Dissociation between morphine-induced spinal gliosis and analgesic tolerance by ultra-low-dose 2-adrenergic and cannabinoid CB1-receptor antagonists

Long-term use of opioid analgesics is limited by tolerance development and undesirable adverse effects. Paradoxically, spinal administration of ultra-low-dose (ULD) G-protein-coupled receptor antagonists attenuates analgesic tolerance. Here, we determined whether systemic ULD (2)-adrenergic receptor (AR) antagonists attenuate the development of morphine tolerance, whether these effects extend to the cannabinoid (CB1) receptor system, and if behavioral effects are reflected in changes in opioid-induced spinal gliosis. Male rats were treated daily with morphine (5mg/kg) alone or in combination with ULD (2)-AR (atipamezole or efaroxan; 17ng/kg) or CB1 (rimonabant; 5ng/kg) antagonists; control groups received ULD injections only. Thermal tail flick latencies were assessed across 7 days, before and 30min after the injection. On day 8, spinal cords were isolated, and changes in spinal gliosis were assessed through fluorescent immunohistochemistry. Both ULD (2)-AR antagonists attenuated morphine tolerance, whereas the ULD CB1 antagonist did not. In contrast, both ULD atipamezole and ULD rimonabant attenuated morphine-induced microglial reactivity and astrogliosis in deep and superficial spinal dorsal horn. So, although paradoxical effects of ULD antagonists are common to several G-protein-coupled receptor systems, these may not involve similar mechanisms. Spinal glia alone may not be the main mechanism through which tolerance is modulated.