ROLE OF PERIPHERALLY EXPRESSED CALCIUM-PERMEABLE AMPA RECEPTORS IN CHRONIC INFLAMMATORY PAIN

Aim of Investigation: Mechanisms underlying chronic, pathological pain are not well-understood. Plasticity in peripheral nociceptors and their synapses with spinal neurons can serve as a cellular basis for the development and maintenance of chronic pain following inflammation or nerve injury. Although there are anatomical evidence for the expression of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type (AMPA-type) glutamate receptors (AMPARs) in the peripheral nervous system, either their role in chronic pain or their relative contribution of peripheral versus central in chronic pain is unknown. To elucidate the function of AMPARs expressed in peripheral nociceptive neurons in pain modulation, we generated a conditional knock-out mouse lacking GluA1 or GluA2 subunit of AMPA receptors specifically in nociceptors, while preserving their expression in the spinal cord and brain using cre-lox recombinase system under the control of Nav1.8 promoter. Methods: All animal experiments were approved by the local ethical committee (Regierungspräsidium Karlsruhe). Mice lacking GluA1 or GluA2 specifically in peripheral nociceptors were generated using Cre-loxP mediated recombination system without affecting its expression in spinal cord and brain, being referred to as SNS-GluA1-/-or SNS-GluA2-/-. Chronic pain hypersensitivity and underlying mechanisms in these mice were tested using a combination of molecular, biochemical, electrophysiological and behavioral analyses. Pain models used in this study includes; capsaicin test, Formalin test, Complete Freund's adjuvant and knee arthritis inflammatory pain models. Results: In this study, we established the role of AMPA receptors located at the peripheral side of the pain pathway in physiological and inflammatory pain states. To this end, we deleted individual subunits and this approach affects the activation, gating, signaling properties of the AMPA receptors without deleting the function of AMPA receptors completely. Interestingly, we observed that the deletion of GluRA1 but not GluRA2 affected the role of AMPA receptor in pain processing. Deletion of GluRA1 reduced the calcium influx triggered by its native agonist, glutamate, by 50%. It also decreases the excitability of nerve fibers in response to exposure of peripheral terminals to different algogens. In contrast, GluRA1 is also contributing to depression of neurotransmitter release in central terminals of nociceptors. Nonetheless, the overall in vivo contributions of GluRA1 at peripheral and central terminals of nociceptors clearly emerged as a pronociceptive, sensitizing role for GluA1-containing AMPARs in inflammatory hyperalgesia. Conclusions: In summary, the results of this study demonstrate an important contribution of GluA1-containing calcium-permeable AMPARs expressed in the peripheral nervous system in modulating the activation properties of nociceptive neurons in response to algogens or in an inflammatory milieu. Furthermore, these findings clearly elucidated and delineated the central versus peripheral components of actions of calcium permeable AMPA receptor in chronic pain. This distinction is clinically very important because if chronic pain is completely centralized, therapeutic approaches targeting peripheral mechanisms are unlikely to be therapeutically beneficial. Conversely, if the peripheral contribution is strong, targeting peripheral mechanisms are offers the unique advantage of bypassing deleterious side effects.