Leukotrienes in Nociceptive Pathway and Neuropathic/Inflammatory Pain

Abstract

The purpose of this review is to summarize the recent studies examining the expression of leukotrienes (LTs) and their receptors in nociceptive pathways, and their crucial roles in pathological pain conditions. LTs belong to a large family of lipid mediators, termed eicosanoids, which are derived from arachidonic acids and released from the cell membrane by phospholipases. LTs are known to be important factors in a variety of local and systemic diseases and allergic/inflammatory diseases. We examined whether LTs were implicated in neuropathic pain following peripheral nerve injury. Using the SNI model in rats, we investigated the expression of LT synthases and receptors mRNAs in the spinal cord and the roles on the pain behaviors. We found the expression of 5-lipoxygenase (5-LO), FLAP and the cysteinyl leukotrienes (CysLT1) mRNAs in spinal microglia, LTA4h and LTC4s mRNAs in both spinal neurons and microglia, and BLT1 mRNA in spinal neurons. Administration of the 5-LO inhibitor or the receptor antagonists suppressed mechanical allodynia. Our findings suggest that the increase of LT synthesis in spinal microglia produced via p38 mitogen-activated protein kinase (MAPK) plays a role in the generation of neuropathic pain. We also examined the expression and roles on pain behaviors of LT receptors in the dorsal root ganglion (DRG) using a peripheral inflammation model. The data indicate CysLT2 expressed in DRG neurons may play a role as a modulator of P2X3, and contribute to the potentiation of the neuronal activity following peripheral inflammation. This review summarizes the hypothesis that LTs might work in the spinal cord and primary afferent in pathological pain conditions.

Similar Neutrophil-Driven Inflammatory and Antibacterial Responses in Elderly Patients with Symptomatic and Asymptomatic Bacteriuria

“…Prostaglandins may act as pro-and anti-inflammatory signals and are not known as effectors of neutrophils (54). Although in-depth characterization of eicosanoids in the urinary tract is required to assess their roles in the sensation of pain and the occurrence of fever, our data support the notion that leukotrienes contribute to inflammation and pain signaling upon activation of the immune system in ASB and UTI cases, consistent with a study on neuropathy where leukotrienes were found to activate their nociceptive receptors (55). Our data also suggest that enzymes degrading leukotrienes, especially those facilitating ␤-oxidation (43), are less active; thus, LTB 4 levels are maintained as long as pathogens are present.…”

A broad-spectrum lipidomics screen of antiinflammatory drug combinations in human blood

“…Considering the involvement of both COX and LOX pathways in common inflammatory diseases, such as atherosclerosis (13, 14), abdominal aortic aneurysm (39–41), asthma (42, 43), arthritis, and inflammatory pain (13, 44, 45), dual inhibitors of both pathways are of interest (46). Concurrent blockade of mPGES-1 with inhibition of various components of the 5-LOX pathway revealed both predicted and unexpected effects on the human plasma lipidome.…”

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

“…As LOX products have been shown to contribute to nociception also at the spinal level (540,731), results obtained employing either systemically administered LOX inhibitors/leukotriene receptor antagonists with possible brain penetration or LOX knockout animals may reflect leukotriene effects exerted not necessarily in the periphery but possibly in the central nervous system. For this reason, several of the above-mentioned studies must be treated with caution when considering the peripheral pronociceptive effects of leukotrienes.…”