Controlling the activation of the Bv8/prokineticin system reduces neuroinflammation and abolishes thermal and tactile hyperalgesia in neuropathic animals

Abstract

BACKGROUND AND PURPOSEChemokines are involved in neuroinflammation and contribute to chronic pain processing. The new chemokine prokineticin 2 (PROK2) and its receptors (PKR1 and PKR2) have a role in inflammatory pain and immunomodulation. In the present study, we investigated the involvement of PROK2 and its receptors in neuropathic pain. EXPERIMENTAL APPROACHEffects of single, intrathecal, perineural and s.c. injections of the PKR antagonist PC1, or of 1 week s.c. treatment, on thermal hyperalgesia and tactile allodynia was evaluated in mice with chronic constriction of the sciatic nerve (CCI). Expression and localization of PROK2 and of its receptors at peripheral and central level was evaluated 10 days after CCI, following treatment for 1 week with saline or PC1. IL-1β and IL-10 levels, along with glia activation, were evaluated. KEY RESULTSSubcutaneous, intrathecal and perineural PC1 acutely abolished the CCI-induced hyperalgesia and allodynia. At 10 days after CCI, PROK2 and its receptor PKR2 were up-regulated in nociceptors, in Schwann cells and in activated astrocytes of the spinal cord. Therapeutic treatment with PC1 (s.c., 1 week) alleviated established thermal hyperalgesia and allodynia, reduced the injury-induced overexpression of PROK2, significantly blunted nerve injury-induced microgliosis and astrocyte activation in the spinal cord and restored the physiological levels of proinflammatory and anti-inflammatory cytokines in periphery and in spinal cord. CONCLUSION AND IMPLICATIONSThe prokineticin system contributes to pain modulation via neuron-glia interaction. Sustained inhibition of the prokineticin system, at peripheral or central levels, blocked both pain symptoms and some events underlying disease progression. AbbreviationsCFA, complete Freund's adjuvant; PC1, prokineticin receptor antagonist; PKR1, prokineticin receptor 1; PKR2, prokineticin receptor 2; PROK2, prokineticin 2

Involvement of Spinal Bv8/Prokineticin 2 in a Rat Model of Cancer‐Induced Bone Pain

“…Recently, Maftei et al . reported that Bv8 expression levels were increased in nociceptors at day 10 after chronic constriction of the sciatic nerve (CCI). Treatment with PC1 (antagonist of prokineticin receptor) ameliorated thermal and mechanical hyperalgesia, and reduced spinal Bv8 and pro‐inflammatory cytokines expression.…”

“…Intraplantar injection of Bv8 induces a localized hyperalgesia by reducing the nociceptive thresholds to thermal, chemical and mechanical stimuli . Recent studies have indicated that Bv8 is involved in inflammatory and neuropathic pain . However, CIBP is a mixed‐mechanism pain state that is not totally similar to inflammatory or neuropathic pain , and the potential role of spinal Bv8 in CIBP has not yet been examined.…”

Inhibitory effect of positively charged triazine antagonists of prokineticin receptors on the transient receptor vanilloid type-1 (TRPV1) channel

“…PKR1 gene deletion or PKR1 blockade with PC-1, markedly reduced the inflammation-induced hypersensitivity and the up-regulation of Bv8/PK2 [15,23,37]. Furthermore, the prokineticin system plays a role in neuroinflammation and in the evolution of the neuropathic pain, and PC-1 administration at peripheral or central levels alleviates an established neuropathic hyperalgesia and prevents the activation of glia and the increased production of inflammatory cytokines [38].…”

The prokineticin Bv8 sensitizes cutaneous terminals of female mice to heat

“…In addition, behavioural tests in mice lacking PKR1 showed impaired response to noxious heat and capsaicin/ acetic acid/complete Freund's adjuvant (CFA) injection (Negri et al, 2006a). In another study, blocking PKRs alleviated thermal hyperalgesia and tactile allodynia in mice following chronic constriction of sciatic nerve (Maftei et al, 2014). While the involvement of the PK receptors in the development of peripheral neuronal sensitization under inflammatory/neuropathic conditions or Bv8 treatment is well established, further insights concerning mechanisms of peripheral activation remain unresolved.…”