KCTD16 MODULATES GABA<SUB>B</SUB> RECEPTOR-MEDIATED BACLOFEN ANALGESIA

Peripheral control of pain relies on the balance between excitation and inhibition within nociceptive circuit comprised of dorsal root ganglia (DRG) and spinal cord neurons. The auxiliary subunit KCTD16 shapes GABA_B receptor kinetics, yet its contribution to pain modulation within nociceptive circuit remains uncharacterized.
We combined immunohistochemistry, calcium imaging and behavioural assay to test the role of KCTD16 in GABA_B signalling in mice. KCTD16 distribution in spinal horn and DRG was assessed using confocal microscopy. Calcium imaging in DRG cultures were used to study GABA_B-mediated inhibition in wild-type (WT) and KCTD16⁻/⁻ mice neurons. Mechanical and thermal nociceptive thresholds and baclofen analgesia were tested in mice under naïve and after carrageenan-induced peripheral inflammation.
KCTD16 was strongly expressed in DRG neurons and superficial dorsal horn. While 30mM KCl-evoked calcium transients were comparable between genotypes, baclofen mediated suppression of calcium influx was significantly reduced in KCTD16⁻/⁻ sensory neurons compared to WT. KCTD16⁻/⁻ mice exhibited elevated baseline mechanical thresholds but normal thermal sensitivity. Systemic baclofen administration produced analgesia in WT animals but not in KCTD16⁻/⁻ mice. In inflammatory pain model, both genotypes developed similar hypersensitivity; however, baclofen-mediated analgesia was transient and markedly attenuated in KCTD16⁻/⁻ mice.
We conclude that KCTD16 is a critical modulator of GABA_B receptor signalling in peripheral sensory neurons, required for analgesic efficacy of baclofen. These findings reveal KCTD16 as a potential target for new analgesic drugs designed to modulate GABAB-mediated signalling. This work was supported by the Grant Agency of the Czech Republic (GACR 25-15684S).