Sex differences and hormonal modulation of deep tissue pain

Abstract

Women disproportionately suffer from many deep tissue pain conditions. Experimental studies show that women have lower pain thresholds, higher pain ratings and less tolerance to a range of painful stimuli. Most clinical and epidemiological reports suggest female gonadal hormones modulate pain for some, but not all, conditions. Similarly, animal studies support greater nociceptive sensitivity in females in many deep tissue pain models. Gonadal hormones modulate responses in primary afferents, dorsal horn neurons and supraspinal sites, but the direction of modulation is variable. This review will examine sex differences in deep tissue pain in humans and animals focusing on the role of gonadal hormones (mainly estradiol) as an underlying component of the modulation of pain sensitivity.

Keywords: Animal; Brain imaging; Dorsal horn neuron; Estrogen; Human; Muscle; Pain; Primary afferents; Testosterone; Viscera.

Figure 1

Sex difference and effect of hormone modulation on the magnitude of the visceromotor response (vmr) to colorectal distention. The vmr was significantly greater in female rats compared to males. Ovariectomy significantly decreased the vmr compared to intact females and replacement E2 restored the vmr to a magnitude similar to intact rats. One way ANOVA p<0.0001, n=55–61/group. *** p<0.001 vs. OVx; +++ p<0.001 vs. female.

Figure 2

The effect of s.c. administration of the ERα agonist PPT and the ERβ agonist DPN on the visceromotor response. The effect of each agonist was significantly greater than baseline four hours after injection and returned to baseline by 48 hours (1 way RM ANOVA). * p<0.05 vs. baseline (B) prior to agonist administration. Figures are derived from data originally published in (Ji et al., 2011) and (Cao et al., 2012) with permission.

Figure 3

Sex difference in magnitude and incidence of windup. Response to electrical stimulation at 1 Hz normalized to response to the first stimulus. Data are mean ± sem. There is a time × sex interaction, p<0.005, n=13 male, 28 female. Inset: Significantly more cells showed windup in female rats compared to males (Chi-square: p<0.001). This parallels greater temporal summation in women.