Pathways to Pain Control

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Science  30 Jun 2000:
Vol. 288, Issue 5475, pp. 2287
DOI: 10.1126/science.288.5475.2287b

Membrane proteins that bind ligands on their extracellular side and G proteins on their intracellular side comprise one of the largest gene families expressed in the brain, the G protein-coupled receptors (GPCRs). The multiplicity of neuronal genes encoding peptides suggests that many of the GPCRs may recognize neuropeptides, but the scarcity of both receptors and ligands has made pairing of these partners difficult.

Elshourbagy et al. follow the same approach that led to their surprising linking of the receptor for orexin-A (a peptide involved in regulation of appetite) to narcolepsy (brief attacks of deep sleep). In this new work they isolate a GPCR that when co-expressed with a promiscuous G protein displayed high affinity binding of peptides ending in -Arg-Phe-amide (that is, the peptide family defined by the molluscan FMRFamide). Further screening indicated that the likely endogenous ligands are two peptides known as NPFF and NPAF, which are known to modulate opiate function in interesting but as yet incompletely understood ways—NPFF administered intracerebroventricularly behaves as an antiopioid, but potentiates morphine analgesia if given intrathecally. (Another neuropeptide-GPCR system with dichotomous effects on pain is described by Pan et al.) Having the receptor in hand will facilitate identification of nociceptive agonists and antagonists.—GJC

J. Biol. Chem., in press; Neuron26, 515 (2000).

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