Accepted

Neuropathic pain is difficult to treat and remains a major clinical challenge worldwide. While the mechanisms which underlie the development of neuropathic pain are incompletely understood, interferon signaling by the immune system is known to play a role. Here, we demonstrate a role for IFNβ in attenuating mechanical allodynia induced by the spared nerve injury in mice. The results show that intrathecal administration of IFNβ (dosages up to 5000U) produces significant, transient, and dose-dependent attenuation of mechanical allodynia without observable effects on motor activity or feeding behavior, as is common with IFN administration. This analgesic effect is mediated by the ubiquitin-like protein ISG15, which is potently induced within the spinal cord following intrathecal delivery of IFNβ. Both free and conjugated ISG15 are elevated following IFNβ treatment, and this effect is increased in UBP43 mice lacking a key deconjugating enzyme. The IFNβ-mediated analgesia reduces MAPK signaling activation following nerve injury, and this effect requires induction of ISG15. These findings highlight a new role for IFNβ, ISG15 and MAPK signaling in immunomodulation of neuropathic pain and may lead to new therapeutic possibilities. Perspective: Neuropathic pain is frequently intractable in a clinical setting, and new treatment options are needed. Characterizing the anti-nociceptive potential of IFNβ and the associated downstream signaling pathways in preclinical models may lead to the development of new therapeutic options for debilitating neuropathies.

Neuropeptide Y (NPY) signaling plays an important role in inhibiting chronic pain in the spinal cord of mice. However, little is known about the respective roles of two major NPY receptors, Y1R and Y2R, in evoked, and spontaneous, pain behavior under normal physiological condition. Using intrathecal (i.t.) administration approach, we found that pharmacological inhibition of Y2R, unexpectedly, gave rise to spontaneous pain behavior. In addition, Y2R antagonism also resulted in long-lasting mechanical but not thermal hypersensitivity. By contrast, no overt spontaneous pain behavior, nor mechanical and thermal hypersensitivity were detected after pharmacological inhibition of Y1R. Remarkably, activation of Y1R produced powerful analgesic effect: blocking both evoked and spontaneous pain behavior resulted from Y2R antagonism. These findings highlight the pivotal role of endogenous Y2R in gating mechanical and spontaneous pain transmission. Importantly, our results suggest that Y1R could be a therapeutic target that may be exploited for alleviating spontaneous pain without affecting acute pain transmission.

Aldosterone is believed to be synthesized exclusively in the adrenal gland through the processing enzyme aldosterone synthaseMineralocorticoid receptors are predominantly expressed in peripheral nociceptive neurons whose activation leads to increased neuronal excitability and mechanical sensitivity WHAT THIS ARTICLE TELLS US THAT IS NEW: Extra-adrenal production of aldosterone by aldosterone synthase within peripheral sensory neurons contributes to ongoing mechanical hypersensitivity via intrinsic activation of neuronal mineralocorticoid receptorsIntrathecally-applied aldosterone synthase inhibitor reduced aldosterone content in peripheral sensory neurons and subsequently attenuated enhanced mechanical hypersensitivity resulting from local inflammation BACKGROUND:: Recent emerging evidence suggests that extra-adrenal synthesis of aldosterone occurs (e.g., within the failing heart and in certain brain areas). In this study, the authors investigated evidence for a local endogenous aldosterone production through its key processing enzyme aldosterone synthase within peripheral nociceptive neurons.