgesics; D001514:Bee Venoms; D009944:Organoplatinum Compounds; D018341:Receptors, Adrenergic, alpha-2; D000077150:Oxaliplatin; D015016:Yohimbine
keywords: Bee venom; intraepidermal nerve fibers; mechanical allodynia; oxaliplatin; α-2 adrenoceptors