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The MRG gene family (also known as SNSR) belongs to the G-protein-coupled receptor (GPCR) superfamily, is expressed specifically in nociceptive neurons, and is implicated in the modulation of nociception. Here, we show that Ka/Ks (the ratio between nonsynonymous and synonymous substitution rates) displays distinct profiles along the coding regions of MRG, with peaks (Ka/Ks&gt;1) corresponding to extracellular domains, and valleys (Ka/Ks&lt;1) corresponding to transmembrane and cytoplasmic domains. The extracellular domains are also characterized by a significant excess of radical amino acid changes. Statistical analysis shows that positive selection is by far the most suitable model to account for the nucleotide substitution patterns in MRG. Together, these results demonstrate that the extracellular domains of the MRG receptor family, which presumably partake in ligand binding, have experienced strong positive selection. Such selection is likely directed at altering the sensitivity and/or selectivity of nociceptive neurons to aversive stimuli. Thus, our finding suggests pain perception as an aspect of the nervous system that may have experienced a surprising level of adaptive evolution.

Adaptive Evolution of MRG, a Neuron-Specific Gene Family Implicated in Nociception