Reduced pain behaviors and extracellular signal‐related protein kinase activation in primary sensory neurons by peripheral tissue injury in mice lacking platelet‐activating factor receptor

Abstract

Peripheral tissue injury causes the release of various mediators from damaged and inflammatory cells, which in turn activates and sensitizes primary sensory neurons and thereby produces persistent pain. The present study investigated the role of platelet-activating factor (PAF), a phospholipid mediator, in pain signaling using mice lacking PAF receptor (pafr)/) mice). Here we show that pafr)/) mice displayed almost normal responses to thermal and mechanical stimuli but exhibit attenuated persistent pain behaviors resulting from tissue injury by locally injecting formalin at the periphery as well as capsaicin pain and visceral inflammatory pain without any alteration in cytoarchitectural or neurochemical properties in dorsal root ganglion (DRG) neurons and a defect in motor function. However, pafr)/) mice showed no alterations in spinal pain behaviors caused by intrathecally administering agonists for N-methyl-D-aspartate (NMDA) and neurokinin 1 receptors. A PAFR agonist evoked an intracellular Ca 2+ response predominantly in capsaicin-sensitive DRG neurons, an effect was not observed in pafr)/) mice. By contrast, the PAFR agonist did not affect C-or Ad-evoked excitatory postsynaptic currents in substantia gelatinosa neurons in the dorsal horn. Interestingly, mice lacking PAFR showed reduced phosphorylation of extracellular signal-related protein kinase (ERK), an important kinase for the sensitization of primary sensory neurons, in their DRG neurons after formalin injection. Furthermore, U0126, a specific inhibitor of the ERK pathway suppressed the persistent pain by formalin. Thus, PAFR may play an important role in both persistent pain and the sensitization of primary sensory neurons after tissue injury. Keywords: mitogen-activated protein kinase, platelet-activating factor receptor, primary afferent sensory neurons, tissue injury pain.

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…Sys-temically applied PAF antagonists reduced the late, but not early, phase of the formalin-induced nocifensive behavior (716). In PAF receptor knockout mice showing normal responses to acute heat and mechanical stimuli, both phases of formalin-induced nocifensive behavior were reduced compared with wild-types (734). In these knockout animals, the number of DRG neurons showing ERK activation in response to formalin was diminished, and the acute nocifensive reaction induced by capsaicin injected intraplantarly or acetic acid applied intraperitoneally was reduced compared with wild-types.…”

“…In cultured mouse DRG neurons, a stable PAF receptor agonist induced an elevation of intracellular Ca 2ϩ (734). Most of the responding neurons were capsaicin-sensitive, suggesting a colocalization of the PAF receptor and TRPV1.…”

A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain

“…The latency to either lick or shake the hindpaw or jump was measured. Noxious heat-evoked tail flick responses were detected by the application of radiant heat (50 V) (Ugo Basile, Italy)53. These behavioral assays were done 120 min after intrathecal administration of NP-1815-PX.…”

“…Each mouse was trained to run in a rotarod until it could remain there for 60 s without falling53. The mice were then evaluated in a rotarod test for 60 s 120 min after intrathecal injection of NP-1815-PX (30 pmol/5 μl).…”

Leukotriene synthases and the receptors induced by peripheral nerve injury in the spinal cord contribute to the generation of neuropathic pain

“…One of most interesting subjects in pain research is the discovery of lipid mediators and their receptors in nociceptive pathways, and their crucial roles in pathological pain conditions (Ma and Quirion, 2008;Tsuda et al, 2007;Yao et al, 2009). The metabolism of arachidonic acid via cyclooxygenase and lipoxygenase pathways produces prostaglandins and several lipoxygenase metabolites, respectively.…”