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. 2020 Apr;161(4):865-874.
doi: 10.1097/j.pain.0000000000001798.

Marked sexual dimorphism in neuroendocrine mechanisms for the exacerbation of paclitaxel-induced painful peripheral neuropathy by stress

Luiz F Ferrari  1 , Dioneia Araldi  1 , Paul G Green  2 , Jon D Levine  1
Affiliations

Marked sexual dimorphism in neuroendocrine mechanisms for the exacerbation of paclitaxel-induced painful peripheral neuropathy by stress

Luiz F Ferrari et al. Pain. 2020 Apr.

Abstract

Chemotherapy-induced neuropathic pain is a serious adverse effect of chemotherapeutic agents. Clinical evidence suggests that stress is a risk factor for development and/or worsening of chemotherapy-induced peripheral neuropathy (CIPN). We evaluated the impact of stress and stress axis mediators on paclitaxel CIPN in male and female rats. Paclitaxel produced mechanical hyperalgesia, over the 4-day course of administration, peaking by day 7, and still present by day 28, with no significant difference between male and female rats. Paclitaxel hyperalgesia was enhanced in male and female rats previously exposed to unpredictable sound stress, but not in rats that were exposed to sound stress after developing paclitaxel CIPN. We evaluated the role of the neuroendocrine stress axes: in adrenalectomized rats, paclitaxel did not produce hyperalgesia. Intrathecal administration of antisense oligodeoxynucleotides (ODN) reduced expression of β2-adrenergic receptors on nociceptors, and paclitaxel-induced hyperalgesia was slightly attenuated in males, but markedly attenuated in females. By contrast, after intrathecal administration of antisense ODN to decrease expression of glucocorticoid receptors, hyperalgesia was markedly attenuated in males, but unaffected in females. Both ODNs together markedly attenuated paclitaxel-induced hyperalgesia in both males and females. We evaluated paclitaxel-induced CIPN in stress-resilient (produced by neonatal handling) and stress-sensitive (produced by neonatal limited bedding). Neonatal handling significantly attenuated paclitaxel-induced CIPN in adult male, but not in adult female rats. Neonatal limited bedding did not affect the magnitude of paclitaxel-induced CIPN in either male or female. This study provides evidence that neuroendocrine stress axis activity has a marked, sexually dimorphic, effect on paclitaxel-induced painful CIPN.

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Conflict of interest statement

The authors have no conflicts of interest.

