The Interaction Between Opioids and Cannabinoids in the Rat Periaqueductal Gray
Wilson, Adrianne R.
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Opioids and cannabinoids are well known for their analgesic properties. Both classes of drugs exert their effects, in part, by activating a descending pain modulatory pathway that includes the midbrain periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM). Individually, the opioid and cannabinoid systems have been well characterized in this pathway. Cannabinoid/opioid interactions however, remain poorly understood. The aim of these studies was to characterize the interaction between opioids and cannabinoids in the descending pain pathway. Behavioral studies demonstrate that repeated morphine microinjections in the rat PAG enhance subsequent cannabinoid antinociception, and vice versa. Furthermore, microinjections of cannabinoids into the PAG also attenuate the development of morphine tolerance. However, when cannabinoids are repeatedly injected into the RVM, they cause neurotoxic lesions. Nonetheless, acute co-administration of morphine and cannabinoids in the RVM produces greater antinociception than when either drug is administered alone, which is consistent with earlier reports of antinociceptive synergy between the drugs. The subsequent anatomical and electrophysiological studies were conducted in order to determine the neural mechanisms underlying the bi-directional antinociceptive enhancement between cannabinoids and opioids. Confocal and electron microscopy revealed that CB1 expression in the PAG is largely somatodendritic, however CB1-labeled axons and axon terminals are widespread. CB1 and mu-opioid receptors co-localized on 32% of PAG neurons, and a subset of mu-opioid-labeled cells received appositions from (presumed presynaptic) CB1 profiles. Thus, interactions between opioids and cannabinoids are likely to occur within the same neuron, but synaptic adaptations could also occur where CB1 terminals synapse onto mu-opioid cells. Synaptic adaptations were next examined using the in vitro whole-cell patch clamp method. Previous research has shown that both cannabinoids and opioids can reduce GABAergic transmission in the PAG, and the ability of opioids to reduce GABAergic transmission is diminished in morphine tolerant animals. The present study demonstrates that chronic morphine has no effect on cannabinoid inhibition of GABAergic transmission. These results indicate a lack of cellular cross-tolerance between opioids and cannabinoids, which correlates with antinociceptive enhancement between the drugs. The results of these studies support the therapeutic potential of combined opioid/cannabinoid administration for pain relief.