Quantitative trait loci influencing morphine antinociception in four mapping populations

Analgesia(pain reduction, or antinociception) is a classical and clinically important effect of morphine administration, and in rodent models sensitiv ity to morphine has been shown to be strongly influenced by genotype. For e xample, several studies have reported marked differences in morphine antino ciception between the insensitive C57BL/6 (B6) and sensitive DBA/2 (D2) inb red mouse strains on the hot-plate assay. This prompted the present genome- wide search for quantitative trait loci (QTLs) that are chromosomal sites i nfluencing the magnitude of antinociception, by using four mapping populati ons derived from the B6 and D2 progenitor inbred strains. These four were t he BXD recombinant inbred (RI) strain set, an F-2 (B6D2F(2)) population, sh ort-term selective breeding for antinociception from a B6D2F(2) founding po pulation, and incipient or completed congenic strains. In the BXD RI set an d in the B6D2F(2), a genome-wide search identified 10-12 provisional QTLs a t a nominal p < .05. The other populations were subsequently used as confir mation steps to test each of the provisional QTL regions. Based on all avai lable mapping populations, four QTLs emerged as significant (p < .00005) on proximal Chromosome (Chr) 1 (females only), proximal Chr 9 (females only), mid Chr 9, and proximal Chr 10. The Chr 10 QTL comaps to the same region a s the mu -opioid receptor gene (Oprm); this receptor is a known mediator of morphine's antinociceptive effects. The Chr 1 QTL was evident only in fema les and comapped with the K-opioid receptor gene, Oprk.