Dissociation between morphine-induced spinal gliosis and analgesic tolerance by ultra-low-dose α2-adrenergic and cannabinoid CB1-receptor antagonists

Abstract

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 α2-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 (5 mg/kg) alone or in combination with ULD α2-AR (atipamezole or efaroxan; 17 ng/kg) or CB1 (rimonabant; 5 ng/kg) antagonists; control groups received ULD injections only. Thermal tail flick latencies were assessed across 7 days, before and 30 min after the injection. On day 8, spinal cords were isolated, and changes in spinal gliosis were assessed through fluorescent immunohistochemistry. Both ULD α2-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.

Biased, Bitopic, Opioid–Adrenergic Tethered Compounds May Improve Specificity, Lower Dosage and Enhance Agonist or Antagonist Function with Reduced Risk of Tolerance and Addiction

“…For example, a series of studies have demonstrated that naloxone, an opioid antagonist, can enhance epinephrine and isoproterenol activity on both cardiac and smooth muscle preparations by mechanisms that do not involve the opioid recep-tor [96][97][98][99][100][101][102]. Similar data demonstrating that β-adrenergic antagonists [52][53][54][55][56][57]103] and α-adrenergic antagonists [50][51][52]58,103] enhance opioid efficacy confirm that the opioid sparing effects and inhibition of tolerance caused by adrenergic drugs and their increase of the duration of opioid analgesia must also be, at least in part, due to direct effects on the opioid receptor rather than through second-messenger mechanisms of cross-talk with adrenergic receptors.…”