Chronic blockade of interleukin‐1 (IL‐1) prevents and attenuates neuropathic pain behavior and spontaneous ectopic neuronal activity following nerve injury

Abstract

Neuropathic pain is a chronic pain state resulting from peripheral nerve injury, characterized by hyperalgesia and allodynia. We have reported that mice with genetic impairment of IL-1 signaling display attenuated neuropathic pain behavior and ectopic neuronal activity. In order to substantiate the role of IL-1 in neuropathic pain, WT mice were implanted subcutaneously with osmotic micropumps containing either IL-1ra or vehicle. Two days following the implantation, two models of neuropathic pain were used; partial nerve injury (spinal nerve transection, SNT), or complete nerve cut (spinal neuroma model). Mechanosensitivity was assessed seven consecutive days following SNT, and on day 7 recordings of spontaneous ectopic activity were performed. In the spinal nerve neuroma model, autotomy scores were recorded up to 35 days. Vehicle-treated mice developed significant allodynia and autotomy, and clear ectopic activity (4.1±1.1% of the axons); whereas IL-1ra-treated mice did not display allodynic response, displayed delayed onset of autotomy and markedly reduced severity of autotomy scores, and displayed reduced spontaneous activity (0.8±0.4% of the axons). To test whether IL-1 is involved in maintenance of mechanical allodynia, a separate group of WT mice was treated with a single injection of either saline or IL-1ra four days following SNT, after the allodynic response was already manifested. Whereas saline-treated mice displayed robust allodynia, acute IL-1ra treatment induced long-lasting attenuation of the allodynic response. The results support our hypothesis that IL-1 signaling plays an important role in neuropathic pain and in the ectopic neuronal activity that underling its development.

Schwann cell interactions with axons and microvessels in diabetic neuropathy

“…Activation of Schwann cells in turn promotes their secretion of proinflammatory cytokines, thereby producing a positive feedback mechanism that perpetuates injury 109,110 . Inflammatory cytokines such as IL-1, tumour necrosis factor (TNF) and IL-17 can be produced by many cell types, including Schwann cells, and these factors sensitize Aδ-fibres and C-fibres, triggering neuropathic pain [111][112][113] . Indeed, blocking the TNF signalling pathway with a recombinant human TNF receptorantibody fusion protein has been shown to be beneficial in animal models of diabetic neuro pathy, leading to recovery of nerve conduction velocity and increased expression of myelin basic protein 109 .…”

Learning and memory … and the immune system

“…Not only are the immune and the nervous systems physically connected-there are resident immune cells in the central nervous system (CNS) and peripheral nerve terminals in immune organs-they also share each other's "languages" for their communication. Thus, cells of the nervous system can use signaling by immune components, such as cytokines and chemokines, to communicate with each other (Steinman 2004;McAllister and van de Water 2009;Ben MenachemZidon et al 2011;Diaz Heijtz et al 2011;Gabay et al 2011;Yirmiya and Goshen 2011), while immune cells possess neurotransmitter receptors and can synthesize neurotransmitter molecules including acetylcholine, glutamate, dopamine, and serotonin (Koval et al 1997;Steinman 2004;Ganea et al 2006;Pocock and Kettenmann 2007;Levite 2008;Kong et al 2010;Patterson 2012).…”

Design of a superior cytokine antagonist for topical ophthalmic use

“…IL-1β is essential for Th17 cell differentiation and maintenance, and Th17 cells are likely the main effector cells that induce epithelial damage (2, 3). Genetic and pharmacologic studies have shown that IL-1β mediates, and IL-1Ra blocks, normal, inflammatory, and neuropathic pain sensations (16)(17)(18)(19).The development of a topical biotherapeutic agent for DED presents a protein engineering challenge, requiring optimization for the biology and topical route of administration. Given the rapid turnover of tear volume (10% min −1 ) (20), blocking the tissue-associated receptor would be preferred over blocking tearassociated ligands, and the agent's target affinity should be maximized to minimize clearance and the frequency of dosing.…”

“…IL-1β is essential for Th17 cell differentiation and maintenance, and Th17 cells are likely the main effector cells that induce epithelial damage (2, 3). Genetic and pharmacologic studies have shown that IL-1β mediates, and IL-1Ra blocks, normal, inflammatory, and neuropathic pain sensations (16)(17)(18)(19).…”