Dual Kv7.2/3-TRPV1 modulators inhibit nociceptor hyperexcitability and alleviate pain without target-related side effects.

ABSTRACT: Persistent or chronic pain is the primary reason people seek medical care, yet current therapies are either limited in efficacy or cause intolerable side effects. Diverse mechanisms contribute to the basic phenomena of nociceptor hyperexcitability that initiates and maintains pain. Two prominent players in the modulation of nociceptor hyperexcitability are the transient receptor potential vanilloid type 1 (TRPV1) ligand-gated ion channel and the voltage-gated potassium channel, Kv7.2/3, that reciprocally regulate neuronal excitability. Across many drug development programs targeting either TRPV1 or Kv7.2/3, significant evidence has been accumulated to support these as highly relevant targets; however, side effects that are poorly separated from efficacy have limited the successful clinical translation of numerous Kv7.2/3 and TRPV1 drug development programs. We report here the pharmacological profile of 3 structurally related small molecule analogues that demonstrate a novel mechanism of action (MOA) of dual modulation of Kv7.2/3 and TRPV1. Specifically, these compounds simultaneously activate Kv7.2/3 and enable unexpected specific and potent inhibition of TRPV1. This in vitro potency translated to significant analgesia in vivo in several animal models of acute and chronic pain. Importantly, this specific MOA is not associated with any previously described Kv7.2/3 or TRPV1 class-specific side effects. We suggest that the therapeutic potential of this MOA is derived from the selective and specific targeting of a subpopulation of nociceptors found in rodents and humans. This efficacy and safety profile supports the advancement of dual TRPV1-Kv7.2/3 modulating compounds into preclinical and clinical development for the treatment of chronic pain.

Sex-dependent control of pheromones on social organization within groups of wild house mice.

Dominance hierarchy is a fundamental social phenomenon in a wide range of mammalian species, critically affecting fitness and health. Here, we investigate the role of pheromone signals in the control of social hierarchies and individual personalities within groups of wild mice. For this purpose, we combine high-throughput behavioral phenotyping with computational tools in freely interacting groups of wild house mice, males and females, in an automated, semi-natural system. We show that wild mice form dominance hierarchies in both sexes but use sex-specific strategies, displaying distinct male-typical and female-typical behavioral personalities that were also associated with social ranking. Genetic disabling of VNO-mediated pheromone detection generated opposite behavioral effects within groups, enhancing social interactions in males and reducing them in females. Behavioral personalities in the mutated mice displayed mixtures of male-typical and female-typical behaviors, thus blurring sex differences. In addition, rank-associated personalities were abolished despite the fact that both sexes of mutant mice formed stable hierarchies. These findings suggest that group organization is governed by pheromone-mediated sex-specific neural circuits and pave the way to investigate the mechanisms underlying sexual dimorphism in dominance hierarchies under naturalistic settings.

Expression of Cntnap2 (Caspr2) in multiple levels of sensory systems.

Genome-wide association studies and copy number variation analyses have linked contactin associated protein 2 (Caspr2, gene name Cntnap2) with autism spectrum disorder (ASD). In line with these findings, mice lacking Caspr2 (Cntnap2(-/-)) were shown to have core autism-like deficits including abnormal social behavior and communication, and behavior inflexibility. However the role of Caspr2 in ASD pathogenicity remains unclear. Here we have generated a new Caspr2:tau-LacZ knock-in reporter line (Cntnap2(tlacz/tlacz)), which enabled us to monitor the neuronal circuits in the brain expressing Caspr2. We show that Caspr2 is expressed in many brain regions and produced a comprehensive report of Caspr2 expression. Moreover, we found that Caspr2 marks all sensory modalities: it is expressed in distinct brain regions involved in different sensory processings and is present in all primary sensory organs. Olfaction-based behavioral tests revealed that mice lacking Caspr2 exhibit abnormal response to sensory stimuli and lack preference for novel odors. These results suggest that loss of Caspr2 throughout the sensory system may contribute to the sensory manifestations frequently observed in ASD.