Ketamine Does Not Produce Relief of Neuropathic Pain in Mice Lacking the β-Common Receptor (CD131)

Abstract

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.

RETRACTED: A non‐erythropoietic peptide derivative of erythropoietin decreases susceptibility to diet‐induced insulin resistance in mice

“…Here we describe for the first time the physical interaction between EpoR and βcR in mouse skeletal muscle by immunoprecipitation assays, showing that the pharmacological target of pHBSP, the EpoR/βcR complex, was expressed in the skeletal muscle of both control and HFHS‐fed mice. pHBSP is known to bind to the EpoR/βcR complex (Brines and Cerami, 2008; 2012; Bohr et al ., ) and no effect of pHBSP in mice lacking the βcR has been reported (Swartjes et al ., 2011; 2013). However, further studies on the effects of pHBSP in βcR knockout mice given a HFHS diet are necessary to confirm that the observed beneficial effects of this peptide are indeed due to activation of the EpoR/βcR complex.…”

ARA 290, a Nonerythropoietic Peptide Engineered from Erythropoietin, Improves Metabolic Control and Neuropathic Symptoms in Patients with Type 2 Diabetes

“…In preclinical models of neuropathy, ARA 290 has been shown to prevent and improve peripheral neuropathic pain, an action that requires the innate repair receptor (25). In these effects, ARA 290 is not acting as an analgesic agent (26), but rather reduces the underlying inflammation (27) and stimulates nerve fiber regrowth from damaged axons. Recent studies of patients with sarcoidosis and SFN have shown that ARA 290 reduces neuropathic symptoms in conjunction with an increase of small nerve fibers as assessed by changes in the density of corneal nerve fibers (19).…”

The Use of Ketamine in Neuropathic Pain

“…A thorough review of our recording and management of side effects is in process. Identifying the patients who may benefit as ketamine responders is ongoing with clinical trials and research that suggest there are certain individuals and etiology subtypes whose NP may or may not respond to ketamine [5]. We find that CRPS patients with refractory pain have demonstrated the greatest benefit from ketamine via IV infusions.…”

“…Mechanisms underlying NP include altered gene expression, changes in gene regulation within the CNS, changes in ion channels that lead to ectopic activity, and synaptic facilitation of the neural axis producing central amplification [3]. The activation and upregulation of dorsal horn excitatory glutamatergic N-methyl-D-aspartate (NMDA) receptors is believed to play a central role in NP, allodynia, and hyperalgesia [4,5].…”