Prostacyclin mediates neuropathic pain through interleukin 1β-expressing resident macrophages

Abstract

Prostacyclin is an important mediator of peripheral pain sensation. Here, we investigated its potential participation in mediating neuropathic pain and found that prostacyclin receptor (IP) knockout mice exhibited markedly decreased pain behavior. Application of an IP antagonist to the injury site or selective IP deficiency in myeloid cells mimicked the antinociceptive effect observed in IP knockout mice. At the site of nerve injury, IP was expressed in interleukin (IL) 1β-containing resident macrophages, which were less common in IP knockout mice. Local administration of the IP agonist cicaprost inhibited macrophage migration in vitro and promoted accumulation of IP- and IL1β-expressing cells as well as an increase of IL1β concentrations at the application site in vivo. Fittingly, the IL1-receptor antagonist anakinra (IL-1ra) decreased neuropathic pain behavior in wild-type mice but not in IP knockout mice. Finally, continuous, but not single administration, of the cyclooxygenase inhibitor meloxicam early after nerve injury decreased pain behavior and the number of resident macrophages. Thus, early synthesis of prostacyclin at the site of injury causes accumulation of IL1β-expressing macrophages as a key step in neuropathic pain after traumatic injury.

Differential Association Between Biomarkers of Subclinical Inflammation and Painful Polyneuropathy: Results From the KORA F4 Study

“…Therefore, a direct effect of IL-1b on the development of neuropathic pain is conceivable (25). Moreover, IL-1b activates macrophages, Schwann cells, and neurons, which in turn release cytokines, prostaglandins, and other mediators, so that indirect effects to the generation of neuropathic pain are also possible (26,27). Thus, IL-1b-mediated mechanisms represent potentially relevant contributors to neuropathic pain despite our null finding for IL-1RA.…”

Prostaglandin I 2 upregulates the expression of anterior pharynx‐defective‐1α and anterior pharynx‐defective‐1β in amyloid precursor protein/presenilin 1 transgenic mice

“…Schuh et al . (2014) also reported that the early induction of PGI 2 at the site of traumatic injury resulted in the aggregation of IL‐1β‐expressing macrophages as a critical reason for neuropathic pain. Although the effects of these cytokines on Aβ production are still in debating, these prior works have indicated that PGI 2 might play its roles in AD via inducing the production of cytokines.…”

Etiology and Pharmacology of Neuropathic Pain

“…The initial inflammatory event at the site of nerve injury is a major trigger for the sequelae that lead to central sensitization (Watkins and Maier, 2002;Scholz and Woolf, 2007;White et al, 2007;Basbaum et al, 2009;Stemkowski and Smith, 2012b;Grace et al, 2014;Schuh et al, 2014;Ko et al, 2016) (Fig. 2A).…”