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 jpet.118.250126
DO 10.1124/jpet.118.250126
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 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/early/2019/03/25/jpet.118.250126.abstract
AB 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.