'Orphan' G-protein-coupled receptors (GPCRs) — receptors that have been identified by genomic techniques, but whose function and ligands are unknown — are proving to be fertile ground for researchers who are looking for potential new drug targets. Writing in Nature Neuroscience, Lembo et al. describe how they have reunited one group of orphan GPCRs with their ligands, and uncovered a new receptor system that might be important as a potential target for analgesia.

The family of GPCRs that are described by Lembo and colleagues is expressed only in small sensory neurons in the dorsal root ganglia and trigeminal ganglia in rats and humans, which led the researchers to name these GPCRs the sensory-neuron-specific receptors (SNSRs). The neurons in which the SNSRs are expressed are involved in the transmission of pain signals. When the researchers searched for ligands for the SNSRs by expressing them in cultured cells and testing a panel of candidates, they discovered that the receptors were activated by a range of opioid-related peptides.

The most potent ligand was bovine adrenal-medulla peptide 22 (BAM22), which is produced by cleavage of the opioid peptide precursor proenkephalin A. BAM22 is expressed in the rat dorsal root ganglion and the dorsal horn of the spinal cord. It has been implicated in nociception, and can bind to all the known opioid receptors, but its function is unclear.

When Lembo et al. compared the abilities of different opioid-related peptides to activate the SNSRs, they found that the structural requirements for activation of SNSRs were different from the requirements of opioid receptors. They also found that, unlike opioid receptors, the SNSRs could not be blocked by naloxone or other opioid-receptor antagonists. They propose that the SNSRs represent a new family of GPCRs — distinct from the opioid receptors — that are likely to be involved in nociception.

Recently, Dong et al. described a family of mouse GPCRs, called MRGs (mas-related genes), and Lembo et al. report that these are identical to the SNSRs. However, Dong et al. found that the neural MRGs, which were also expressed in a specific subset of sensory neurons, were most potently activated by peptides such as neuropeptide FF (NPFF), which has also been implicated in pain systems, but which activates the SNSRs only weakly. As there are many MRGs, it is possible that their sensitivities to NPFF and BAM22 vary.

The discovery of a family of receptors that is expressed only in nociceptive neurons, and which recognizes an opioid-type ligand through a non-opioid mechanism, might provide a new target for analgesic therapies. In particular, as the authors point out, the very specific localization of the SNSRs to the nociceptive neurons might indicate that drugs that target these receptors will have fewer side effects than compounds that target opioid receptors, which are widely expressed in the brain.