Individuals infected with human immunodeficiency virus-1 who abuse opiates can have a higher incidence of virus-associated neuropathology. Human immunodeficiency virus does not infect neurons, but viral proteins such as transactivator of transcription and glycoprotein 120, originating from infected glia, are neurotoxic. Moreover, functional changes in glial cells that enhance inflammation and reduce trophic support are increasingly implicated in human immunodeficiency virus neuropathology. In previous studies, co-exposure with morphine enhanced transactivator of transcription neurotoxicity towards cultured striatal neurons. Since those cultures contained µ-opioid receptor-expressing astroglia and microglia, and since glia are the principal site of infection in the central nervous system, we hypothesized that morphine synergy might be glially mediated. A 60 hour, repeated measures paradigm and multiple co-culture models were used to investigate the cellular basis for opiate-enhanced human immunodeficiency virus neurotoxicity. Morphine co-exposure significantly enhanced transactivator of transcription-induced neuron death when glia were present. Synergistic effects of morphine on transactivator of transcription neurotoxicity were greatest with neuron-glia contact, but also occurred to a lesser extent with glial conditioned medium. Importantly, synergy was lost if glia, but not neurons, lacked µ-opioid receptors, indicating that opiate interactions with human immunodeficiency virus converge at the level of µ-opioid receptor-expressing glia. Morphine enhanced transactivator of transcription-induced inflammatory effectors released by glia, elevating reactive oxygen species, increasing 3-nitrotyrosine production by microglia, and reducing the ability of glia to buffer glutamate. But neuron survival was reduced even more with glial contact than with exposure to conditioned medium, suggesting that noxious elements associated with cell contact augment the toxicity due to soluble factors. Similar morphine-transactivator of transcription synergy was also observed in studies with the clade C sequence of HIV-1 transactivator of transcription, which did not cause neuron death unless morphine was present. Several paradoxical observations related to opiate effects were noted when µ-opioid receptors were specifically ablated from either glia or neurons. This suggests that µ-opioid receptor loss in isolated cell types can fundamentally distort cell-to-cell signalling, revealing opponent processes that may exist in individual cell types. Our findings show the critical role of glia in orchestrating neurotoxic interactions of morphine and transactivator of transcription, and support the emerging concept that combined exposure to opiates and human immunodeficiency virus drives enhanced pathology within the central nervous system.

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Previous studies have demonstrated a functional interaction between cannabinoid and opioid systems in the development and expression of morphine tolerance and dependence. In these experiments, we examined the effect of a low oral dose of ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC) on the development of oral morphine tolerance and the expression of naloxone-precipitated morphine withdrawal signs of jumping and diarrhea in ICR mice. Chronic treatment with high-dose oral morphine produced a 3.12-fold antinociceptive tolerance. Tolerance to morphine was prevented in groups receiving a daily cotreatment with a nonanalgetic dose (20 mg/kg p.o.) of ⌬ 9 -THC, except when challenged with a very high dose of morphine. The chronic coadministration of low-dose ⌬ 9 -THC also reduced naloxone-precipitated (1 mg/kg s.c.) platform jumping by 50% but did not reduce diarrhea. In separate experiments, mice treated chronically with high-dose morphine p.o. were not cross-tolerant to ⌬ 9 -THC; in fact, these morphine-tolerant mice were more sensitive to the acute antinociceptive effects of ⌬ 9 -THC. ⌬ 9 -THC (20 mg/kg p.o.) also reduced naloxone-precipitated jumping but not diarrhea when administered acutely to morphine-tolerant mice. These results represent the first evidence that oral morphine tolerance and dependence can be circumvented by coadministration of a nonanalgetic dose of ⌬ 9 -THC p.o. In summary, cotreatment with a combination of morphine and ⌬ 9 -THC may prove clinically beneficial in that long-term morphine efficacy is maintained.The clinical use of morphine for long periods of time is limited by its propensity to cause tolerance and physical dependence after repeated administration. To overcome tolerance to the analgesic effects of morphine, higher doses are necessary for adequate pain relief but are often accompanied by undesirable side effects such as constipation, nausea, and respiratory depression (Ellison, 1993). Morphine tolerance has been developed in rodent models using subcutaneously implanted morphine pellets (Cicero and Meyer, 1973;Bhargava, 1978), but little is known about tolerance to oral doses of morphine in mice. Mao et al. (1996) observed a decrease in antinociception produced by oral morphine in rats as measured by the tail-flick test over a period of several days.Our laboratory and others have shown that combinations of cannabinoids with morphine profoundly enhance morphine-induced analgesia. ⌬ 9 -THC at a nonanalgetic dose administered p.o. to mice significantly enhances the potency of opioids such as morphine and codeine (Smith et al., 1998;Cichewicz et al., 1999). This enhancement is theorized to be due to a combination of morphine's direct effects on the -opioid receptor and the effect of endogenous opioids whose release is stimulated by ⌬ 9 -THC (Smith et al., 1994;Pugh et al., 1996). In addition, the CB1 cannabinoid receptor and -opioid receptor have been found to be colocalized in areas important for the expression of morphine abstinence: nucleus accumbens, septum, striatum, periaqueductal ...

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