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Papers of the Week


Papers: 23 Mar 2019 - 29 Mar 2019


Animal Studies, Pharmacology/Drug Development


2019 Jun


J Pharmacol Exp Ther


369


3

Modulation of TARP γ8-containing AMPA Receptors as a Novel Therapeutic Approach for Chronic Pain.

Authors

Knopp KL, Simmons R MA, Guo W, Adams BL, Gardinier KM, Gernert DL, Ornstein PL, Porter W, Reel J, Ding C, Wang H, Qian Y, Burris KD, Need A, Barth V, Swanson S, Catlow J, Witkin J, Zwart R, Sher E, et al.
J Pharmacol Exp Ther. 2019 Jun; 369(3):345-363.
PMID: 30910921.

Abstract

Non-selective glutamate AMPA receptor antagonists are efficacious in chronic pain, but have significant tolerability issues, likely arising from the ubiquitous expression of AMPA receptors in CNS. Recently, LY3130481 has been shown to selectively block AMPA receptors co-assembled with the auxiliary protein, TARP γ8, which is highly expressed in hippocampus, but also in pain pathways, including anterior cingulate (ACC) and somatosensory (SS) cortices and spinal cord, suggesting that selective blockade 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 co-expression 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 non-selective AMPA antagonist GYKI53784 completely blocked AMPA receptor-dependent EPSPs in ACC and spinal neurons in vitro. Similarly, LY3130481 attenuated short-term synaptic plasticity in spinal sensory neurons in vivo in response 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.