Role of CNS Phospholipase A2 In Orofacial Pain

Introduction: Phospholipases A2 (PLA2) are enzymes that hydrolyze the sn-2 position of phospholipids to produce free fatty acids and lysophospholipids. Metabolites of arachidonic acid are not only inflammatory mediators but also messengers in the CNS. Objective: To determine if CNS PLA2s play a role in central sensitization and chronic orofacial pain. Materials and methods: PLA2 expression and enzyme activity in the CNS, and behavioral effects of inhibition were analyzed in untreated control animals and after hyperalgesia induced by facial carrageenan injection. A possible role of PLA2 on neurotransmitter release was also studied in vitro. Results: High levels of expression of cytosolic PLA2 (cPLA2) and secretory PLA2 (sPLA2) are present in neurons of the rat spinal trigeminal nucleus and dorsal horn. Significant decrease in phosphatidylethanolamine but increase in lysophosphatidylethanolamine species, indicating increased PLA2 activity is detected in the cervical spinal cord by lipidomic analyses after facial carrageenan injection. Intracerebroventricular injection of the sPLA2 inhibitor, 12-episcalaradial results in significant and prolonged reduction of carrageenan-induced nociceptive responses. sPLA2-IIA induces neurotransmitter release from neurons, and is itself released from neurons, via glutamatergic stimulation. sPLA2-IIA-EGFP fusion protein is concentrated in secretory granules in stably transfected SH-SY5Y neuroblastoma cells, and exocytosis of the enzyme is induced by glutamate or its analogs in a PKC-dependent manner. Conclusion: Together, the results suggest that CNS sPLA2 could play an important role in enhancing glutamatergic signaling in the brainstem and spinal cord during central sensitization and chronic pain.