Morphine-induced glial proinflammatory responses have been documented to contribute to tolerance to
opioid analgesia. Here, we examined whether drugs previously shown to suppress glial proinflammatory responses can alter other clinically relevant
opioid effects; namely, withdrawal or acute
analgesia.
AV411 (
ibudilast) and
minocycline, drugs with distinct mechanisms of action that result in attenuation of glial proinflammatory responses, each reduced
naloxone-precipitated withdrawal. Analysis of brain nuclei associated with
opioid withdrawal revealed that
morphine altered expression of glial activation markers,
cytokines,
chemokines, and a
neurotrophic factor.
AV411 attenuated many of these
morphine-induced effects.
AV411 also protected against spontaneous withdrawal-induced hyperactivity and
weight loss recorded across a 12-day timecourse. Notably, in the spontaneous withdrawal study,
AV411 treatment was delayed relative to the start of the
morphine regimen so to also test whether
AV411 could still be effective in the face of established
morphine dependence, which it was.
AV411 did not simply attenuate all
opioid effects, as co-administering
AV411 with
morphine or
oxycodone caused three-to-five-fold increases in acute
analgesic potency, as revealed by leftward shifts in the
analgesic dose response curves. Timecourse analyses revealed that plasma
morphine levels were not altered by
AV411, suggestive that potentiated
analgesia was not simply due to prolongation of
morphine exposure or increased plasma concentrations. These data support and extend similar potentiation of acute
opioid analgesia by
minocycline, again providing converging lines of evidence of glial involvement. Hence, suppression of glial proinflammatory responses can significantly reduce
opioid withdrawal, while improving
analgesia.