Prokineticin 2 Upregulation in the Peripheral Nervous System Has a Major Role in Triggering and Maintaining Neuropathic Pain in the Chronic Constriction Injury Model

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.

Prokineticins are neuroprotective in models of cerebral ischemia and ischemic tolerance in vitro

“…20 mM), and that the effect of glutamate was dependent on the activation of NMDA receptors. Similarly to what reported by Lattanzi et al (Lattanzi et al, 2015), the increase in PK2 protein levels under our experimental conditions was dependent on the activation of PK receptors, again suggesting a possible paracrine mechanism for the increase in prokineticin expression. Fig.…”

Maternal exposure to low levels of corticosterone during lactation protects adult rat progeny against TNBS-induced colitis: A study on GR-mediated anti-inflammatory effect and prokineticin system

“…Here, we have shown that inflammatory colitis induced a significant increase in colonic PK2 mRNA levels and protein expression in control colitic animals, with respect to control healthy rats. The increase in PK2 under inflammatory conditions is well-demonstrated in different animal models of inflammation [42–44]. In particular, in agreement with our results, Watson and collaborators also showed that TNBS instillation increases colonic PK2 levels in rats [54].…”

Bv8/prokineticin 2 is involved in Aβ-induced neurotoxicity

“…It was previously reported that PC1 is able to reduce PROK2 up-regulation in DRG neurons and in activated astrocytes of spinal cord following nerve injury 22 27 . qRT-PCR experiments demonstrated, also in this system, that co-incubation with Aβ 1–42 and PC1 (100 nM) prevented the Aβ-induced PROK2 mRNA up-regulation ( Fig.…”