Differential Activation of the Periaqueductal Gray by Mild Anxiogenic Stress at Different Stages of the Estrous Cycle in Female Rats

Abstract

The effect of acute exposure to mild anxiogenic stress on cutaneous nociceptive threshold was investigated in female Wistar rats at different stages of the estrous cycle. Baseline tail flick latencies did not change significantly during the cycle. However after brief exposure to vibration stress (4 Hz for 5 min), rats in late diestrus, but not at other cycle stages, developed a hyperalgesia (decrease in tail flick latency). Animals in late diestrus revealed a more than fivefold increase in the density of Fos-like immunoreactive nuclei in the dorsolateral, lateral, and ventrolateral columns in the caudal half of the periaqueductal gray matter (PAG). There was no change in the density of Fos-like immunoreactive nuclei in the PAG in rats in estrus and early diestrus, although rats in proestrus showed a smaller (50%) but significant increase. Rats undergoing withdrawal from a progesterone dosing regimen (5 mg/kg i.p. twice daily for 6 days) designed to mimic the fall in progesterone that occurs naturally during late diestrus, exhibited a stress-induced hyperalgesia that was similar to animals in late diestrus and a significant increase in Fos-positive cells in the PAG. We suggest that falling levels of progesterone during late diestrus may be a predisposing factor for the development of stress-induced hyperalgesia, which is linked to differential activation of descending pain control circuits in the PAG. Similar changes in women, when progesterone levels fall during the late luteal phase of the menstrual cycle, may contribute to the development of premenstrual symptoms that include increased anxiety and hyperalgesia.

Sex differences in anxiety and emotional behavior

“…The fact that a panicogenic challenge with CO 2 [132, 196] or intravenous sodium lactate [113, 318] causes premenstrual dysphoric disorder (PMDD) patients to display panic attacks at about the same rate as in panic disorder patients further indicates a common underlying psychobiology [368]. Rodent as well as human research [190, 260, 274, 333] now proposes a three-factor interaction between (a) the rate at which progesterone and its anxiolytic metabolite allopregnanolone drop during the late luteal phase (humans) or during late diestrus (comparable phase in rodents) [221, 222, 314], (b) γ-aminobutyric acid (GABA) A receptor sensitivity, kinetics, and subunit assembly in stress-coping circuitries including the amygdala and the periaqueductal gray (PAG) [143, 147], and (c) external stressors [94, 95, 340] as a model of sex-dependent predisposition for panic disorder [268]. …”

“…During late diestrus (late luteal phase in humans), concentrations of progesterone and its anxiolytic metabolite allopregnanolone [400, 401] rapidly drop, and this decrease in allopregnanolone alters the subunit composition of the GABA A receptor, meaning a shift towards decreased expression of the α1 subunit and increased expression of the α4, β1, and δ subunits [143]. This reduces the ongoing inhibitory output of the GABA neurons within the PAG [222] and is correlated with increased anxiety-like behaviors in diestrus rats, but not proestrus, metaestrus, or estrus rats [93, 94]. Decreased inhibitory output from GABAergic PAG neurons during diestrus is likely to disinhibit the DPAG and thus reduce the suppression of panic-like responses.…”

Sex differences and hormonal modulation of deep tissue pain

“…Alternatively, it may not be the absolute level of E2 that is important, but changes in concentration (i.e., fluctuating levels during the estrous or menstrual cycle). Estrogen or progesterone withdrawal may be more significant in modulating nociceptive sensitivity than maintaining a high level of either hormone (Devall and Lovick, 2010; Heitkemper and Chang, 2009; Ji et al, 2003; Martin et al, 2007; Martin, 2008; Puri et al, 2011; Robbins et al, 2010). Finally, the site where hormones produce their effect, peripheral tissue or the central nervous system (CNS), likely influences any conclusions.…”

Sex Differences in Antinociceptive Effects Induced by Gravity Stress in Rats

“…On the contrary, decreased withdrawal thresholds were observed in males, but not in females. It is reported that brief exposure to vibration-stress (4 Hz for 5 min) causes hyperalgesia in rats, as evidenced by a decrease in tail flick latency [37]. This kind vibration may be regarded as a mild, non-noxious type of stressor.…”