Modulation of Oral Morphine Antinociceptive Tolerance and Naloxone-Precipitated Withdrawal Signs by Oral Δ⁹-Tetrahydrocannabinol

Abstract

Previous studies have demonstrated a functional interaction between cannabinoid and opioid systems in the development and expression of morphine tolerance and dependence. In these experiments, we examined the effect of a low oral dose of ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC) on the development of oral morphine tolerance and the expression of naloxone-precipitated morphine withdrawal signs of jumping and diarrhea in ICR mice. Chronic treatment with high-dose oral morphine produced a 3.12-fold antinociceptive tolerance. Tolerance to morphine was prevented in groups receiving a daily cotreatment with a nonanalgetic dose (20 mg/kg p.o.) of ⌬ 9 -THC, except when challenged with a very high dose of morphine. The chronic coadministration of low-dose ⌬ 9 -THC also reduced naloxone-precipitated (1 mg/kg s.c.) platform jumping by 50% but did not reduce diarrhea. In separate experiments, mice treated chronically with high-dose morphine p.o. were not cross-tolerant to ⌬ 9 -THC; in fact, these morphine-tolerant mice were more sensitive to the acute antinociceptive effects of ⌬ 9 -THC. ⌬ 9 -THC (20 mg/kg p.o.) also reduced naloxone-precipitated jumping but not diarrhea when administered acutely to morphine-tolerant mice. These results represent the first evidence that oral morphine tolerance and dependence can be circumvented by coadministration of a nonanalgetic dose of ⌬ 9 -THC p.o. In summary, cotreatment with a combination of morphine and ⌬ 9 -THC may prove clinically beneficial in that long-term morphine efficacy is maintained.The clinical use of morphine for long periods of time is limited by its propensity to cause tolerance and physical dependence after repeated administration. To overcome tolerance to the analgesic effects of morphine, higher doses are necessary for adequate pain relief but are often accompanied by undesirable side effects such as constipation, nausea, and respiratory depression (Ellison, 1993). Morphine tolerance has been developed in rodent models using subcutaneously implanted morphine pellets (Cicero and Meyer, 1973;Bhargava, 1978), but little is known about tolerance to oral doses of morphine in mice. Mao et al. (1996) observed a decrease in antinociception produced by oral morphine in rats as measured by the tail-flick test over a period of several days.Our laboratory and others have shown that combinations of cannabinoids with morphine profoundly enhance morphine-induced analgesia. ⌬ 9 -THC at a nonanalgetic dose administered p.o. to mice significantly enhances the potency of opioids such as morphine and codeine (Smith et al., 1998;Cichewicz et al., 1999). This enhancement is theorized to be due to a combination of morphine's direct effects on the -opioid receptor and the effect of endogenous opioids whose release is stimulated by ⌬ 9 -THC (Smith et al., 1994;Pugh et al., 1996). In addition, the CB1 cannabinoid receptor and -opioid receptor have been found to be colocalized in areas important for the expression of morphine abstinence: nucleus accumbens, septum, striatum, periaqueductal ...

The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model

“…However, the present study did not assess the full dose-response relationship of these drugs in combination to infer whether these drugs offer protection against one another's side effects. Interestingly, other studies demonstrated that THC, as well as fatty acid amide hydrolase inhibitors and MAGL inhibitors, block opioid withdrawal somatic signs (Cichewicz and Welch, 2003;Ramesh et al, 2011Ramesh et al, , 2013. The present results suggest that a low dose of MJN110 and morphine in combination produced enhanced antinociception, while decreasing the likelihood of at least some untoward side effects.…”

“…In current times, preclinical studies have established that the combination of opiates and cannabinoids produce enhanced antinociceptive effects. Coadministration of the primary psychoactive component of marijuana, D 9 -tetrahydrocannabinol (THC) (Gaoni and Mechoulam, 1964), and morphine produces synergistic antinociceptive effects in acute pain tests (Cichewicz and Welch, 2003) and in the rat Freund's complete adjuvantinduced arthritic model (Cox et al, 2007). Additionally, the potent synthetic cannabinoid receptor agonist CP55,940 produces a leftward shift of the morphine dose response curve in the acetic acid abdominal stretching pain assay (Miller et al, 2012).…”

“…Since significant untoward side effects associated with opioids and cannabinoids could limit therapeutic utility when given in combination, we examined the consequences of dual administration of morphine and MJN110 on gastric motility, to infer opioid-induced constipation (Ross et al, 2008) and cannabimimetic interoceptive effects in mice trained to discriminate the potent cannabinoid receptor agonist CP55,940 from vehicle in the drug discrimination paradigm Walentiny et al, 2013;Ignatowska-Jankowska et al, 2014). Additionally, because the antinociceptive effects of morphine (Cichewicz and Welch, 2003;Smith et al, 2007) and MAGL inhibitors (Schlosburg et al, 2010) undergo tolerance after repeated administration, we examined the consequences of repeated injections of MJN110 and morphine given in combination in the CCI model of neuropathic pain. Finally, we quantified levels of endocannabinoids in brain and spinal cord following acute or repeated administration of the combination of morphine and MJN110 in mice subjected to CCI.…”

Peripheral cannabinoids attenuate carcinoma-induced nociception in mice

“…Cannabinoids also potentiate the analgesic effects of morphine and prevent tolerance. [4,5] These desirable effects of cannabinoids show promise for management of cancer pain and may lead to improved analgesic therapy. Mean percent change in paw withdrawal threshold relative to baseline reading prior to SCC or sham inoculation.…”

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

“…For example, the antinociceptive potency of cannabinoids is decreased in morphine-tolerant monkeys (Gerak et al, 2015) and in some morphine-tolerant rats (Basilico et al, 1999;Yesilyurt and Dogrul, 2004;Maguma and Taylor, 2011). When opioids and cannabinoids are combined, tolerance and cross-tolerance might develop concurrently and produce a greater decrease in antinociceptive potency than would be observed when either drug is given alone; however, some studies in rodents receiving morphine and cannabinoids concurrently report that antinociceptive tolerance is not greater for the combination (Cichewicz and Welch, 2003;Smith et al, 2007;Fischer et al, 2010). The goal of the current study was to determine whether THC alters tolerance to and dependence on morphine in monkeys.…”