The sensitization of pronociceptive pathways in response to<unk>  treatment appears to involve several pathways. Research thus far has primarily implicated the μ-opioid receptors (MOR) abnormal activation of NMDA receptors in the central nervous system, and long-term potentiation of synapses between nociceptive C fibers and neurons in the spinal dorsal horn. μ-opioid receptors In clinical trials, the MOR is the main target of<unk>  ligand binding. While binding of the<unk>  to the MOR typically causes analgesia, there can be instances where<unk>  occurs. It has been speculated that the opposite analgesic and hyperanalgesic effects are due to different isoforms of the receptor. The MOR is a G protein-coupled receptor with seven transmembrane domains. Variants of the receptor have been discovered and are due to alternative splicing mechanisms. A particular receptor variant, 6TM MOR, has been heavily studied because of its role in nociception. The 6TM MOR is missing residues in the N-terminal region which has implications for the extracellular tail and first transmembrane domain. This causes an excitatory effect compared to the inhibition in the normal seven transmembrane domain receptor because of differences in G-protein activation. Studies on mice have shown silencing of the 6TM MOR variant decreased morphine-induced<unk>  which suggested G-protein coupling in the 6TM isoform could be a factor in the development of<unk> . NMDA Receptors<unk>  shares commonalities with chronic pain in their neural mechanisms and specifically their usage of the glutaminergic system and NMDA glutamate receptors. NMDA receptors can be found presynaptically on central terminals of primary afferent neurons and postsynaptically on spinal dorsal horn neurons. it has been shown experimentally that introduction of an NMDA receptor antagonist to mice and rats greatly reduces or even prevents<unk> . B-arrestin 2 transcripts (Arrb2) are implicated in<unk>  because of their upregulation during analgesic tolerance in the periaqueductal gray, cortex and striatum. NMDA receptor antagonists combined with morphine in<unk>  conditions have been shown to reduce Arr2b in the entirety of the mouse's brain. These findings implicate Arr2b activity as a factor in<unk> . Long-Term Potentiation Long-Term Potentiation (LTP) is the increase in sensitivity of homosynapses that augment the synapse's strength and signal transduction. In the context of<unk> , LTP has been shown to contribute to<unk>  by hypersensitizing areas of nociceptive processing, particularly at synapses between C fibers and the spinal cord dorsal horn. Studies that attempted to link LTP and<unk>  have found that drugs able to block LTP (ketamine and minocycline) also decrease<unk> . In addition, LTP and<unk>  both utilize NMDA receptors and their activity can be reduced by NMDA receptor antagonists (i.e. ketamine).
Opioid-induced hyperalgesia
Nociplastic pain
Hypoalgesic effect of swearing
Central pain syndrome
Psychogenic pain
Neurogenic inflammation
Neuraxial blockade
Neuropathic pain