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

Morphine enhances IL-1β release through toll-like receptor 4-mediated endocytic pathway in microglia

“…Although it was long assumed that morphine-induced microglial activation must be mediated via activation of classic opioid receptors, recent data from Hutchinson et al [10,22] contested this assumption. Their studies have suggested that such proinflammatory effects of morphine are not via classic opioid receptors, while via TLR4 signaling.…”

Novel imaging tools for investigating the role of immune signalling in the brain

“…The neuroimmune system is an incredibly diverse and intricate system comprised of endogenous (astrocytes, microglia, neurons and oligodendrocytes) and exogenous (infiltrating monocytes and T cells) immune-functioning cells and their associated signalling factors within the central nervous system (CNS) (table 1) (Hutchinson et al 2011). These immunocompetent cells are pivotal to both the homeostatic and disease states of the brain and spinal cord (Grace et al 2014;Ousman & Kubes 2012).…”

“…These sub-inflammatory responses do not function in a traditional inflammatory manner. Rather, this response more closely resembles the discrete and localised nature of neurotransmission and hence requires a separate terminology of neurokine or central immune signalling (Jacobsen et al 2014;Hutchinson et al 2011). …”

Opportunities for the Development of Neuroimmune Therapies in Addiction

“…Naloxone is also an opioid receptor antagonist with similar affinity to mu opioid receptors as naltrexone, but relatively lower affinity to kappa and delta opioid receptors. Each of these medications is available in two isomers: the (À) isomer is the common opioid receptor antagonist form of each drug, whereas the (+) isomer does not bind (or has significantly reduced binding affinity) to opioid receptors (Hutchinson et al, 2008(Hutchinson et al, , 2011. However, both the (+) and (À) forms of each drug are antagonists at the Toll-like receptor 4 (TLR4; Hutchinson et al, 2008).…”

“…Importantly, these TLR4-related processes are involved in the behavioral and neuroinflammatory effects of drugs of abuse (Mayfield et al, 2013), as TLR4 activation has been shown to be integral to alcohol-induced glial activation and proinflammatory signaling (Alfonso-Loeches, Pascual-Lucas, Blanco, Sanchez-Vera, & Guerri, 2010;Blanco, Pascual, Valles, & Guerri, 2004;Blanco, Valles, Pascual, & Guerri, 2005;Fernandez-Lizarbe, Pascual, & Guerri, 2009), as well as alcohol's behavioral effects in rodents (Wu et al, 2012). Furthermore, in rodents, naltrexone attenuates proinflammatory TLR4-related signaling (Hutchinson et al, 2011) and blocks ethanolinduced glial activation and neuronal death (Qin & Crews, 2012), while (+) naloxone reduces acute alcohol-induced sedation and motor impairment (Wu et al, 2012). In sum, these findings may indicate that TLR4 signaling is involved in both the acute behavioral and chronic inflammatory effects of alcohol and other drugs of abuse and also that such TLR4-mediated processes may be ameliorated by the opioid receptor antagonists naltrexone and naloxone.…”