RT Journal Article SR Electronic T1 Modulation of TARP γ8–Containing AMPA Receptors as a Novel Therapeutic Approach for Chronic Pain JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 345 OP 363 DO 10.1124/jpet.118.250126 VO 369 IS 3 A1 Kelly L. Knopp A1 Rosa Maria A. Simmons A1 Wenhong Guo A1 Benjamin L. Adams A1 Kevin M. Gardinier A1 Douglas L. Gernert A1 Paul L. Ornstein A1 Warren Porter A1 Jon Reel A1 Chunjin Ding A1 He Wang A1 Yuewei Qian A1 Kevin D. Burris A1 Anne Need A1 Vanessa Barth A1 Steven Swanson A1 John Catlow A1 Jeffrey M. Witkin A1 Ruud Zwart A1 Emanuele Sher A1 Kar-Chan Choong A1 Theron M. Wall A1 Douglas Schober A1 Christian C. Felder A1 Akihiko S. Kato A1 David S. Bredt A1 Eric S. Nisenbaum YR 2019 UL http://jpet.aspetjournals.org/content/369/3/345.abstract AB Nonselective glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists are efficacious in chronic pain but have significant tolerability issues, likely arising from the ubiquitous expression of AMPA receptors in the central nervous system (CNS). Recently, LY3130481 has been shown to selectively block AMPA receptors coassembled with the auxiliary protein, transmembrane AMPA receptor regulatory protein (TARP) γ8, which is highly expressed in the hippocampus but also in pain pathways, including anterior cingulate (ACC) and somatosensory cortices and the spinal cord, suggesting that selective blockade of γ8/AMPA receptors may suppress nociceptive signaling with fewer CNS side effects. The potency of LY3130481 on recombinant γ8-containing AMPA receptors was modulated by coexpression with other TARPs; γ2 subunits affected activity more than γ3 subunits. Consistent with these findings, LY3130481 had decreasing potency on receptors from rat hippocampal, cortical, spinal cord, and cerebellar neurons that was replicated in tissue from human brain. LY3130481 partially suppressed, whereas the nonselective AMPA antagonist GYKI53784 completely blocked, AMPA receptor–dependent excitatory postsynaptic potentials in ACC and spinal neurons in vitro. Similarly, LY3130481 attenuated short-term synaptic plasticity in spinal sensory neurons in vivo in response to stimulation of peripheral afferents. LY3130481 also significantly reduced nocifensive behaviors after intraplantar formalin that was correlated with occupancy of CNS γ8-containing AMPA receptors. In addition, LY3130481 dose-dependently attenuated established gait impairment after joint damage and tactile allodynia after spinal nerve ligation, all in the absence of motor side effects. Collectively, these data demonstrate that LY3130481 can suppress excitatory synaptic transmission and plasticity in pain pathways containing γ8/AMPA receptors and significantly reduce nocifensive behaviors, suggesting a novel, effective, and safer therapy for chronic pain conditions.