Conotoxins (conopeptides) are a diverse group of peptides isolated from the venom of marine cone snails. Numerous Conus peptides modulate pain by interacting with voltage-gated ion channels and G protein-coupled receptors (GPCRs). Opiate drugs targeting the µ-opioid GPCR have long been used due to their efficacy despite the many undesirable side effects associated with their use, including addiction and overdose. It has been shown that various high voltage-activated (HVA) calcium channels and inwardly rectifying potassium channels respond to the activation of a variety of GPCRs. Thus, regulation of these ion channels by other GPCRs may be a viable alternative in the management of pain. Analgesic α-conotoxins Vc1.1 and RgIA have been shown to activate GABAB receptors (GABABR) resulting in the inhibition of Cav2.2 and Cav2.3 channels and potentiation of GIRK-mediated K+ currents in mammalian primary afferent neurons [1,2]. Furthermore, Vc1.1 and the GABABR agonist, baclofen, potentiate inwardly-rectifying K+ currents in HEK293 cells recombinantly expressing human GIRK1/2 channels and GABABR. Hyperexcitability and ectopic firing are characteristic sensory neuron responses to nerve injury and chronic pain. In adult mouse dorsal root ganglion (DRG) neurons, GABABR-dependent GIRK channel potentiation by Vc1.1 and baclofen hyperpolarize the cell membrane potential and reduce excitability. Similarly, in human pluripotent stem cell (hPSC)-derived sensory neurons both baclofen (100 mM) and Vc1.1 (1 mM) significantly reduced membrane excitability by hyperpolarizing the resting membrane potential and increasing the rheobase for action potential firing. In voltage-clamp mode, Vc1.1 and baclofen inhibited HVA Ca2+ channel currents and potentiated hyperpolarization-activated K+ currents in hPSC-derived sensory neurons which was attenuated by the selective GABABR antagonist CGP 55845. Our recent research, driven by coupling molecular dynamics simulations and docking studies with site-directed mutagenesis and patch clamp electrophysiology, has identified a putative binding site for the analgesic α-conotoxins on the GABABR, which is distinct from the orthosteric binding site for GABA on the extracellular Venus Flytrap (VFT) domain of the GABAB R1 subunit. The allosteric binding site for the analgesic a-conotoxins is at the interface of the VFT domains of the GABAB R1 and R2 subunits [3]. Our findings are consistent with the functional expression of Cav and GIRK channels in DRG neurons and their involvement in GABABR-mediated anti-nociceptive activity in response to baclofen and a-conotoxin Vc1.1. A new scenario involving diverse GABABR signaling mechanism(s) underlies the analgesic properties of α-conotoxins is emerging.