Figures

Figure 1.
Figure 1.. Effect of paclitaxel on mechanical nociceptive threshold in female and male rats.
Female and male rats received paclitaxel (1 mg/kg, i.p.) administered every other day for a total of 4 injections, on days 0, 2, 4 and 6. Percentage reduction in nociceptive baseline (left panel): The magnitude of hyperalgesia, measured after the last paclitaxel administration (i.e. days 7 – 28), showed a significant interaction effect, but sex differences approached significance differences (P=0.0522). However, post-hoc analysis revealed significantly lower hyperalgesia in males on days 21 and 28 (2-way repeated measures ANOVA: Interaction, F(3, 30) = 20.52, P<0.0001; Time, F(3, 30) = 3.228, P=0.0363; Sex, F(1, 10) = 4.851, P=0.0522. Bonferroni’s post-hoc test, Day 21: P=0.045; Day 28: P=0.0226. n=6 per group). Nociceptive threshold (right panel): While the magnitude of hyperalgesia, measured after the last paclitaxel administration (i.e. days 7 – 28), showed a significant interaction effect, there was no significance difference for sex (2-way repeated measures ANOVA: Interaction, F(3, 30) = 16.60, P<0.0001; Time, F(3, 30) = 2.125, P=0.1180; Sex, F(1, 10) = 0.002, P=0.9619).
Figure 2.
Figure 2.. Effect of sound stress on paclitaxel-induced hyperalgesia.
Rats were exposed to unpredictable sound stress before (left panels) or after (right panels) paclitaxel treatment. Males (left 4 panels) Stress before paclitaxel (left 2 panels): Sound stress exposure occurred on days −4, −2 and −1. Twenty-four hours after the last exposure to sound stress, paclitaxel (1 mg/kg, i.p.) was administered on days 0, 2, 4 and 6. Mechanical nociceptive threshold was measured before the first sound stress, and again on days 0 (30 min after first dose of paclitaxel), 1, 3, 5, 7, 14, 21 and 28. Percentage reduction from baseline: The magnitude of hyperalgesia measured after the last paclitaxel administration (i.e. days 7 – 28) was significantly greater in the rats exposed to sound stress (2-way repeated measures ANOVA: Interaction, F(3, 30) = 4.710, P=0.0082; Time, F(3, 30) = 6.52, P=0.0026; Stress, F(1, 10) = 83.56, P<0.0001), sound stress + paclitaxel vs. sham sound stress + paclitaxel *P=0.0459, Bonferroni’s multi-comparison test, (n=6 per group). Nociceptive threshold: While in paclitaxel-treated rats at every time point from day 7 to 28 in sound stress-exposed rats had a lower threshold than non-stressed rats, this difference was not significant (2-way repeated measures ANOVA: Interaction, F(3, 30) = 1.58, P=0.2156; Time, F(3, 30) = 15.9, P<0.0001; Stress, F(1, 10) = 1.43, P=0.2598). Stress after paclitaxel (second from left 2 panels): Paclitaxel (1 mg/kg, i.p.) was administered on days 0, 2, 4 and 6, and, sound stress sessions started 24 h after the last paclitaxel injection, on days 7, 9 and 10. Mechanical nociceptive threshold was evaluated on days 0 (30 min after first dose of paclitaxel), 1, 3, 5, 7, 14, 21 and 28. Percentage reduction from baseline: There was no significant difference between paclitaxel + sound stress and paclitaxel + sham sound stress groups of rats (2-way repeated measures ANOVA: Interaction, F(3, 30) = 3.650, P=0.0235; Time, F(3, 30) = 14.87, P<0.0001; Stress, F(1, 10) = 0.5977, P=0.4573, n=6 per group). Nociceptive threshold: There was no significant difference between paclitaxel + sound stress and paclitaxel + sham sound stress (2-way repeated measures ANOVA: Interaction, F(3, 30) = 1.75, P=0.1782; Time, F(3, 30) = 7.46, P=0.0007; Stress, F(1, 10) = 0.84, P=0.3813). Females (right 4 panels): Stress before paclitaxel (second from right 2 panels): Sound stress exposure occurred on days −4, −2 and −1. Twenty-four hours after the last exposure to sound stress, paclitaxel (1 mg/kg, i.p.) was administered on days 0, 2, 4 and 6. Mechanical nociceptive threshold was measured before the sound stress, and again on days 0 (30 min after first dose of paclitaxel), 1, 3, 5, 7, 14, 21 and 28. Percentage reduction from baseline: The magnitude of hyperalgesia measured after the last paclitaxel administration (i.e. days 7 – 28) was significantly greater in the sound stress exposed rats (2-way repeated measures ANOVA: Interaction, F(3, 