The glial activation inhibitor AV411 reduces morphine-induced nucleus accumbens dopamine release

Abstract

Glial activation has recently been discovered to modulate several effects of morphine, including analgesia, tolerance, and dependence. The present studies extend this line of investigation by exploring whether glial activation may also affect extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) shell, a neurochemical corollary of morphine-induced drug reward, during a challenge dose of morphine in experiments both with and without precipitated withdrawal. Morphine or vehicle was administered s.c. for 4 days (starting at 15 mg/kg/day up to 20 mg/kg/day), and the glial activation inhibitor AV411 (7.5 mg/kg) or vehicle was administered twice daily. A challenge dose of morphine (22.5 mg/kg) or saline was then given during dialysis. In the first experiment, naloxone (10 mg/kg) was administered 1 hr after morphine during dialysis in AV411-or vehicle-treated rats, and behavioral signs of somatic withdrawal were assessed during microdialysis. In the second experiment, using the same dosing regimen, sampling continued 3 hr after morphine or saline in AV411-or vehicle-treated rats. NAc DA increased in vehicle-treated rats significantly more than in AV411-treated rats before naloxone treatment, and withdrawal symptoms were significantly reduced in AV411-treated rats. The decrease in morphine-induced NAc DA by AV411 was persistent, lasting 3+ hr post-morphine. These results indicate that glial activation contributes to the effects of morphine on NAc DA, which is associated with somatic signs of precipitated withdrawal.

Association of IL-1B genetic polymorphisms with an increased risk of opioid and alcohol dependence

“…Alterations in glial glutamate transporter expression have also been shown to substantially modify opioid reward and dependence [28,29]. Attenuation of CNS proinflammation and associated reductions in IL-1b expression has been shown to not only reduce opioid reward behaviour and reward neurochemistry, but also the presentation of withdrawal behaviours [24,30,37].…”

“…Moreover, attenuation of CNS proinflammation significantly reduced the rewarding effects of morphine [25,26]. Hutchinson et al [24] also reported that in rats, minocycline, an attenuator of CNS proinflammation, significantly reduced morphine-induced behavioural reward, whereas Bland et al [30] showed that glial attenuation reduced the neurochemical indices of reward. Two different CNS immune inhibitors, minocycline and AV411, which are capable of reducing the opioid-induced proinflammatory activation but have distinct functional mechanisms, can both reduce opioid withdrawal [24,37].…”

“…Specifically, opioids and alcohol interact with glia (step A) resulting in proinflammatory activation of glia (step B) (reviewed [23]), causing the release of proinflammatory cytokines such as interleukin1beta (IL-1b, step C). This series of events not only results in decreased glial glutamate transporter activity [27] and hence increased glutamate in the synapse, but also increased neuronal N-methyl-D-aspartic acid receptor activity and dopamine release (step D) in the nucleus accumbens which alters neuroplasticity [28][29][30] and increases drug reward and dependence potential. This mechanism is supported by both animal and human studies, which have highlighted the role of IL-1b after glial activation by opioids and alcohol.…”

Imaging Biomarkers of the Neuroimmune System among Substance Use Disorders: A Systematic Review

“…Ibudilast is a phosphodiesterase inhibitor that suppresses pro-neuroinflammatory glial responses [16, 249]. In preclinical studies, minocycline and ibudilast have been shown to attenuate alcohol self-administration [250, 251], morphine-induced dopamine release in the nucleus accumbens [252], and morphine-conditioned place preference [253]. Recent studies have begun to investigate these medications in humans.…”

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

“…For opioids, based on preclinical evidence, central immune signaling is now a recognized contributor. Although not discussed here, other adverse actions of opioids, such as respiratory depression, addiction, and dependence are also associated with induction of central immune signaling (Hutchinson et al, 2007(Hutchinson et al, , 2008b(Hutchinson et al, , 2009a(Hutchinson et al, , 2010cBland et al, 2009;. Thus, to maintain the beneficial use of opioids, measures to minimize central immune signaling must be taken.…”