Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast)

Abstract

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 3-to-5-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, whilst improving analgesia.

Drug addiction: targeting dynamic neuroimmune receptor interactions as a potential therapeutic strategy

“…36,37 Morphine (behavioural withdrawal) Increased CCL5 expression in the nucleus accumbens and ventral tegmental area but not the dentate gyrus, hippocampus, dorsal periaqueductal grey, substantia nigra, central nucleus of the amygdala or medial prefrontal cortex. 14 Morphine + CCL5 (intra periaqueductal grey) Increased the antinociceptive response from rats undergoing cold water tail flick test. 38 However, the interactions between CCR5 and the µ opioid receptor extend beyond associative evidence.…”

“…13 Similarly, morphine increases the expression of CCL2, CCL5 and IFNγ-inducible protein. 14 In vivo, systemic injections of either opioids and alcohol increases the expression of inflammatory mediators in key neuroanatomical areas associated with addiction such as the prefrontal cortex and hippocampus but not the cortex within mice. [14][15][16] Furthermore, both opioids and alcohol drug classes increase inflammatory-related transcription factor activation in microglia and astrocytes in the aforementioned brain regions in both rodents and humans.…”

“…14 In vivo, systemic injections of either opioids and alcohol increases the expression of inflammatory mediators in key neuroanatomical areas associated with addiction such as the prefrontal cortex and hippocampus but not the cortex within mice. [14][15][16] Furthermore, both opioids and alcohol drug classes increase inflammatory-related transcription factor activation in microglia and astrocytes in the aforementioned brain regions in both rodents and humans. 10,17 However, just as these drugs of abuse have specific neurotransmitter profiles, as determined by the neurotransmitters released following exposure to drugs of abuse, there is also a neuroimmune profile.…”

“…14,18 It is worth highlighting, an immune challenge results in wide and systemic release of inflammatory mediators, whereas an immune response to drugs of abuse within the CNS results in a more localised immune response. This localised response is termed neurokine signalling.…”

“…Ibudilast, a pharmacological glial attenuator, blocks self-administration of a variety of drugs such as alcohol, methamphetamine and opioids in rodents. 14,24,25 In humans, ibudilast successfully reduced characteristics of opioid withdrawal compared to placebo controls. 26 Furthermore, in preclinical models global knockout and selective knockout (via siRNA) of immune receptors and related molecules attenuate addiction-like behaviours such as impulsive consumption and craving.…”