Sex differences in thermal nociception and morphine antinociception in rodents depend on genotype

Abstract

It has been appreciated for some time that the sexes can differ in their sensitivity to pain and its inhibition. Both the human and rodent literatures remain quite contentious, with many investigators failing to observe sex differences that others document clearly. Recent data from our laboratory have pointed to an interaction between sex and genotype in rodents, such that sex differences are observed in some strains but not others. However, these studies employed inbred mouse strains and are thus not directly relevant to existing data. We presently examined whether the observation of statistically significant sex differences in nociception and morphine antinociception might depend on the particular outbred rodent population chosen for study. Rats of both sexes and three common outbred strains were obtained from three suppliers (Long Evans, Simonsen; Sprague Dawley, Harlan; Wistar Kyoto, Taconic) and tested for nociceptive sensitivity on the 49°C tail-withdrawal assay, and antinociception following morphine (1–10 mg/kg, i.p.). In further studies, three outbred populations of mice (CD-1, Harlan; Swiss Webster, Harlan; Swiss Webster, Simonsen) were bred in our vivarium for several generations and tested for tail-withdrawal sensitivity and morphine antinociception (1–20 mg/kg, i.p.). We observed all possible sex comparison patterns for these two traits in different rodent populations: male>female, female>male, and no significant difference. In a separate study in which the estrous cycle was tracked in female mice, we found evidence for an interaction between genotype and estrous phase relevant to morphine antinociception. However, estrous cyclicity did not explain the observed sex differences. These data are discussed with respect to the existing sex difference and pain literature, and also as they pertain to future investigations of these phenomena.

Introduction

It has long been suspected that men and women have different thresholds for and tolerance to painful stimuli (see [16], [35], [96] for reviews). In human populations, these differences are often attributed to the cognitive and sociocultural processes involved in labeling stimuli as painful and not to primary biological differences in pain processing between the sexes. Although it is difficult to eliminate these influences in laboratory tests of sex differences in human pain processing, it seems reasonable to expect that uncovering possible sex differences in the processing of nociceptive stimuli in animal subjects should be relatively straightforward. However, as in the human pain experimental literature, there exists a lack of consensus as to the existence and direction of sex differences in rodent subject populations.

Although the use of varying methodologies clearly contribute to the inconsistencies in laboratory studies, this factor cannot account for all of the contradictory reports. One interpretation of these conflicting findings is that sex differences in nociceptive processing do exist, but we have not yet identified all of the modulating variables that must be controlled for in experimental studies in order to clearly and consistently demonstrate them. Another possibility is that sex differences exist in some subject populations, but not in others (or that they exist in all populations, but to differing degrees). It is also likely that some experimental designs are simply not sufficiently powerful to detect existing differences, especially those of modest magnitude. Indeed, numerous reports indicate that although differences between males and females in nociceptive responses seemed apparent, these differences did not reach the criterion for statistical significance. The purpose of this investigation was to clarify the nature of the existing rodent literature and to attempt to reconcile inconsistencies, by demonstrating that the detection of sex differences is dependent on the particular subject population under study.