Molecular mechanisms involved in the asymmetric interaction between cannabinoid and opioid systems |
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Authors: | Daniela?Viganò Tiziana?Rubino Angelo?Vaccani Silvia?Bianchessi Patrick?Marmorato Chiara?Castiglioni Email author" target="_blank">Daniela?ParolaroEmail author |
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Affiliation: | (1) DBSF, Pharmacology Section and Neuroscience Center, University of Insubria, via A. da Giussano 10, 21052 Busto Arsizio, VA, Italy |
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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 μ 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]GTPγS binding showed a significant decrease in receptor/G protein coupling in the limbic area. In CP-55,940 exposed rats,
μ opioid receptor binding was significantly raised in the lateral thalamus and periaqueductal gray (PAG), with an increase
in DAMGO-stimulated 35S]GTPγS 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. |
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Keywords: | Opioids Cannabinoids Interaction Binding cAMP pathway |
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