Interleukin-10 resolves pain hypersensitivity induced by cisplatin by reversing sensory neuron hyperexcitability

Abstract

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.

Targeting the A3 adenosine receptor to prevent and reverse chemotherapy-induced neurotoxicities in mice

“…Moreover, prevention of chemotherapy-induced allodynia by co-administration of an A 3 AR agonist is IL10 mediated as well [ 53 ]. Notably, we showed recently that the spontaneous resolution of cisplatin-induced neuropathy is dependent on IL10 signaling as well [ 27 ]. Moreover, the resolution of cisplatin-induced neuropathic pain in response to nasal administration of mesenchymal stem cells was also mediated by IL10 [ 3 ], indicating that IL10 signaling to peripheral sensory neurons could represent a common mechanism underlying resolution of neuropathic pain.…”

IL4-10 Fusion Protein Shows DMOAD Activity in a Rat Osteoarthritis Model

“… 15 Indeed various studies showed that cytokines, such as IL-10 and IL-4 may have direct effects on neurons and control their excitability. 25 - 29 Although IL4-10 FP may have direct analgesic properties through direct effects on sensory neurons, subchondral bone osteoclasts and chondrocytes also contribute to OA pain 30 , 31 and are known to express IL-4 and IL-10 receptors. 13 , 32 , 33 Thus it is likely that the observed analgesic effect of IL4-10 FP is also mediated (in part) through indirect actions through osteoclast and chondrocytes or even other intermediate cells.…”

RNA Profiling of Neuropathic Pain-Associated Human DRGs Reveal Sex-differences in Neuro-immune Interactions Promoting Pain

“…Ectopic activity can originate from axons, in particular early after injury, but it can also emerge from the DRG soma (Amir et al, 2005). This likely happens due to changes in expression of ion channels in the DRG neuronal soma (Devor, 2006), or due to signaling events that cause the neuron to generate ectopic action potentials and instability in the resting membrane potential (Devor and Yarom, 2002; Odem et al, 2018; Garza Carbajal et al, 2020; Laumet et al, 2020; Lopez et al, 2021). Our previous work clearly showed that human DRG neuron somata from neuropathic pain patients could display ectopic activity, even after surgical removal and culturing (North et al, 2019).…”