30) = 03764, P=0.7706; Time, F(2.3, 22.6) = 2.83, P=0.1095; Stress, F(1, 10) = 180.5, P<0.0001, n=6 per group). Nociceptive threshold: The magnitude of hyperalgesia measured after the last paclitaxel administration (i.e. days 7 – 28) was significantly greater in the sound stress exposed rats (2-way repeated measures ANOVA: Interaction, F(3, 30) = 7.243, P=0.0009; Time, F(2.9, 22.9) = 15.44, P<0.0001; Stress, F(1, 10) = 25.04, P=0.0005). Stress after paclitaxel (right two panels): Paclitaxel (1 mg/kg, i.p.) was administered on days 0, 2, 4 and 6, and, sound stress sessions started 24 h after the last paclitaxel injection, on days 7, 9 and 10. Mechanical nociceptive threshold was evaluated on days 0 (30 min after first dose of paclitaxel), 1, 3, 5, 7, 14, 21 and 28. Percentage reduction from baseline: There was no significant difference between paclitaxel + sound stress and paclitaxel + sham sound stress groups (2-way repeated measures ANOVA: Interaction, F(3, 30) = 3.650, P=0.0235; Time, F(3, 30) = 14.87, P<0.0001; Stress, F(1, 10) = 0.5977, P=0.4573, n=6 per group). Nociceptive threshold: The magnitude of hyperalgesia measured after the last paclitaxel administration (i.e. days 7 – 28) was not significantly different in the sound stress exposed rats (2-way repeated measures ANOVA: Interaction, F(3, 30) = 0.0923, P=0.9637; Time, F(2.9, 22.9) = 15.31, P<0.0001; Stress, F(1, 10) = 0.1573, P=0.7000).
Figure 3.
Figure 3.. Effect of adrenalectomy on paclitaxel-induced hyperalgesia.
One week after bilateral adrenalectomy (with basal level corticosterone replacement), rats received paclitaxel (1 mg/kg, i.p.) on days 0, 2, 4 and 6. Mechanical nociceptive threshold was evaluated before surgery, and again on days 0 (30 min after first paclitaxel), 1, 3, 5, 7, 14, 21 and 28. Males: The magnitude of hyperalgesia measured after paclitaxel administration (i.e., on days 7 – 28) was markedly attenuated in adrenalectomized rats (2-way repeated measures ANOVA: Interaction, F(3, 48) = 3.373, P=0.0259; Time, F(3, 48) = 1.974, P=0.1304; Stress, F(1, 16) = 44.59, P<0.0001). (n=6 per group). Females: The magnitude of hyperalgesia measured after paclitaxel administration (i.e., on days 7 – 28) was also markedly attenuated in adrenalectomized rats (2-way repeated measures ANOVA: Interaction, F(3, 30) = 14.47, P<0.0001; Time, F(3, 30 = 18.98, P<0.0001; Stress, F(1, 10) = 381.0, P<0.0001. n=6 per group).
Figure 4.
Figure 4.. Role of β2-adrenergic and glucocorticoid receptors in paclitaxel-induced mechanical hyperalgesia in male and female rats.
Male and female rats were treated intrathecally with injections of ODN antisense or mismatch for the β2-adrenergic receptor (left panels) or glucocorticoid receptor (middle panels) mRNA, or their combination (right panels), for 10 consecutive days (80 μg/day). Beginning on the 4th day of ODN treatment (day 0), paclitaxel (1 mg/kg, i.p.) was administered on days 0, 2, 4 and 6. Mechanical nociceptive threshold was evaluated before ODN treatment was started, and again on days 0 (30 min after first paclitaxel), 1, 3, 5, 7, 14, 21 and 28. Males: The magnitude of hyperalgesia measured after administration of the last dose of paclitaxel (i.e. days 7 – 28) was significantly attenuated in the β2-adrenergic receptor antisense ODN treated group (Interaction, F(3, 30) = 1.022, P=0.3970; Time, F (3, 30) = 5.952, P=0.0026; Treatment, F(1, 10) = 5.773, *P=0.0371), glucocorticoid receptor antisense ODN treated group (Interaction, F(3, 30) = 0.5439, P=0.6560; Time, F(3, 30) = 3.602, P=0.0247; Treatment, F(1, 10) = 11.68, **P=0.0066) and in the group treated with the combination of the β2-adrenergic receptor and glucocorticoid receptor ODN (Interaction, F(3, 30) = 0.5107, P=0.6780; Time, F(3, 30) = 5.261, **P=0.0049; Treatment, F(1, 10) = 128.6, ***P<0.0001), when antisense and mismatch groups are compared over time, two-way repeated measures ANOVA). (n = 6 per group). The glucocorticoid + β2-adrenergic receptor ODN treated group was not significantly different from glucocorticoid receptor ODN treated group (Interaction, F(3, 30) = 1.057, P=0.3818; Time, F (3, 30) = 1.792, P=0.1699; Treatment, F(1, 10) = 1.952, P=0.1926). Females: