Yiguanjian Cataplasm Attenuates Opioid Dependence in a Mouse Model of Naloxone-Induced Opioid Withdrawal Syndrome

EXPERIMENTAL STUDYTOPIC Yiguanjian cataplasm attenuates opioid dependence in a mouse model of naloxone-induced opioid withdrawal syndrome

Gao Shuai, Gao Hong, Fan Yuchen, Zhang Guanghua, Sun Fengkai, Zhao Jing, Li Feng, Yang Yang, Wang Kai aa Gao Shuai, Sun Fengkai, Zhao Jing, Li Feng, Yang Yang, morphine administration on day 3 and subsequent- Department of Hepatology, Qilu Hospital of Shandong Uni- ly removed at the end day 5. On day 6, naloxone (8 versity, jinan 250012, China mg/kg) was intraperitoneally injected to precipi- Gao Hong, Zhang Guanghua, Research Center for Material tate opioid withdrawal syndrome. Behavioral obser- Evidence Identification, Shandong Public Security Bureau, ji- vation was performed in two 30-min phases imme- nan 250012, China Fan Yuchen, Wang Kai, Department of Hepatology, Qilu diately after naloxone injection. Hospital of Shandong University, Jinan 250012, China and Institute of Hepatology, Shandong University, jinan 250012, RESULTS: The YGJ cataplasm significantly and China dose-dependently attenuated morphine-nalox- Supported by Shandong Foundation for Development of one-induced experimental opioid withdrawal, in Science and Technology, China (Research and Development terms of withdrawal severity score and the frequen- of Umbilical Treatment Cataplasm for Drug Rehabilitation, cies of jumping, rearing, forepaw licking, and cir- No. 2009GG10008007) cling behaviors. However, YGJ cataplasm treatment Correspondence to: Prof. Wang Kai, Department of Hepa- did not alter the acute analgesic effect of morphine. tology, Qilu Hospital of Shandong University, Jinan 250012, China; Institute of Hepatology, Shandong University, Jinan CONCLUSION: YGJ cataplasm could attenuate opi- 250012, China. [email protected]; wangdoc2010@163. oid dependence and its associated withdrawal com Telephone: +86-531-82169596 symptoms. Therefore, YGJ cataplasm could serve as Accepted: January 25, 2016 a potential therapy for opioid addiction in the fu- ture.

© 2016 JTCM.T his is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Abstract Key words: Yi Guan Jian; Paste; Morphine; Nalox- OBJECTIVE: To investigate the effect of Yiguanjian one; Opioid dependence (YGJ) cataplasm on the development of opioid dependence in a mouse model of naloxone-induced opioid withdrawal syndrome. INTRODUCTION

METHODS: One hundred Swiss albino mice, of Opioid drugs are used primarily for pain control and can produce a state of euphoria or well-being during equal male to female ratio, were randomly and their use. Owing to these mood-enhancing effects, opi- equally divided into 10 groups. A portion (3 cm2) of oid drugs have become the most commonly abused the backside hair of the mice was removed 1 day psychoactive substances worldwide. Continuous ad- prior to the experiment. Morphine (5 mg/kg) was ministration of opioid drugs can elicit opioid depen- intraperitoneally administered twice daily for 5 dence, while their abrupt withdrawal may result in the days. YGJ cataplasm was prepared and pasted on precipitation of an abstinence syndromes.1 Opioid de- the bare region of the mice immediately before pendence is usually associated with serious medical, le-

