Figure 3.

Mechanisms engaged in the formation and maintenance of OIH. OIH, Hyperalgesia induced by opioids; BDNF, brain derived neurotrophic factor; Cx3Cl1, chemokine Cx3Cl1; EAAC1, glutamate transporter EAAC1; GABAR, gamma aminobutyric acid receptor; GRK, G protein coupled receptor kinase; IL1β, interleukin beta; IP3, inositol triphosphate; KCC2, K+/Cl cotransporter 2; LTP, long-term potentiation; MOR, mu-opioid receptor; mTOR, mammalian target of rapamycin; NO, nitric oxide; NOS, nitric oxide synthase; NK1, neurokinin 1 receptor; NMDAR, N-methyl-D-aspartic acid receptor; PKC, protein kinase C; SP, substance P; TNFα, tumor necrosis factor alpha; TrkB, tyrosine kinase B; TRPV1, transient receptor potential vanilloid 1; Ca²⁺, calcium; Cl⁻, chlorine; +, excitatory; –, inhibitory. (1) Morphine activates the neuronal MOR and generates an intracellular process that culminates in the OIH; (2) Signaling mTOR is activated by morphine engaged in neuroexcitation that lead to OIH; (3) The synaptic concentration of glutamate is elevated when the glutamate transporter EEAC1 are blocked by morphine. (4) Glutamate coupling in your NMDA receptors activates the calcium influx inducing the LTP that lead an OIH. (5) The BDNF receptor TrkB reduces the action of the cotransporter KCC2 evolved in ions chlorine homeostasis that modifies the inhibitory function of GABA for an excitatory function that which promote OIH. (6) Morphine also activates the glial cells and neurons that generate pro-inflammatory cytokines (IL1β and TNFα) that induce LTP and lead to OIH.