Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

• Published in: PloS one 2020-12, Vol.15 (12), p.e0232864-e0232864
• Main Authors: Margolis, Elyssa B, Wallace, Tanya L, Van Orden, Lori Jean, Martin, William J
• Format: Article
• Language: English
• Subjects: Agonists; Analgesics, Opioid - pharmacology; Animals; Benzamides - pharmacology; Biology and Life Sciences; Biphenyl Compounds - pharmacology; Brain research; Brain slice preparation; Circuits; Disorders; Dopamine; Dopamine receptors; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Electrophysiology; Enkephalin, D-Penicillamine (2,5)- - pharmacology; Enkephalins; Experiments; Health aspects; Laboratory animals; Male; Medicine and Health Sciences; Membrane Potentials - drug effects; Mesencephalon; Mesencephalon - metabolism; Narcotic antagonists; Narcotic Antagonists - pharmacology; Narcotics; Neurogenesis; Neurons; Opioid receptors (type delta); Opioid receptors (type kappa); Opioid receptors (type mu); Opioids; Oxadiazoles - pharmacology; Patch-Clamp Techniques - methods; Physical Sciences; Physiological aspects; Piperidines - pharmacology; Pyrrolidines - pharmacology; Quinolines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors; Receptors, Opioid, kappa - antagonists & inhibitors; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - metabolism; Recovery of function; Research and Analysis Methods; Sulfonamides - pharmacology; Ventral Tegmental Area - drug effects; Ventral tegmentum
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0232864

Activation of the kappa opioid receptor (KOR) contributes to the aversive properties of stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to aversive responses (Margolis et al. 2003, 2006); therefore, selective KOR antagonists represent a novel therapeutic approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and BTRX-395750 fully blocked U-69,593 currents (IC50 = 1.2 ± 0.9 and 1.2 ± 1.3 nM, respectively). JNJ-67953964 showed an IC50 of 3.0 ± 4.6 nM. PF-04455242 exhibited partial antagonist activity asymptoting at 55% blockade (IC50 = 6.7 ± 15.1 nM). In 3/8 of neurons, 1 μM PF-04455242 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked DAMGO and DPDPE responses. Importantly, BTRX-335140 (10 nM) rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we show electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems. The results of this study demonstrate the value of characterizing compounds in native neuronal tissue and within circuits implicated in the neurobehavioral disorders of interest.