Co-administration of ultra-low dose naloxone attenuates morphine tolerance in rats via attenuation of NMDA receptor neurotransmission and suppression of neuroinflammation in the spinal cords

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

“…It is noteworthy that altered glutamate homeostasis due to decreased glial glutamate transporter expression has been demonstrated in several CNS disturbances in which glia assume a reactive phenotype (Tilleux and Hermans, 2007). Long-term morphine administration results in an elevation of cerebrospinal fluid levels of aspartate and glutamate (Wen et al, 2005;Tai et al, 2007;Wu et al, 2008), most likely resulting from down-regulation of glial GLT-1 and GLAST glutamate transporters (Ozawa et al, 2001;Mao et Tai et al, 2006Tai et al, , 2007Lin et al, 2010a;Rawls et al, 2010). This elevation of aspartate and glutamate seems to involve aquaporin 4 and is sensitive to coadministration with dexamethasone (Wen et al, 2005), ceftriaxone (Rawls et al, 2010), naloxone (Mao et al, 2002), and amitriptyline (Tai et al, 2006(Tai et al, , 2007.…”

“…Such changes in glutamate expression have profound implications for neuroexcitability, including increased NMDA receptor signaling, as demonstrated by increased phosphorylation of the NR1 subunit (Lin et al, 2010a). It is noteworthy that these changes could be blocked by ultra-low-dose naloxone, which induced antiinflammatory central immune signaling (discussed above) (Lin et al, 2010a).…”

“…Another critical modulation in glial function related to opioid-induced central immune signaling that contributes to the development of tolerance is down-regulation of glial GLT-1 and GLAST glutamate transporters (Ozawa et al, 2001;Mao et al, 2002;Nakagawa and Satoh, 2004;Wen et al, 2005;Tai et al, 2006Tai et al, , 2007Wu et al, 2008;Lin et al, 2010a;Rawls et al, 2010). The effects of such down-regulation are blocked by coadministration of any of the following substances: synthetic glucocorticoid dexamethasone (Wen et al, 2005); the glutamate transporter up-regulator ceftriaxone (Rawls et al, 2010); (Ϫ)-naloxone (Mao et al, 2002); ultra-lowdose naloxone (Lin et al, 2010a); or amitriptyline, which produces its effect via induction of IL-10 expression and hence indirect induction of an anti-inflammatory response (Tai et al, 2006(Tai et al, , 2007.…”

“…The effects of such down-regulation are blocked by coadministration of any of the following substances: synthetic glucocorticoid dexamethasone (Wen et al, 2005); the glutamate transporter up-regulator ceftriaxone (Rawls et al, 2010); (Ϫ)-naloxone (Mao et al, 2002); ultra-lowdose naloxone (Lin et al, 2010a); or amitriptyline, which produces its effect via induction of IL-10 expression and hence indirect induction of an anti-inflammatory response (Tai et al, 2006(Tai et al, , 2007. In addition to these pharmacological treatments that restore glutamate transporter homeostasis, tolerance can also be reduced by the NMDA receptor antagonist dizocilpine maleate (MK801) (Wen et al, 2008;Guo et al, 2009), which can in turn reduce the opioid-induced reactivity of astrocytes (Wen et al, 2008).…”

Phosphorylation of the N-methyl-d-aspartate receptor is increased in the nucleus accumbens during both acute and extended morphine withdrawal

“…These findings indicate that phosphorylation of NR1 could be a common mechanism of plastic disease states. Other studies have linked opioid exposure to NR1 phosphorylation previously (Lin et al, 2010;Rodriguez-Munoz et al, 2012), but little work has been performed during or after withdrawal. PKA activation increases NMDA receptor currents (Westphal et al, 1999), increases the sensitivity of the NMDA receptor to glutamate (Dudman et al, 2003), and increases cell surface delivery of the NR1 subunit of the NMDA receptor Lau and Zukin, 2007).…”