Molecular mechanisms involved in the asymmetric interaction between cannabinoid and opioid systems

Abstract

The aim of this work was to study the mechanism of cross-modulation between cannabinoid and opioid systems for analgesia during acute and chronic exposure. Acute coadministration of ineffectual subanalgesic doses of the synthetic cannabinoid CP-55,940 (0.2 mg/kg i.p.) and morphine (2.5 mg/kg i.p.) resulted in significant antinociception. In chronic studies, a low dose of CP-55,940 (0.2 mg/kg, i.p.) that per se did not induce analgesia in naive animals produced a significant degree of antinociception in rats made tolerant to morphine, whereas in rats made tolerant to CP-55,940, morphine challenge did not produce any analgesic response. To identify the mechanism of these asymmetric interactions during chronic treatment, we investigated the functional activity of cannabinoid and mu opioid receptors and their effects on the cyclic AMP (cAMP) cascade. Autoradiographic-binding studies indicated a slight but significant reduction in cannabinoid receptor levels in the hippocampus and cerebellum of morphine-tolerant rats, whereas CP-55,940-stimulated [35S]GTPgammaS binding showed a significant decrease in receptor/G protein coupling in the limbic area. In CP-55,940 exposed rats, mu opioid receptor binding was significantly raised in the lateral thalamus and periaqueductal gray (PAG), with an increase in DAMGO-stimulated [35S]GTPgammaS binding in the nucleus accumbens. Finally, we tested the cAMP system's responsiveness to the cannabinoid and opioid in the striatum and dorsal mesencephalon. In vivo chronic morphine did not affect CP-55,940's ability to inhibit forskolin-stimulated cAMP production in vitro and actually induced sensitization in striatal membranes. In contrast, in vivo chronic CP-55,940 desensitized DAMGO's efficacy in inhibiting forskolin-stimulated cAMP production in vitro. The alterations to the cAMP system seem to mirror the behavioral responses, indicating that the two systems may interact at the postreceptor level. This might open up new therapeutic opportunities for relief of chronic pain through cannabinoid-opioid coadministration.

Prior Exposure to THC Increases the Addictive Effects of Nicotine in Rats

“…In animals, subchronic THC exposure can decrease the density and expression of cannabinoid CB 1 receptors in many areas of the brain, and pharmacodynamic changes such as these underlie tolerance to cannabinoids (Maldonado, 2002). Behavioral sensitization induced by repeated acute exposure to cannabinoid agonists is associated with increased intracellular activation of CB 1 receptors in the caudate putamen and cerebellum (Rubino et al, 2003; see also Rubino et al, 2004), increased m-opioid receptor binding in the lateral thalamus and periaqueductal gray (PAG), and increased intracellular activation of m-opioid receptors in the nucleus accumbens (Viganò et al, 2005). Using a THC pre-exposure regimen that increases heroin intake in rats under an FR1 schedule, Ellgren et al (2007Ellgren et al ( , 2008 found lasting alterations of both the cannabinoid and opioid systems in rats exposed to THC during adolescence.…”

Low-pressure water vapour plasma treatment of surfaces for biomolecules decontamination

“…An integrated horizontal CCD camera allowed controlling drop volumes for determining the deposited protein amounts. BrH stock was prepared according to the method described in Viganò et al [29] and stored at −20 • C. Aliquots from the stock were thawed and used for suspensions preparation right before the microspotting.…”

Knockout of the mu opioid receptor enhances the survival of adult-generated hippocampal granule cell neurons

“…E-mail: amelia.eisch@utsouthwestern.edu.1995, Uhl et al, 1999, Kreek et al, 2005. However, recent evidence points to a more novel role for MOR: regulating hippocampal structure and function (Morris and Johnston, 1995, Martinez and Derrick, 1996, Terman et al, 2000, Kearns et al, 2001, Harrison et al, 2002, Guo et al, 2005, Vigano et al, 2005a, Vigano et al, 2005b. MOR is expressed on interneurons and primary cell types in all hippocampal regions (Meibach and Maayani, 1980, Arvidsson et al, 1995, Mansour et al, 1995, Svoboda et al, 1999, Drake and Milner, 2002, including in the granule cell layer (GCL) of the dentate gyrus.…”