Acutely, non-selective
cannabinoid (CB) agonists have been shown to increase
morphine antinociceptive effects, and we and others have also demonstrated that non-selective CB agonists attenuate
morphine antinociceptive tolerance. Activation of
cannabinoid CB2 receptors reverses
allodynia and
hyperalgesia in models of
chronic pain, and co-administration of
morphine with
CB2 receptor selective agonists has been shown to be synergistic.
CB2 receptor activation has also been shown to reduce
morphine-induced
hyperalgesia in rodents, an effect attributed to
CB2 receptor modulation of
inflammation. In the present set of experiments, we tested both the acute and chronic interactions between
morphine and the
CB2 receptor selective agonist
O-1966 treatments on antinociception and antinociceptive tolerance in C57Bl6 mice. Co-administration of
morphine and
O-1966 was tested under three dosing regimens: simultaneous administration,
morphine pre-treated with
O-1966, and
O-1966 pre-treated with
morphine. The effects of
O-1966 on
mu-opioid receptor binding were determined using [3H]
DAMGO and [35S]GTPγS binding assays, and these interactions were further examined by FRET analysis linked to flow cytometry. Results yielded surprising evidence of interactions between the
CB2 receptor selective agonist
O-1966 and
morphine that were dependent upon the order of administration. When
O-1966 was administered prior to or simultaneous with
morphine,
morphine antinociception was attenuated and antinociceptive tolerance was exacerbated. When
O-1966 was administered following
morphine,
morphine antinociception was not affected and antinociceptive tolerance was attenuated. The [35S]GTPγS results suggest that
O-1966 interrupts functional activity of
morphine at the
mu-opioid receptor, leading to decreased potency of
morphine to produce acute thermal antinociceptive effects and potentiation of
morphine antinociceptive tolerance. However,
O-1966 administered after
morphine blocked
morphine hyperalgesia and led to an attenuation of
morphine tolerance, perhaps due to well-documented anti-inflammatory effects of
CB2 receptor agonism.