Contents lists available at ScienceDirect Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr Research report TRPV1 modulates morphine-induced conditioned place preference via p38 MAPK in the nucleus accumbens Sa-Ik Hong a,1 , Thi-Lien Nguyen a,1 , Shi-Xun Ma a , Hyoung-Chun Kim b , Seok-Yong Lee a , Choon-Gon Jang a, ⁎ a Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea b Neurotoxicology Program, College of Pharmacy, Korea Institute of Drug Abuse, Kangwon National University, Chuncheon, 24341, Republic of Korea ARTICLE INFO Keywords: TRPV1 Morphine Conditioned place preference p38 MAPK Nucleus accumbens ABSTRACT Emerging evidence suggests that the transient receptor potential vanilloid type 1 channel (TRPV1) is a novel target for the treatment of drug addiction, such as cocaine and morphine. Previously we reported that TRPV1 inhibition reduced morphine reward in the dorsal striatum (DSt) of mice and morphine self-administration through a decrease in accumbal activity in rats. However, the role of TRPV1 on morphine-conditioned reward in addiction-related brain regions, such as the nucleus accumbens (NAc), has not been previously established. Here, we investigated the effects of TRPV1 on morphine conditioned place preference (CPP) and intracellular me- chanisms of TRPV1 using Western blot analysis and immunohistochemistry (IHC) in morphine-administered mice. TRPV1 knockout mice did not exhibit morphine reward responses, and both i.p. and intra-NAc injections of SB366791, a selective TRPV1 antagonist, reduced morphine-induced CPP in wild-type mice. Furthermore, i.p. injection of SB203580, a selective p38 MAPK inhibitor, also dampened morphine-induced CPP. To determine the molecular mechanisms of the TRPV1/p38 MAPK pathway in morphine CPP, we investigated the expression of adenylyl cyclase type 1 (AC1) and phospho-p38 mitogen-activated protein kinase (MAPK) and nuclear factor- kappa B (NF-κB) in the NAc. Either SB366791 or SB203580 decreased the protein expression levels of phospho- p38 MAPK, phosphor-NF-κB, and AC1 in the NAc of morphine CPP mice. Taken together, our findings suggest that TRPV1 may modulate morphine-induced conditioned reward effects via the p38 MAPK signaling pathway in the NAc. Therefore, blockade of TRPV1 may provide a novel therapeutic approach for the prevention and treatment of opioid addiction. 1. Introduction The transient receptor potential vanilloid type 1 channel (TRPV1), a member of the TRP family, is a cation channel that is activated by capsaicin, heat, and low pH [1]. Although TRPV1 is well-known as a mediator of pain-related neuronal signaling [2,3], emerging evidence suggests that TRPV1 is a novel target that modulates many mental ill- nesses, such as anxiety, depression, and drug addiction [4–6]. TRPV1 is expressed and activated in the brain regions that are closely involved in drug addiction, such as the frontal cortex, hippocampus, ventral teg- mental area, and striatum [5,7,8]. Although the role of TRPV1 is not well understood, several studies recently reported that the TRPV1 an- tagonist SB366791 inhibited the reinstatement of cocaine-seeking behavior in rats and reduced morphine-induced addictive behaviors in mice and rats, while the TRPV1 agonist capsaicin promoted morphine reward [5,9,10]. In addition, the withdrawal duration of morphine- conditioned place preference (CPP) in rats was shortened by intra-nu- cleus accumbens injection of the TRPV1 antagonist capsazepine [11]. However, the mechanisms of TRPV1 in the nucleus accumbens (NAc) during the development of morphine reward remain largely un- determined. Morphine binds to μ-opioid receptors, which are expressed throughout the brain, and a study recently reported that μ-opioid re- ceptor-mRNA was expressed in the NAc [12]. Once morphine binds to μ-opioid receptors in the NAc, GABA release is decreased, which causes an increase in dopamine release [13], thereby activating the morphine http://dx.doi.org/10.1016/j.bbr.2017.07.017 Received 18 April 2017; Received in revised form 21 June 2017; Accepted 17 July 2017 ⁎ Corresponding author at: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea. 1 These authors contributed equally to this work. E-mail address: jang@skku.edu (C.-G. Jang). Abbreviations: AC1, adenylyl cyclase type 1; AC8, adenylyl cyclase type 8; CPP, conditioned place preference; DAB, 3,3′-diaminobenzidine; DSt, dorsal striatum; IHC, im- munohistochemistry; MAPK, mitogen-activated protein kinase; NAc, nucleus accumbens; NF-κB, nuclear factor-kappa B; TBS, Tris-buffered saline; TRPV1, transient receptor potential vanilloid type 1 channel Behavioural Brain Research 334 (2017) 26–33 Available online 19 July 2017 0166-4328/ © 2017 Elsevier B.V. All rights reserved. MARK