Bao et al. studied the relationship between neuropeptide release and insertion of δ opioid receptors (DORs) into the plasma membrane of sensory neurons and discovered a novel positive-feedback mechanism whereby DOR activation led to DOR insertion and the release of the excitatory neuropeptide, calcitonin gene related peptide (CGRP). The analgesic effects of opiates are effected in part through an inhibition of evoked neuropeptide release, mediated by presynaptic μ and δ opiate receptors located on the terminals of dorsal root ganglion neurons (DRGs). In small DRGs, most DORs are cytoplasmic and are often associated with large dense core vesicles (LDCVs) that store neuropeptides, rather than being found on the cell surface. Bao et al. stimulated dissociated DRGs or PC12 cells with deltorphin-1 (delt), a selective DOR agonist, and observed redistribution of DOR-immunoreactive (DOR-Ir) LDCVs toward the cell surface as well as the appearance of DOR-Ir on the cell surface. Membrane capacitance measurements confirmed that delt, as well as leucine-enkephalin, stimulated slow, prolonged vesicular exocytosis. The authors used Ca2+-imaging in combination with Ca2+ replacement and pharmacological analysis to show that DOR redistribution and exocytosis in response to delt depended on both Ca2+ influx and Ca2+ release from intracellular inositol 1,4,5-trisphosphate-sensitive stores. DOR stimulation also stimulated movement of CGRP-immunoreactive (CGRP-Ir) vesicles toward the cell surface and the appearance of CGRP-Ir in the incubation medium. The stimulation of CGRP release and DOR insertion by DOR agonists suggests that combining μ opiate receptor agonists with DOR antagonists may be more effective in producing analgesia than stimulating both classes of receptor.
L. Bao, S.-X. Jin, C. Zhang, L.-H. Wang, Z.-Z. Xu, F.-X. Zhang, L.-C. Wang, F.-S. Ning, H.-J. Cai, J.-S. Guan, H.-S. Xiao, Z.-Q. D. Xu, C. He, T. Hökfelt, Z. Zhou, X. Zhang, Activation of delta opioid receptors induces receptor insertion and neuropeptide secretion. Neuron 37, 121-133 (2003). [Online Journal]