Combined Treatment with Morphine and  9-Tetrahydrocannabinol in Rhesus Monkeys: Antinociceptive Tolerance and Withdrawal

Abstract

Opioid receptor agonists are effective for treating pain; however, tolerance and dependence can develop with repeated use. Combining opioids with cannabinoids can enhance their analgesic potency, although it is less clear whether combined treatment alters opioid tolerance and dependence. In this study, four monkeys received 3.2 mg/kg morphine alone or in combination with 1 mg/kg D 9 -tetrahydrocannabinol (THC) twice daily; the antinociceptive effects (warm water tail withdrawal) of morphine, the cannabinoid receptor agonists WIN 55,212, and the k opioid receptor agonist U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide methanesulfonate) were examined before, during, and after treatment. To determine whether concurrent THC treatment altered morphine dependence, behavioral signs indicative of withdrawal were monitored when treatment was discontinued. Before treatment, each drug increased tail withdrawal latency to 20 seconds (maximum possible effect). During treatment, latencies did not reach 20 seconds for morphine or the cannabinoids up to doses 3-to 10-fold larger than those that were fully effective before treatment. Rightward and downward shifts in antinociceptive dose-effect curves were greater for monkeys receiving the morphine/THC combination than monkeys receiving morphine alone. When treatment was discontinued, heart rate and directly observable withdrawal signs increased, although they were generally similar in monkeys that received morphine alone or with THC. These results demonstrated that antinociceptive tolerance was greater during treatment with the combination, and although treatment conditions were sufficient to result in the development of dependence on morphine, withdrawal was not markedly altered by concurrent treatment with THC. Thus, THC can enhance some (antinociception, tolerance) but not all (dependence) effects of morphine.

Behavioral Characterization of κ Opioid Receptor Agonist Spiradoline and Cannabinoid Receptor Agonist CP55940 Mixtures in Rats

“…Unlike m opioid receptor agonists, synthetic k opioid receptor agonists are not likely to be abused because they are devoid of positive reinforcing effects Chavkin, 2011;Tejeda et al, 2013;Lalanne et al, 2014). The antinociceptive effects of k opioid receptor agonists are comparable to those of m opioid receptor agonists in various animal models of pain (Desmeules et al, 1993;Binder et al, 2001;Smith et al, 2008;Kivell and Prisinzano, 2010;Gerak and France, 2016); however, doses producing antinociception also produce conditioned place aversion and diuresis (Leander, 1983;Shippenberg and Herz, 1987;Zhang et al, 2005). Significant adverse effects of k opioids that preclude their use in the clinic include dysphoria, hallucinations, and diuresis (Pfeiffer et al, 1986;Peters et al, 1987;Walsh et al, 2001).…”

Impact of synthetic cannabinoids on the duration of opioid‐related withdrawal and craving among patients of addiction clinics in Kazakhstan: A prospective case–control study

“…However, contrasting findings exist; for example, Nava, Manzato, & Lucchini () did not detect significant correlations between chronic cannabis use and heroin withdrawal or craving in patients receiving methadone maintenance therapy, whereas Wasserman, Weinstein, Havassy, & Hall () revealed the acceleration of heroin relapses during cannabinoid consumption in a similar group otic, rather than natural cannabinoids of methadone‐treated patients. For what concerns SCs, one study revealed that SCs can increase mu‐opioids signaling and potentiate opioid antinociceptive effects (Gerak & France, ), which can contribute to explain our study finding of individuals using SCs as an alternative to opioids. The cross‐tolerance of SCs and opioids can lead to coaddictive effects for both classes of substances (Gerak et al, ).…”

“…According to animal studies, the agonistic influence of cannabinoids supports the growth of antinociceptive tolerance as well as it attenuates and modulates morphine withdrawal syndrome (Gerak, Zanettini, Koek, & France, 2015). (Gerak & France, 2016), which can contribute to explain our study finding of individuals using SCs as an alternative to opioids. The cross-tolerance of SCs and opioids can lead to coaddictive effects for both classes of substances (Gerak et al, 2015).…”

Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel

“…The endocannabinoid (eCB) system is a promising target to mitigate pain as an alternative to the opioid system. There is also evidence that there is a synergism between the eCB and the opioid system that reduces the need for high doses of opioids 8 . Hence, it is important to understand the function of eCBs and their metabolites as endogenous and exogenous ligands of the receptors that are involved in pain response modulation.…”

“…Additionally, cannabis has been used for centuries to reduce nociceptive pain either alone or in combination with opioids 8 . The primary components of cannabis interact in the body with cannabinoid receptors 1 and 2 (CB1 and CB2) and other GPCRs [9][10][11] .…”