JTCM | www. journaltcm. com 464 August 15, 2016 |Volume 36 | Issue 4 | Gao S et al. / Experimental Study gal, social problems, and is associated with comorbid gelicae Sinensis), Maidong (Radix Ophiopogonis Japoni- psychiatric disorders. In 2002, the cost of opioid de- ci), Gouqizi (Fructus Lycii), Dangshen (Radix Codonop- pendence to society was approximately 181 billion US sis) and Baizhu (Rhizoma Atractylodis Macrocephalae). dollars.2 All crude herbs were the products of Jianlian TCM Until now, several approaches have been proposed for Co., Ltd. (Jinan, China).7 The herbs were chopped the management of opioid dependence. Opioid replace- finely and extracted twice with 10-fold 75% ethanol ment therapy is an effective method in preventing (Tianjin Guangcheng Chemical Reagent Co., Ltd., acute withdrawal and maintaining long-term absti- Tianjin, China) under reflux. The 75% ethanol extract nence; however, acceptance of this therapy has been was then filtered through absorbent gauze, and the fil- rather slow.3 Other treatment approaches, such as the trate was concentrated under reduced pressure to re- administration of 2-adrenergic agonists, were also ex- move the ethanol and produce the dried extract pow- amined in previousα studies.4 Unfortunately, none of der. Then, the extract powder, artificial moschus (Bei- these therapies have promised to conclusively treat opi- jing Lianxin Pharmaceutic Co., Ltd., Beijing, China), oid dependence and its related abstinence syndromes. emodin (Shanghai Yantuo Biosciences Co., Ltd., Therefore, new approaches for the management of opi- Shanghai, China) and borneol (Hebei Jinmu Pharma- oid dependence are urgently needed. ceutic Group Co., Ltd., Hebei, China) were mixed in- Traditional Chinese Medicine (TCM) has been applied to a cream with excipients, including plasdone K-90, in medical care throughout East Asia for thousands of polyplasdone XL-10, and viscomate NP700 (Guang- years.5,6 Although the active ingredients in most mixed zhou Biours Biosciences Co., Ltd., Guangzhou, Chi- herbal formulas/medications have not been fully identi- na), according to the requirements of the medicinal fied, it has been widely recognized that synergism paste detailed in the Pharmacopoeia of the People's Re- among all components within the prescription is an im- public of China.17 The cream was then coated onto rub- portant characteristic.7,8 The Yiguanjian recipe (YGJ) is berized fabric with herb extract powders at a concentra- a traditional Chinese herbal formula that possesses the tion of 1 mg/cm2 and the resulting plaster was cut into medical function of nourishing liver-Yin and dispers- 1 cm2, 2 cm2 and 3 cm2 pieces, which were stored in ing stagnated liver-Qi. It has been widely used in Chi- desiccators until use.18 The procedure generally corre- na for the treatment of diseases with liver-Yin deficien- sponded to the pharmaceutical quality standards cur- cy.9-11 We found that liver-Yin deficiency was a com- rently under the guidance of pharmaceutical experts mon clinical syndrome of TCM in opioid dependence from Qilu Hospital of Shandong University. The man- in clinical examinations. Therefore, we examined the ufacturing procedure of placebo cataplasm was the use of YGJ for the treatment of opioid dependence and same as that of YGJ cataplasm. The placebo cataplasm showed good effect. contained all of the excipients that were used in YGJ Transdermal drug delivery refers to the topical applica- cataplasm without the herb extracts. tion of drugs to healthy intact skin, either for localized treatment or systemic therapy.12 The potential of skin Animals to serve as a pathway for drug administration has al- One hundred Swiss albino mice of specific patho- ready been demonstrated previously.13 Compared with gen-free grade (50 males and 50 females), aged 7 weeks conventional drug administration routes, the transder- old, weighing (25 ± 2) g, were used in this study. The mal drug delivery system (TDDS) has several addition- mice were obtained from the Laboratory Animal Cen- al advantages. It can maintain constant drug levels in ter of Shandong University (Certificate of quality num- the blood, while minimizing first-pass metabolism asso- ber: SCXK [Lu] 20090001). The mice were fed on ciated with gastro-intestinal administration of standard laboratory diet and tap water and were drugs.14-16 It is more convenient and has increased pa- housed in the Laboratory Animal Center of Shandong tient compliance compared with oral administration University. The mice were divided into 10 groups us- routes. To date, the transdermal drug delivery of tradi- ing a random number table method. The experiments tional herbal medicine has been used to treat many dis- were conducted in a semi-soundproof laboratory. The eases.17 mice were exposed to a 12 h/12 h light/dark cycle, In this study, we established a mouse model of nalox- with the light period between 08：00 to 20：00 h. Be- one-induced opioid withdrawal syndrome and ana- haviors were observed using a 30 cm3 large transparent lyzed the effectiveness of YGJ cataplasm in treating opi- Perspex observation chamber. Two observers who were oid dependence. blind to the treatment schedule simultaneously observed the withdrawal measurements. The mean value of both observations was recorded. The experimental MATERIALS AND METHODS protocol was performed in accordance with the Institu- tional Animal Ethics Committee. The study was ap- Preparation of YGJ cataplasm proved by the local Research and Ethics Committee at The YGJ formula consists of Dihuang (Radix Rehman- Qilu Hospital of Shandong University, in accordance niae), Beishashen (Radix Glehniae), Danggui (Radix An- with the guidelines of the 1975 Declaration of Helsinki.

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