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.