inistration in male rats led to visceral hyperalgesia in response to colorectal distension, accompanied by increased AEA, decreased CB1 expression, and increased TRPV1 expression in dorsal root ganglia. Co-treatment with the corticoid receptor antagonist RU-486 prevented these changes. In summary, preclinical rodent studies indicate that acute glucocorticoid administration enhances the activity of eCBs. The clinical phenomenon of acute “corticosteroid mania”may have a cannabimimetic component. Chronic exposure to glucocorticoids downregulates the eCB system, a scenario consistent with chronic stress, which we review below. Opiates. Naloxone, a m-opioid receptor antagonist, inhibited THC-induced Fos immunoreactivity in several regions of the rat central nervous system, including the ventral tegmental area, hypothalamus, caudate-putamen, and periaqueductal grey. Conversely, naloxone and THC had an additive effect on Fos immunoreactivity in the amygdala, stria terminalis, insular cortex, and paraventricular nucleus of the thalamus. Short-term co-administration of morphine with THC caused an upregulation of CB1 protein in the spinal column of rats, far greater than THC or morphine given alone. A rodent study of chronic but voluntary intake of opiates enhanced CP55,940 binding in the amygdala and ventral tegmental area, plus a marked increase in cannabinoidstimulated GTPcS binding in the nucleus accumbens, caudate putamen, and amygdala. Superperfusion of ex vivo rat nucleus accumbens slices with 4-aminopyridine and NMDA released glutamate and GABA, respectively, and either morphine or the CB1 agonist HU210 predictably inhibited these responses. Combining HU210 and morphine caused a c-Met inhibitor 2 site synergistic inhibition of GABA release, but a non-additive response in glutamate release. Chronic morphine exposure in rats caused a reduction in hippocampal and cerebellar CB1 density measured with CP55,940, and a strong reduction in CP55,940-stimulated GTPcS binding; 2-AG contents were also reduced. Another rat study showed that chronic morphine exposure caused variable, regionally-specific modulations in CP55,940 binding and CB1 mRNA levels; CB1 upregulated in some regions and dowregulated in other PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19632393 regions. In human CB1-transfected HEK293 cells, morphine induced a desensitization of the m-opioid receptor and heterologous desensitization of CB1, demonstrated by a reduction in WIN55212-2-induced i release. mopioid receptor knockout mice showed a dramatic reduction in WIN55212-2-stimulated GTPcS binding. In human SHSY5Y neuroblastoma cells, sequential activation of CB1 and dopioid receptor produced synergistic elevations of intracellular Ca2+, a response that each receptor alone did not trigger in an efficacious way. In behavioral studies, heroin reinstated “drug-seeking”behavior for WIN55,212-2 in rats. Morphine did the same for THC in monkeys. The rewarding effects of THC, measured by conditioned place-preference, were reversed by naloxone in rats. In rats trained to discriminate THC, morphine administration markedly potentiated the THC discriminative PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19632179 stimulus. Morphine or codeine potentiated THC-induced antinociception and analgesia in mice and rats; inactive doses of the drugs in combination produce potent, synergistic analgesia. Synergistic analgesia was confirmed in an isobolographic analysis. Historically this is the first isobolographic analysis of a cannabinoid since the days Walter Siegfried Loewe, who invented the isobologram to test drug combinations f