Modulation of TARP γ 8-Containing AMPA Receptors as a Novel Therapeutic Approach for Chronic Pain.

Autor:	Knopp KL; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.) k.knopp@lilly.com., Simmons RMA; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Guo W; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Adams BL; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Gardinier KM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Gernert DL; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Ornstein PL; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Porter W; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Reel J; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Ding C; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Wang H; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Qian Y; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Burris KD; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Need A; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Barth V; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Swanson S; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Catlow J; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Witkin JM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Zwart R; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Sher E; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Choong KC; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Wall TM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Schober D; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Felder CC; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Kato AS; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Bredt DS; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.)., Nisenbaum ES; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.).
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2019 Jun; Vol. 369 (3), pp. 345-363. Date of Electronic Publication: 2019 Mar 25.
DOI:	10.1124/jpet.118.250126
Abstrakt:	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) γ 8, 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 γ 8/AMPA receptors may suppress nociceptive signaling with fewer CNS side effects. The potency of LY3130481 on recombinant γ 8-containing AMPA receptors was modulated by coexpression with other TARPs; γ 2 subunits affected activity more than γ 3 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 γ 8-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 γ 8/AMPA receptors and significantly reduce nocifensive behaviors, suggesting a novel, effective, and safer therapy for chronic pain conditions. (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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