Low dose combination of morphine and Δ9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors
Introduction
Both opioids and cannabinoids produce analgesia, hypothermia, sedation, hypotension, slowed intestinal motility, immunomodulation and motor depression (Holtzman et al., 1969, Bloom and Dewey, 1978). These effects are mediated by distinct opioid and cannabinoid receptors that are G-protein coupled and primarily activate Gi/Go proteins (Childers, 1991, Howlett et al., 2002). Each receptor system includes multiple receptor subtypes; most clinically relevant analgesic opioids activate mainly mu opioid receptors and the CNS effects of cannabinoids are produced primarily by cannabinoid CB1 receptors. Mu opioid and cannabinoid CB1 receptors modulate a similar profile of effectors, including adenylyl cyclase, cAMP-dependent protein kinase (PKA), mitogen-activated protein kinase (MAPK), and voltage-dependent potassium and calcium channels (Childers, 1991, Howlett et al., 2002). Thus, the major intracellular effects of mu opioid or cannabinoid CB1 receptor activation include decreased calcium and cAMP levels, which leads to inhibition of neurotransmitter release.
Opioids are considered highly effective analgesic agents, whereas clinical use of cannabinoids for treatment of pain remains controversial. A major limitation to the use of opioid analgesics is the development of tolerance and dependence with chronic use (Ellison, 1993). These adaptive changes have also been observed following chronic cannabinoid administration (Sim-Selley, 2003, Lichtman and Martin, 2005). At the cellular level, adaptation of G-protein-coupled receptors to chronic agonist administration occurs in two closely related steps: 1) uncoupling of receptor from G-protein activation (desensitization) and 2) internalization leading to receptor recycling or downregulation (Zhang et al., 1997). Chronic opioid administration produces region-specific desensitization of mu opioid receptors in the brain, with brainstem nuclei showing the greatest response (Noble and Cox, 1996, Sim et al., 1996b, Sim-Selley, 2000). Mu opioid receptor downregulation in brain occurs with certain chronic administration paradigms, but does not appear to be required for mu opioid receptor adaptation following chronic morphine treatment (reviewed in Sim-Selley, 2005). Chronic administration of cannabinoids, such as THC, produces cannabinoid CB1 receptor desensitization and downregulation (reviewed in Sim-Selley, 2003). Although region-specific changes are found in cannabinoid CB1 receptor adaptation, most CNS regions exhibit both responses following chronic cannabinoid treatment.
We have previously reported that simultaneous administration of sub-analgesic doses of morphine and THC in a 1:1 ratio (combination treatment) produces an analgesic effect equal to that of higher doses of either drug alone (Smith et al., 1998, Cichewicz et al., 1999) via a synergistic interaction (Cichewicz and McCarthy, 2003). We hypothesize that administration of the low dose combination of THC and morphine circumvents the development of analgesic tolerance while producing similar analgesic efficacy as a higher dose of morphine or THC alone. The current studies investigated the mechanisms involved in prevention of tolerance to low dose morphine–THC combination by examining receptor-mediated G-protein activity using agonist-stimulated [35S]GTPγS binding. The goal of this study was to characterize the effects of THC, morphine, or the combination of the two drugs on G-protein activation by mu opioid and cannabinoid CB1 receptors. Studies were conducted in membranes prepared from periaqueductal gray or spinal cord because these regions have been implicated in opioid- and cannabinoid-mediated antinociception (Yaksh, 1981, Basbaum and Fields, 1984, Lichtman and Martin, 1991, Lichtman et al., 1996).
Section snippets
Animals
Male Sprague Dawley rats (Harlan Laboratories, Indianapolis IN) weighing approximately 325–350 g were housed two per cage in animal quarters maintained at 22 +/− 2 °C on a 12 h light/dark cycle. Food and water were available ad libitum. The rats were brought to the test room prior to testing and were allowed to acclimate and recover from transport. 8–10 rats were used for each treatment group.
Morphine
Rats were rendered tolerant by subcutaneous (s.c.) implantation of morphine pellets (75 mg). Rats were
Paw withdrawal
Rats were treated chronically with morphine, THC or a low dose combination of the two drugs that produced 80% MPE, as described in Methods, and paw withdrawal thresholds were obtained on days 1, 3, 5, and 7. The results of paw withdrawal testing in high dose morphine-treated rats are shown in Fig. 1A. The rats implanted with 75 mg morphine pellets exhibited significant antinociception compared to the placebo-pellet implanted rats on day 1 (p < 0.001, ANOVA with post-hoc Newman–Keuls test). By day
Discussion
Morphine and THC are effective in producing analgesia, but can produce dose-related side-effects. Moreover, long-term administration of therapeutic doses of either morphine or THC results in the development of tolerance and physical dependence, thus reducing analgesic potency and necessitating the administration of higher drug doses which are associated with increased side-effects. Therefore, low dose combination therapy might offer a safer, more effective alternative than either drug alone by
Acknowledgements
The authors thank Michael P. Cassidy for excellent technical assistance. These studies were supported by USPHS grants DA14277 (LJS), DA107710 (DES) and DA05274 (DES, SPW) from the National Institute on Drug Abuse.
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