Multiple groups have reported the functional cross-regulation between mu-
opioid (MOP) receptor and
glutamate ionotropic receptor N (GluN), and the post-synaptic association of these receptors has been implicated in the transmission and modulation of nociceptive signals.
Opioids, such as
morphine, disrupt the MOP receptor-GluN receptor complex to stimulate the activity of GluN receptors via
protein kinase C (PKC)/Src. This increased GluN receptor activity opposes MOP receptor signalling, and via neural
nitric oxide synthase (nNOS) and
calcium and
calmodulin regulated
kinase II (
CaMKII) induces the phosphorylation and uncoupling of the
opioid receptor, which results in the development of
morphine analgesic tolerance. Both experimental in vivo activation of GluN receptors and
neuropathic pain separate the MOP receptor-GluN receptor complex via
protein kinase A (PKA) and reduce the
analgesic capacity of
morphine. The
histidine triad
nucleotide-
binding protein 1 (HINT1) associates with the MOP receptor C-terminus and connects the activities of MOP receptor and GluN receptor. In HINT1⁻/⁻ mice,
morphine promotes enhanced
analgesia and produces tolerance that is not related to GluN receptor activity. In these mice, the GluN receptor agonist
N-methyl-D-aspartate acid (
NMDA) does not antagonise the
analgesic effects of
morphine. Treatments that rescue
morphine from
analgesic tolerance, such as GluN receptor antagonism or PKC, nNOS and
CaMKII inhibitors, all induce MOP receptor-GluN receptor re-association and reduce GluN receptor/
CaMKII activity. In mice treated with
NMDA or suffering from
neuropathic pain (induced by chronic constriction injury, CCI), GluN receptor antagonists, PKA inhibitors or certain
antidepressants also diminish
CaMKII activity and restore the MOP receptor-GluN receptor association. Thus, the HINT1
protein stabilises the association between MOP receptor and GluN receptor, necessary for the
analgesic efficacy of
morphine, and this coupling is reduced following the activation of GluN receptors, similar to what is observed in
neuropathic pain.