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

Erratum to: ARA 290 Improves Symptoms in Patients with Sarcoidosis-Associated Small Nerve Fiber Loss and Increases Corneal Nerve Fiber Density

Albert Dahan, Ann Dunne, Maarten Swartjes, Paolo L Proto, Lara Heij, Oscar Vogels, Monique van Velzen, Elise Sarton, Marieke Niesters, Martijn R Tannemaat, Anthony Cerami, and Michael Brines. (2013) ARA 290 Improves Symptoms in Patients with Sarcoidosis-Associated Small Nerve Fiber Loss and Increases Corneal Nerve Fiber Density. Mol. Med. 19:334–45

Ketamine and ARA 290 differ in effects on acute nociceptive pain and side effects.

<p><b>A.</b> Ketamine administration increases the latency of tail withdrawal to a thermal stimulus (treatment effect, p<0.001), whereas ARA 290 does not. <b>B.</b> Ketamine treatment had significant biphasic effects on stereotypic behavior: after a period of transient sedation, the animals showed signs of psychomimetic disturbances that lasted for about 20 minutes (treatment effect, p<0.001). ARA 290 did not display these side effects. <b>C.</b> Treatment with ketamine was associated with a biphasic activation of generalized activity (treatment effect, p<0.001) causing an increase in restlessness and explorative behavior after a period of transient sedation.</p

QRT-PCR primers and probes used in this study.

<p>Primers and probes used for the quantification of mRNA from NMDA receptor subtypes NR1, NR2A and NR2B (Grin); microglia marker Iba-1 (AIF-1), astrocyte (GFAP) and CCL2; f, Reporter dye1 (FAM:6-carboxyfluorescein); t, Reporter dye2 (TET:Tetrachloro-6-carboxyfluorescein); q, Quencher dye (TAMRA: 6-carboxytetramethyl1-rhodamine).</p

Ketamine and ARA 290 reduce inflammatory mediators in the spinal cord following sciatic nerve injury.

<p>One week post surgery, animals showed a marked elevation of CCL2 (panel <b>A</b>), Iba1 (panel <b>B</b>), and GFAP (panel <b>C</b>) compared to naïve controls. Both ketamine and ARA 290 significantly reduced the mRNA levels of these genes to a similar extent. *p<0.05 <i>versus</i> vehicle, #p<0.05 between ketamine and ARA 290 treatments, **p<0.05 <i>versus</i> naïve.</p

Ketamine and ARA 290 have similar effects on allodynia.

<p><b>A.</b> Treatment with both ketamine and ARA 290 prevented the full development of allodynia (treatment effect, p = 0.049 and p = 0.03, respectively). <b>B.</b> The effects of ketamine on acute nociceptive pain remained unchanged over time (treatment effect, p<0.001).</p

Neuropathic pain involves a pathway that utilizes the Innate Immune Receptor.

<p>Nerve injury results in microglial recruitment, increased expression of NMDAR, and proinflammatory cytokine production, ultimately resulting in allodynia. Activation of the innate immune receptor (IRR), e.g., by ARA 290, antagonizes this pathway. Ketamine also requires the IRR to reduce allodynia. This may be via a direct interaction with the IRR or alternatively, via modulation of intermediate processes that are upstream of the IRR. Additionally, ketamine interacts with NMDARs that mediate antinociception and psychomotor effects. ARA 290 does not interact with the NMDAR and therefore lacks these additional effects.</p