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Abstract
The new chemokine Prokineticin 2 (PROK2) and its receptors (PKR1 and PKR2) have a role in inflammatory pain and immunomodulation. Here we identified PROK2 as a critical mediator of neuropathic pain in the chronic constriction injury (CCI) of the sciatic nerve in mice and demonstrated that blocking the prokineticin receptors with two PKR1-preferring antagonists (PC1 and PC7) reduces pain and nerve damage. PROK2 mRNA expression was upregulated in the injured nerve since day 3 post injury (dpi) and in the ipsilateral DRG since 6 dpi. PROK2 protein overexpression was evident in Schwann Cells, infiltrating macrophages and axons in the peripheral nerve and in the neuronal bodies and some satellite cells in the DRG. Therapeutic treatment of neuropathic mice with the PKR-antagonist, PC1, impaired the PROK2 upregulation and signalling. This fact, besides alleviating pain, brought down the burden of proinflammatory cytokines in the damaged nerve and prompted an anti-inflammatory repair program. Such a treatment also reduced intraneural oedema and axon degeneration as demonstrated by the physiological skin innervation and thickness conserved in CCI-PC1 mice. These findings suggest that PROK2 plays a crucial role in neuropathic pain and might represent a novel target of treatment for this disease.
Highlights
Identification of the neurobiological processes engaged in the pathological state that occurs during neuropathic pain may provide future therapeutic targets
Availability of a new Bv8 antagonist, named PC7, able to antagonize the Bv8-induced hyperalgesia at doses ten times lower than PC1 and endowed with higher selectivity for the PKR1 [15] pushed us to evaluate its efficacy in this neuropathic pain model
In support of this hypothesis, we show that blocking the prokineticin receptors with two PKR1preferring antagonists reduced pain and nerve damage
Summary
Identification of the neurobiological processes engaged in the pathological state that occurs during neuropathic pain may provide future therapeutic targets. Chemokines and their receptors are receiving growing interest as modulators of neuronal plasticity and for their ability to enhance nociceptive transmission under conditions of neuropathic pain [1]. In an animal model of CFA-induced paw inflammation, we brought evidence that Bv8/PROK2, upregulated in granulocyte invading the inflamed tissue is a major determinant in triggering and maintaining inflammatory pain [3]. Neutrophils and macrophages are the major sources of PROK2 which is strongly upregulated in inflammatory diseases and tumours, associated with infiltrating cells [4, 5]. In vivo and in vitro experiments from our and other groups demonstrated
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