Understanding the mechanisms that drive transition from acute to chronic pain is essential to identify new therapeutic targets. The importance of endogenous resolution pathways acting as a "brake" to prevent development of chronic pain has been largely ignored. We examined the role of IL-10 in resolution of neuropathic pain induced by cisplatin. In search of an underlying mechanism, we studied the effect of cisplatin and IL-10 on spontaneous activity (SA) in DRG neurons. Cisplatin (2 mg/kg daily for 3 days) induced mechanical hypersensitivity that resolved within 3 weeks. In both sexes, resolution of mechanical hypersensitivity was delayed in Il10 −/− mice, in WT mice treated intrathecally with neutralizing anti-IL-10 antibody, and in mice with cell-targeted deletion of IL-10R1 on advillin-positive sensory neurons. Electrophysiologically, small to medium-sized DRG neurons from cisplatin-treated mice displayed an increase in the incidence of spontaneous activity. Cisplatin treatment also depolarized the resting membrane potential, and decreased action potential voltage threshold and rheobase, while increasing ongoing activity at −45 mV and the amplitude of depolarizing spontaneous fluctuations (DSFs). In vitro addition of IL-10 (10 ng/ml) reversed the effect of cisplatin on SA and on the DSFs amplitudes, but unexpectedly had little effect on the other electrophysiological parameters affected by cisplatin. Collectively, our findings challenge the prevailing concept that IL-10 resolves pain solely by dampening neuroinflammation and demonstrate in a model of chemotherapy-induced neuropathic pain that endogenous IL-10 prevents transition to chronic pain by binding to IL-10 receptors on sensory neurons to regulate their activity.

The mechanisms responsible for the persistence of chemotherapy-induced peripheral neuropathy (CIPN) in a significant proportion of cancer survivors are still unknown. Our previous findings show that CD8 + T cells are necessary for the resolution of paclitaxel-induced mechanical allodynia in male mice. In the present study, we demonstrate that CD8 + T cells are not only essential for resolving cisplatin-induced mechanical allodynia, but also to normalize spontaneous pain, numbness, and the reduction in intra-epidermal nerve fiber density in male and female mice. Resolution of CIPN was not observed in Rag2 −/− mice that lack T and B cells. Reconstitution of Rag2 −/− mice with CD8 + T cells prior to cisplatin treatment normalized the resolution of CIPN. In vivo education of CD8 + T cells by cisplatin was necessary to induce resolution of CIPN in Rag2 −/− mice because adoptive transfer of CD8 + T cells from naïve WT mice to Rag2 −/− mice after completion of chemotherapy did not promote resolution of established CIPN. The CD8 + T cell-dependent resolution of CIPN does not require epitope recognition by the T cell receptor (TCR). Moreover, adoptive transfer of cisplatin-educated CD8 + T cells to Rag2 −/− mice prevented CIPN development induced by either cisplatin or paclitaxel, indicating that the activity of the educated CD8 + T is not cisplatin-specific. In conclusion, resolution of CIPN requires in vivo education of CD8 + T cells by exposure to cisplatin. Future studies should examine whether ex vivo CD8 + T cell education could be applied as a therapeutic strategy for treating or preventing CIPN in patients.

Pain and depression often co-occur, but the underlying mechanisms have not been elucidated. Here, we used the spared nerve injury (SNI) model in mice to induce both neuropathic pain and depression-like behavior. We investigated whether brain IL-1 signaling and activity of kynurenine 3-monoxygenase (KMO), a key enzyme for metabolism of kynurenine into the neurotoxic NMDA receptor agonist quinolinic acid, are necessary for comorbid neuropathic pain and depression-like behavior. SNI mice showed increased expression levels of Il1b and Kmo mRNA in the contralateral side of the brain. The SNI-induced increase of Kmo mRNA was associated with increased KMO protein and elevated quinolinic acid and reduced kynurenic acid in the contralateral hippocampus. The increase in KMO-protein in response to SNI mostly took place in hippocampal NeuN-positive neurons rather than microglia. Inhibition of brain IL-1 signaling by intracerebroventricular administration of IL-1RA after SNI prevented the increase in Kmo mRNA and depression-like behavior measured by forced swim test. However, inhibition of brain IL-1 signaling has no effect on mechanical allodynia. In addition, intracerebroventricular administration of the KMO inhibitor Ro 61-8048 abrogated depression-like behavior without affecting mechanical allodynia after SNI. We show for the first time that the development of depression-like behavior in the SNI model requires brain IL-1 signaling and activation of neuronal KMO, while pain is independent of this pathway. Inhibition of KMO may represent a promising target for treating depression.

In humans, depression is often associated with low-grade inflammation, activation of the tryptophan/kynurenine pathway, and mild lymphopenia. Preclinical research confirms that inflammation induces depression-like behavior through activation of the tryptophan/kynurenine pathway. However, the mechanisms governing recovery from depression are unknown. Understanding the pathways leading to resolution of depression will likely lead to identification of novel targets for treatment. We investigated the contribution of T lymphocytes to the resolution of lipopolysaccharide-induced depression-like behavior. Duration of depression-like behavior was markedly prolonged in mice without mature T or B lymphocytes (Rag1 mice). This prolonged depression-like behavior was associated with persistent upregulation of the tryptophan-metabolizing enzyme indoleamine-2,3-dioxygenase (Ido)1 in the prefrontal cortex (PFC). Reconstitution of Rag1 mice with T lymphocytes normalized resolution of depression-like behavior and expression of Ido1 in the PFC. During resolution of inflammation-induced depression-like behavior, T lymphocytes accumulated in the meninges and were required for induction of interleukin (IL)-10 in the meninges and the PFC. Inhibition of IL-10 signaling by nasal administration of neutralizing anti-IL-10 antibody to WT mice led to persistent upregulation of Ido1 in the PFC and prolonged depression-like behavior. Conversely, nasal administration of recombinant IL-10 in Rag1 mice normalized Ido1 expression and resolution of depression-like behavior. In conclusion, the present data show for the first time that resolution of inflammation-induced depression is an active process requiring T lymphocytes acting via an IL-10-dependent pathway to decrease Ido1 expression in the brain. We propose that targeting the T lymphocyte/IL-10 resolution pathway could represent a novel approach to promote recovery from major depressive disorder.

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