Viganò Daniela, Rubino Tiziana, Vaccani Angelo, Bianchessi Silvia, Marmorato Patrick, Castiglioni Chiara, Parolaro Daniela
DBSF, Pharmacology Section and Neuroscience Center, University of Insubria, via A. da Giussano 10, 21052, Busto Arsizio, VA, Italy.
Psychopharmacology (Berl). 2005 Nov;182(4):527-36. doi: 10.1007/s00213-005-0114-4. Epub 2005 Oct 19.
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.
这项工作的目的是研究大麻素和阿片类系统在急性和慢性暴露期间镇痛的交叉调制机制。急性联合给予无效的亚镇痛剂量的合成大麻素CP-55,940（0.2mg/kg腹腔注射）和吗啡（2.5mg/kg腹腔注射）导致显著的抗伤害感受作用。在慢性研究中，低剂量的CP-55,940（0.2mg/kg，腹腔注射）本身在未用药的动物中不会诱导镇痛作用，但在对吗啡产生耐受性的大鼠中产生了显著程度的抗伤害感受作用，而在对CP-55,940产生耐受性的大鼠中，吗啡激发并未产生任何镇痛反应。为了确定慢性治疗期间这些不对称相互作用的机制，我们研究了大麻素和μ阿片受体的功能活性及其对环磷酸腺苷（cAMP）级联反应的影响。放射自显影结合研究表明，吗啡耐受大鼠海马和小脑中大麻素受体水平略有但显著降低，而CP-55,940刺激的[35S]GTPγS结合显示边缘区域受体/G蛋白偶联显著减少。在CP-55,940暴露的大鼠中，外侧丘脑和导水管周围灰质（PAG）中的μ阿片受体结合显著升高，伏隔核中DAMGO刺激的[35S]GTPγS结合增加。最后，我们测试了纹状体和中脑背侧cAMP系统对大麻素和阿片类药物的反应性。体内慢性吗啡不影响CP-55,940在体外抑制福司可林刺激的cAMP产生的能力，实际上还诱导了纹状体膜致敏。相反，体内慢性CP-55,940降低了DAMGO在体外抑制福司可林刺激的cAMP产生的功效。cAMP系统的改变似乎反映了行为反应，表明这两个系统可能在受体后水平相互作用。这可能为通过联合使用大麻素和阿片类药物缓解慢性疼痛开辟新的治疗机会。
