IL-1β Stimulates COX-2 Dependent PGE2 Synthesis and CGRP Release in Rat Trigeminal Ganglia Cells

Abstract

ObjectivePro-inflammatory cytokines like Interleukin-1 beta (IL-1β) have been implicated in the pathophysiology of migraine and inflammatory pain. The trigeminal ganglion and calcitonin gene-related peptide (CGRP) are crucial components in the pathophysiology of primary headaches. 5-HT1B/D receptor agonists, which reduce CGRP release, and cyclooxygenase (COX) inhibitors can abort trigeminally mediated pain. However, the cellular source of COX and the interplay between COX and CGRP within the trigeminal ganglion have not been clearly identified.Methods and Results1. We used primary cultured rat trigeminal ganglia cells to assess whether IL-1β can induce the expression of COX-2 and which cells express COX-2. Stimulation with IL-1β caused a dose and time dependent induction of COX-2 but not COX-1 mRNA. Immunohistochemistry revealed expression of COX-2 protein in neuronal and glial cells. 2. Functional significance was demonstrated by prostaglandin E2 (PGE2) release 4 hours after stimulation with IL-1β, which could be aborted by a selective COX-2 (parecoxib) and a non-selective COX-inhibitor (indomethacin). 3. Induction of CGRP release, indicating functional neuronal activation, was seen 1 hour after PGE2 and 24 hours after IL-1β stimulation. Immunohistochemistry showed trigeminal neurons as the source of CGRP. IL-1β induced CGRP release was blocked by parecoxib and indomethacin, but the 5-HT1B/D receptor agonist sumatriptan had no effect.ConclusionWe identified a COX-2 dependent pathway of cytokine induced CGRP release in trigeminal ganglia neurons that is not affected by 5-HT1B/D receptor activation. Activation of neuronal and glial cells in the trigeminal ganglion by IL-β leads to an elevated expression of COX-2 in these cells. Newly synthesized PGE2 (by COX-2) in turn activates trigeminal neurons to release CGRP. These findings support a glia-neuron interaction in the trigeminal ganglion and demonstrate a sequential link between COX-2 and CGRP. The results could help to explain the mechanism of action of COX-2 inhibitors in migraine.

Trigeminal Pain Molecules, Allodynia, and Photosensitivity Are Pharmacologically and Genetically Modulated in a Model of Traumatic Brain Injury

“…[54][55][56][57] Prostaglandin E2 stimulates neuronal excitability, triggers the trigeminal ganglia neurons to release CGRP, and, in turn, signals pain. 58,59 Neurons, microglia, and astrocytes not only release proinflammatory molecules, but also play a role in handling or reacting with pronociceptive mediators (e,g., glutamate, CGRP, and substance P) that contribute to neuronal sensitization and chronic pain. [60][61][62][63] Cortical injury increases iNOS gene and protein synthesis in the ascending trigeminal pain pathway.…”

Translocation of NF-κB and Expression of Cyclooxygenase-2 Are Enhanced by Ketamine-Induced Ulcerative Cystitis in Rat Bladder

“…Rat bladder urothelium and human bladder J82 cells were treated with ketamine in the range of 0.5 to 8.0 mmol/L 31 with or without COX-2 inhibitor (parecoxib 10 nmol/L) 35 diluted with Dulbecco's modified Eagle's medium. In the urine obtained from rats treated with ketamine and ketamine þ COX-2 inhibitor, the urinary concentrations of ketamine were 1468 and 1406 ng/mL, respectively, and those of norketamine were 38,720 and 32,720 ng/mL Q18 ( Table 1).…”

Genetic Polymorphism of Cytokines as a Predictor of Phenotypic Development of Chronic Pain Syndrome in Cancer Patients

“…(26) Polymorphism of the IL1β gene also predetermines differences in pain perception and changes in morphine consumption during the postoperative period, (10) and in the development of depression (28) and fatigue. (10,28) An increase in the expression of the IL1β gene causes peripheral hyperalgesia, and vice versa: administration of the IL-1 receptor antagonist leads to suppression of the nociceptive reaction.…”

“…(10,28) An increase in the expression of the IL1β gene causes peripheral hyperalgesia, and vice versa: administration of the IL-1 receptor antagonist leads to suppression of the nociceptive reaction. (5,28,29) SNPs of the following genes are reported to be associated with the burden of pain and with the development of depression and fatigue in patients with lung malignancy NOS3 (1474 T>A, rs1800783), IL1B (allele 31C, rs1143627), TNFR2 (Met196Arg, rs1061622), PTGS2 (837T>C, rs5275), IL10RB (Lys47Glu, rs2834167) (30) against the background of existing non-genetic factors (the patient's sex, the stage of cancer).…”