Ketamine does not produce relief of neuropathic pain in mice lacking the β-common receptor (CD131).
Neuropathic pain (NP) is a debilitating condition associated with traumatic, metabolic, autoimmune and neurological etiologies. Although the triggers for NP are diverse, there are common underlying pathways, including activation of immune cells in the spinal cord and up-regulation of the N-methyl-D-aspartate receptor (NMDAR). Ketamine, a well-known NDMAR antagonist, reduces neuropathic pain in a sustained manner. Recent study has shown that the novel 11-amino acid peptide erythropoietin derivative ARA290 produces a similar, long-lasting relief of NP. Here, we show that both drugs also have similar effects on the expression of mRNA of the NMDAR, as well as that of microglia, astrocytes and chemokine (C-C motif) ligand 2, all-important contributors to the development of NP. Although the effects of ketamine and ARA 290 on NP and its molecular mediators suggest a common mechanism of action, ARA 290 has no affinity for the NMDAR and acts specifically via the innate repair receptor (IRR) involved in tissue protection. We speculated therefore, that the IRR might be critically involved in the action of ketamine on neuropathic pain. To evaluate this, we studied the effects of ketamine and ARA 290 on acute pain, side effects, and allodynia following a spared nerve injury model in mice lacking the β-common receptor (βcR), a structural component of the IRR. Ketamine (50 mg/kg) and ARA 290 (30 µg/kg) produced divergent effects on acute pain: ketamine produced profound antinociception accompanied with psychomotor side effects, but ARA290 did not, in both normal and knock out mice. In contrast, while both drugs were antiallodynic in WT mice, they had no effect on NP in mice lacking the βcR. Together, these results show that an intact IRR is required for the effective treatment of NP with either ketamine or ARA 290, but is not involved in ketamine's analgesic and side effects.
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
Maarten
M
Swartjes
Marieke
M
Niesters
Lara
L
Heij
Ann
A
Dunne
Leon
L
Aarts
Carla Cerami
CC
Hand
Hyung-Suk
HS
Kim
Michael
M
Brines
Anthony
A
Cerami
Albert
A
Dahan
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D053648:Cytokine Receptor Common beta Subunit / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D055786:Gene Knockout Techniques; D007649:Ketamine / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D059225:Nociception / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
D053648:Cytokine Receptor Common beta Subunit; D009842:Oligopeptides; D012333:RNA, Messenger; D007649:Ketamine; C576178:cibinetide