NMDA receptors are involved in upstream of the spinal JNK activation in morphine antinociceptive tolerance

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

“…The role of JNK is less clear, in that it has been reported to be phosphorylated by morphine in astrocytes in a NDMA receptor-dependent fashion (Guo et al, 2009), whereas others have reported it to be unaffected ). Parallel to the MAPK pathway is the IP 3 /Akt pathway, which is also activated by opioid exposure and seems to be involved in activation of microglial ERK (Takayama and Ueda, 2005a;Horvath and DeLeo, 2009).…”

“…It is clear from the preclinical literature than opioid tolerance involves several aspects of central immune signaling, because tolerance can be prevented, attenuated, and/or reversed by blockade of the action or formation of the proinflammatory cytokines IL-1␤, TNF-␣, and/or IL-6 (Raghavendra et al, 2002;Shavit et al, 2005a;Hutchinson et al, 2008a;Shen et al, 2011) or chemokines such as CX3CL1 (Johnston et al, 2004); inhibition of MEK activity (and hence blockade of ERK activation) ; selective reductions in microglial p38 or JNK NEUROIMMUNOPHARMACOLOGIC IMPLICATIONS FOR OPIOID ANALGESIA activation (Guo et al, 2009); decreased P2X4 (Horvath et al, 2010b) or P2X7 signaling (Zhou et al, 2010); reduced ceramide/sphingosine signaling Muscoli et al, 2010); inhibition of matrix metalloproteinase 9 (Liu et al, 2010b); nitric oxide and related superoxide protein damage (Muscoli et al, 2007;Batinić-Haberle et al, 2009); or by general anti-inflammatory treatments such as IL-10 (Johnston et al, 2004), fluorocitrate (Song and Zhao, 2001), minocycline (Mika et al, 2007;Cui et al, 2008;Mika et al, 2009), pentoxifylline (Mika et al, 2007), propentofylline (Raghavendra et al, 2003b;Raghavendra et al, 2004a), ibudilast (Ledeboer et al, 2006a;Lilius et al, 2009), and, interestingly, also by ultra-low-dose naloxone, which acts via elevations of IL-10 expression (Lin et al, 2010b). It is noteworthy that blockade of TLR4 using (ϩ)-naloxone also attenuates the development of morphine tolerance, suggesting that one of the initiating triggers of opioid tolerance is direct activation of TLR4 signaling by opioids (Hutchinson et al, 2010c).…”

“…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). Therefore, the activation of central immune signaling that contributes to morphine tolerance is somewhat cyclical, and interventions at multiple points can act to reduce opioid tolerance.…”

“…Neuronal nitric-oxide synthase (leading to p38 activation) (Liu et al, 2006) elevates neuronal CGRP which, in turn, leads to elevations in IL-1␤, TNF-␣, IL-6, prostaglandin E synthase-1, NMDA receptor subunit expression, and activation of ERK, signal transducer and activator of transcription 3, p38, and NF-B ; neuronal NMDA receptor subunit expression favored for neuroexcitability (Guo et al, 2009;Lin et al, 2010a;Wang et al, 2010a); neuronal protein kinase C␥ expression (leading to astrocyte reactivity) (Narita et al, 2004b;Lin et al, 2010a); and cAMP response element-binding and calmodulin-dependent protein kinase II activation ) (see Figs. 3-5 for summaries).…”

Effects of Magnesium sulfate and Bupropion on Morphine Induced tolerance in mice

“…This opiate related activation of NMDA-receptors initiates intracellular changes such as influx of Ca2+ and subsequent production of nitric oxide (NO) and increase in cGMP level, which all have been shown to contribute critically to the opioid tolerance development (22,23). NO is able to further increase excitotoxicity by enhancing glutamate release from presynaptic neurons and inhibiting glial glutamate transporters (24)(25)(26)(27)(28)(29). Although the exact mechanism of tolerance development is not well-understood, some mechanisms such as norepinephrine dopamine reuptake inhibition and also glutamate release inhibition have been reported to play role (30).…”