The magnitude of hyperalgesia measured after the last dose of paclitaxel (i.e. days 7 – 28) was significantly attenuated in the β2-adrenergic receptor antisense ODN treated group (Interaction, F(3, 30) = 2.899, P=0.0512; Time, F (3, 30) = 10.36, P<0.0001; Treatment, F(1, 10) = 38.41, ***P=0.0001), but was not attenuated in the glucocorticoid receptor antisense ODN treated group (Interaction, F(3, 30) = 3.003, P=0.0459; Time, F(3, 30) = 2.389, P=0.8685; Treatment, F(1, 10) = 0.2463, P=0.6304). Paclitaxel-induced hyperalgesia was significantly attenuated in the group receiving the combination of β2-adrenergic receptor and glucocorticoid receptor antisense ODN (Interaction, F(3, 30) = 1.106, P=0.3622; Time, F(3, 30) = 1.533, P=0.2263; Treatment, F(1, 10) = 46.19, ***P<0.0001) groups, when antisense and mismatch groups are compared over time by two-way repeated measures ANOVA). The glucocorticoid + β2-adrenergic receptor ODN treated group was not significantly different from β2-adrenergic receptor ODN treated group (Interaction, F(3, 30) = 2.587, P=0.0715; Time, F (3, 30) = 5.804, P=0.0030; Treatment, F(1, 10) = 0.0983, P=0.0.7604. n = 6 per group).
Figure 5.
Figure 5.. Effect of neonatal handling (NH) and neonatal limited bedding (NLB) on paclitaxel-induced hyperalgesia in male and female rats.
Neonatal rats were exposed to either NH (resilient phenotype) or NLB (stressed phenotype). Approximately 5 weeks later, adult rats received paclitaxel (1 mg/kg, i.p.) administered on days 0, 2, 4 and 6. Mechanical nociceptive thresholds were evaluated before the paclitaxel treatment was started, and again on days 0 (30 min after first paclitaxel), 1, 3, 5, 7, 14, 21 and 28. Males (left 4 panels) Percentage reduction from baseline: The magnitude of hyperalgesia measured after the last paclitaxel administration (i.e. days 7 – 21) was significantly attenuated in NH males (Interaction, F(2, 20) = 5.636, P=0.0114; Time, F (2, 20) = 2.669, P=0.0939; Neonatal handling, F(1, 10) = 90.92, ***P<0.0001, n=6 per group). In NLB rats, the magnitude of hyperalgesia measured after the last paclitaxel administration (i.e. days 7 – 21) was not significant compared to controls (Interaction, F(2, 20) = 0.5073, P=0.6097; Time, F(2, 20) = 2.547, P=0.1034; Neonatal limited bedding, F(1, 10) = 0.1302, P=0.7258). Nociceptive threshold: The magnitude of hyperalgesia measured after the last paclitaxel administration (i.e. days 7 – 21) was significantly attenuated in NH males (Interaction, F(2, 20) = 5.515, P=0.0124; Time, F (2, 20) = 2.503, P=0.1071; Neonatal handling, F(1, 10) = 17.52, ***P=0.0019). In NLB rats, the magnitude of hyperalgesia measured after the last paclitaxel administration (i.e. days 7 – 21) was not significant compared to controls (Interaction, F(2, 20) = 0.7462, P=0.4869; Time, F(2, 20) = 2.341, P=0.1220; Neonatal limited bedding, F(1, 10) = 2.562, P=0.1406). Females (right 4 panels) Percentage reduction from baseline: The magnitude of hyperalgesia measured after the last paclitaxel administration (i.e. days 7 – 21) was slightly, but significantly less in NH females (Interaction, F(2, 32) = 1.749, P=0.1901; Time, F(2, 32) = 0.5997, P=0.5550; Neonatal handling, F(1, 16) = 4.898, P=0.0418, Control n=6, NH n=12). In NLB females, the magnitude of hyperalgesia measured after the last paclitaxel administration (i.e. days 7 – 21) was not significant from control (Interaction, F(2, 20) = 6.738, P=0.0058; Time, F(2, 20) = 34.14, P<0.0001; Neonatal limited bedding, F(1, 10) = 1.275, P=0.2852, n=6 per group). Nociceptive threshold: he magnitude of hyperalgesia measured after the last paclitaxel administration (i.e. days 7 – 21) was slightly, but significantly less in NH females (Interaction, F(2, 32) = 1.714, P=0.1963; Time, F(2, 32) = 0.3806, P=0.6865; Neonatal handling, F(1, 16) = 45.52, P<0.0001, Control n=6, NH n=12). In NLB females, the magnitude of hyperalgesia measured after the last paclitaxel administration (i.e. days 7 – 21) was not significant from control (Interaction, F(2, 20) = 8.128, P=0.0026; Time, F(2, 20) = 39.24, P<0.0001; Neonatal limited bedding, F(1, 10) = 1.190, P=0.3010).
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