Genetic sensitivity to hot-plate nociception in DBA/2J and C57BL/6J inbred mouse strains: possible sex-specific mediation by δ2-opioid receptors

Abstract

The inbred mouse strains, DBA/2J (D2) and C57BL/6J (B6), display differential sensitivity to acute, thermal nociception as measured on the hot-plate (HP) assay. In an ongoing quantitative trait locus (QTL) mapping study designed to reveal genomic loci showing genetic linkage to HP sensitivity, a putative QTL on chromosome 4 (50-80 cM from the centromere) has been identified that appears to account for variability in this trait in male, but not female mice. An obvious candidate gene located in this same chromosomal region is Oprd1, which encodes the murine delta-opioid receptor. In an attempt to evaluate whether Oprd1 represents this sex-specific QTL for HP sensitivity, we tested D2 and B6 mice of both sexes for HP latencies (hindpaw-lift, -lick or -flutter) following systemic injections of saline, or the opioid receptor antagonists naloxone (NAL; 0.1 and 10 mg/kg), nor-binaltorphimine (nor-BNI; 5 mg/kg), naltrindole (NTI; 5 mg/kg), 7-benzylidenenaltrexone (BNTX; 0.7 mg/kg), or naltriben (NTB; 1 mg/kg). High-dose (10 mg/kg) NAL lowered HP latencies in D2, but not B6 mice, suggesting that the higher HP latencies exhibited by D2 mice reflect opioid mechanisms. HP latencies in both strains and both sexes were unaffected by pretreatment with low-dose (0.1 mg/kg) NAL or nor-BNI, suggesting that neither mu nor kappa receptors affect basal nociceptive sensitivity. The delta-receptor antagonist, NTI, and the delta2-specific antagonist, NTB, (but not the delta1-specific antagonist, BNTX) effectively lowered HP latencies in a strain- and sex-dependent manner: D2 male > B6 male > D2 female > B6 female. These data support the possibility that Oprd1 is a QTL mediating HP sensitivity in mice, and more generally illustrate the important roles of genetic background and gender in the perception of pain.

Sex and rat strain determine sensitivity to κ opioid-induced antinociception

“…In Lewis rats, sex differences in baseline tail-withdrawal latencies were not obtained, nor were there consistent differences in κ opioid sensitivity. Studies in mice have found a similar correlation between baseline nociceptive latencies and sensitivity to morphine-induced antinociception, with morphine being more potent in strains with longer baseline latencies (Mogil et al 1996(Mogil et al , 1997Elmer et al 1998).…”

Injury Type-Specific Calcium Channel α2δ-1 Subunit Up-Regulation in Rat Neuropathic Pain Models Correlates with Antiallodynic Effects of Gabapentin

“…Injury Type-Specific Ca 2؉ Channel ␣ 2 ␦-1 Subunit Regulation onist treatment in mice with acute, thermal nociception (Mogil et al, 1997). Even though it was not proven, it was less likely that altered pharmacokinetics of gabapentin accounted for the gabapentin insensitivity in VIN rats because the antiallodynic effects of gabapentin in other models, including the DB model, occurred quickly after intraperitoneal administration.…”

The genetic mediation of individual differences in sensitivity to pain and its inhibition

“…By using similar methodology to that described above, we recently mapped basal thermal nociceptive sensitivity by using the hot-plate test (94). The most promising of six putative linkages in BxD RI strains-the D4Mit71 region (50-70 cM) of mouse chromosome 4-was largely confirmed by using F 2 mice.…”