Morphine-induced side effects can be differentially modulated by cannabidiol in male and female rats

Opioid use disorder (OUD) is a public health problem that includes symptoms such as withdrawal syndrome and opioid-induced hyperalgesia (OIH). Currently, drugs to treat side effects of opioids also have undesirable effects, which lead to limitations. This study investigated the effect of a treatment with cannabidiol (CBD) in morphine-induced hyperalgesia and withdrawal signs in morphine-dependent rats. Male and female rats were submitted to morphine-induced physical dependence protocol consisting of a twice daily treatment with morphine (7.89 mg/kg, 1ml/kg, s.c.) for 10 days. Nociception was measured using the hot plate test and morphine-induced thermal hyperalgesia was equally achieved following 7-10 days of morphine administration in male and female rats. Repeated treatment with CBD (30 mg/kg) was sufficient to prevent thermal hyperalgesia in male and female rats. Subsequently, rats received an acute administration of naloxone (2 mg/kg. s.c.), 90 minutes after the morphine treatment on day 11, the number of withdrawal signs was scored. Rats that received treatment exclusively with morphine presented significant withdrawal signs compared to control (Water). Morphine-dependent female rats showed a prevalent stereotyped behavior of rearing, whereas male rats had the sign of teeth chattering as the most preeminent. Treatment with CBD on day 11 partially attenuated the withdrawal signs in morphine-dependent male rats, but not female rats. Altogether, our data provide evidence of an anti-hyperalgesic effect of CBD in rats. Male and female rats treated chronically with morphine exhibited withdrawal signs in different ratios, indicating sex-differences in withdrawal behavior and CBD attenuated withdrawal signs in a sex-dependent manner. ### Competing Interest Statement JASC is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE) National Health and Medical Research Council (NHMRC). JASC has received travel support to attend scientific meetings and personal consultation fees from BSPG-Pharm. JASC is a co-inventor of the patent Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023, Def. US number Reg. 62193296; July 29, 2015; INPI on August 19, 2015 (BR1120150164927; Mechoulam R, Zuardi AW, Kapczinski F, Hallak JEC, Guimaraes FS, Crippa JAS, Breuer A). Universidade de Sao Paulo (USP) has licensed this patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1) and has an agreement with Prati-Donaduzzi to develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinsons disease, and anxiety disorders. JASC is a co-inventor of the patent Cannabinoid-containing oral pharmaceutical composition, method for preparing and using same, INPI on September 16th, 2016 (BR 112018005423-2). The other authors declare that they have no conflicts of interest. JASC is a consultant and/or has received speaker fees and/or sits on the advisory board and/or receives research funding from Janssen-Cilag, Torrent Pharm, Prati-Donaduzzi, PurMed Global, and BSPG Pharm over the past 3 years. * 5HT1A : serotonin 1A receptor AMPA : α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ANOVA : analysis of variance CBD : cannabidiol CB1 : cannabinoid receptor type 1 CPP : conditioned place preference MOR : morphine OUD : opioid use disorder OIH : opioid-induced hyperalgesia TRPV1 : transient receptor potential channel subfamily V member 1 Veh : vehicle;