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. 2021 Mar 1;162(3):907-918.
doi: 10.1097/j.pain.0000000000002073.

Sexual dimorphism in the contribution of neuroendocrine stress axes to oxaliplatin-induced painful peripheral neuropathy

Larissa Staurengo-Ferrari  1 , Paul G Green  2 , Dionéia Araldi  1 , Luiz F Ferrari  3 , Christine Miaskowski  4 , Jon D Levine  1
Affiliations

Sexual dimorphism in the contribution of neuroendocrine stress axes to oxaliplatin-induced painful peripheral neuropathy

Larissa Staurengo-Ferrari et al. Pain. .

Abstract

Although clinical studies support the suggestion that stress is a risk factor for painful chemotherapy-induced peripheral neuropathy (CIPN), there is little scientific validation to support this link. Here, we evaluated the impact of stress on CIPN induced by oxaliplatin, and its underlying mechanisms, in male and female rats. A single dose of oxaliplatin produced mechanical hyperalgesia of similar magnitude in both sexes, still present at similar magnitude in both sexes, on day 28. Adrenalectomy mitigated oxaliplatin-induced hyperalgesia, in both sexes. To confirm the role of neuroendocrine stress axes in CIPN, intrathecal administration of antisense oligodeoxynucleotide targeting β₂-adrenergic receptor mRNA both prevented and reversed oxaliplatin-induced hyperalgesia, only in males. By contrast, glucocorticoid receptor antisense oligodeoxynucleotide prevented and reversed oxaliplatin-induced hyperalgesia in both sexes. Unpredictable sound stress enhanced CIPN, in both sexes. The administration of stress hormones, epinephrine, corticosterone, and their combination, at stress levels, mimicked the effects of sound stress on CIPN, in males. In females, only corticosterone mimicked the effect of sound stress. Also, a risk factor for CIPN, early-life stress, was evaluated by producing both stress-sensitive (produced by neonatal limited bedding) and stress-resilient (produced by neonatal handling) phenotypes in adults. Although neonatal limited bedding significantly enhanced CIPN only in female adults, neonatal handling significantly attenuated CIPN, in both sexes. Our study demonstrates a sexually dimorphic role of the 2 major neuroendocrine stress axes in oxaliplatin-induced neuropathic pain.

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Conflict of interest statement

Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Figure 1.
Figure 1.. Comparison of oxaliplatin-induced hyperalgesia in male and female rats.
Oxaliplatin (2 mg/kg) or saline (i.v.) was administered to male and female rats, and mechanical nociceptive threshold evaluated before, and 30 min and 1, 7, 14, 21, and 28 days after administration of oxaliplatin. Oxaliplatin was administered on day 0. Results are presented as change in mechanical paw-withdrawal threshold, expressed as percentage change from baseline. In males and females, oxaliplatin decreased mechanical nociceptive threshold (i.e. produced hyperalgesia), observed 30 min after injection and persisting until day 28. Data from male rats is shown as mean ± SEM, ####P<0,0001, ###P<0,001, #P<0,001: oxaliplatin vs saline (n=6 paws per group). Data from female rats is shown as mean ± SEM, ****P<0,0001, ***P<0,001, **P<0,01: oxaliplatin vs saline. Treatment F (3, 120) = 98.00, Time F (5,120) = 0.9645, Interaction F (15,120) = 1.639, using two-way repeated measures ANOVA followed by Bonferroni post hoc test (n=6 paws per group). No difference in magnitude of the hyperalgesia was observed between male and female oxaliplatin-treated rats.
Figure 2.
Figure 2.. Effect of adrenalectomy on oxaliplatin-induced hyperalgesia.
Male and female rats were submitted to bilateral adrenalectomy and one week later, oxaliplatin (2 mg/kg, i.v.) was administered (day 0). Mechanical nociceptive threshold was evaluated before oxaliplatin injection and again 30 min, 1, 7, 14, 21 and 28 days after oxaliplatin. (A) When the magnitude of oxaliplatin-induced hyperalgesia was evaluated in adrenalectomized (Adx) male rats, a marked attenuation was observed compared to the adrenal intact oxaliplatin-treated group. Data shown as mean ± SEM, Time F (5, 120) = 2.871, Treatment F (3, 120) = 84.02, Interaction F (15, 120) = 1.042, ****P<0,0001, ***P<0,001: intact oxaliplatin vs intact saline; ####P<0,0001, ###P<0,001, ##P<0,01: Adx oxaliplatin vs intact oxaliplatin, using 2-way repeated measures ANOVA followed by Bonferroni post hoc test, (n=6 paws per group). No differences in the magnitude of the hyperalgesia between the adrenal intact saline-treated group and Adx-saline group was observed in male rats. (B) When the magnitude of oxaliplatin-induced hyperalgesia was evaluated in Adx female rats, a marked attenuation was observed compared to the adrenal intact oxaliplatin-treated group. Data shown as mean ± SEM, Time F (5, 120) = 3.102, Treatment F (3, 120) = 79.29, Interaction F (15, 120) = 1.516, ****P<0,0001, **P<0,001: intact oxaliplatin vs intact saline; ####P<0,0001, ##P<0,001, #P<0,001: Adx oxaliplatin vs intact oxaliplatin, using 2-way repeated measures ANOVA followed by Bonferroni post hoc tests (n=6 paws per group). No differences in the magnitude of the hyperalgesia between intact saline group and Adx-saline group was observed in female rats.
Figure 3.
Figure 3.. Role of β2-adrenergic receptor (ADRB2) in oxaliplatin-induced hyperalgesia.
Male and female rats were treated with intrathecal injections of ODN AS or MM to ADRB2 mRNA, for 10 consecutive days (80 μg/day, 20 μl) in prevention (A and B) or reversal (C and D) protocols. Prevention protocol: oxaliplatin (2 mg/kg, i.v.) was administered approximately 17 hours after the third daily intrathecal injection of ADRB2 ODN (day 0). Mechanical nociceptive threshold was evaluated before ODN treatment was started and again on days 0 (30 min), 1, 7, 14, 21, and 28 days after oxaliplatin. (A) The magnitude of oxaliplatin-induced hyperalgesia was significantly attenuated in males treated with ADRB2 AS-ODN, when it was compared with the ADRB2 MM-ODN-treated group. Data shown as mean ± SEM, Treatment F (1,60) = 139.7, Time F (5, 60) = 2.634, Interaction F (5,60) = 8.180, ****P<0,0001, ***P<0,001: ADRB2 AS-ODN vs ADRB2 AS-MM (n=6 paws per group). (B) The magnitude of oxaliplatin-induced hyperalgesia was not affected by ADRB2 AS-ODN in the prevention protocol, in females. Data shown as mean ± SEM, Treatment F (1,60) = 6.620, Time F (5,60) = 2.452, Interaction F (5,60) = 1.498, ADRB2 AS-ODN vs ADRB2 AS-MM (n=6 paws per group). Reversal protocol: intrathecal treatment with ADRB2 AS- or MM-ODN started 3 days after intravenous administration of oxaliplatin (2 mg/kg). Mechanical nociceptive threshold was evaluated before oxaliplatin administration and again 30 min, 1, 7, 14, 21, and 28 days later (n=6 paws per group). (C) Oxaliplatin-induced hyperalgesia was significantly reversed in males treated with ADRB2 AS-ODN, when compared with the ADRB2 MM-ODN-treated group. Data shown as means ± SEM, Treatment F (1,60) =33.76, Time (5,60) = 2.318, Interaction F (5,60) = 4.256, ****P<0,0001, ***P<0,001, **P<0,01: ADRB2 AS-ODN vs ADRB2 AS-MM (n=6 paws per group). (D) The magnitude of oxaliplatin-induced hyperalgesia was not affected by ADRB2 AS-ODN in the reversal protocol, in females. Data shown as means ± SEM, Treatment F (1,60) = 6.293, Time (5,60) = 8.433, Interaction F (5,60) = 0.1567 (n=6 paws per group). Two-way repeated measures ANOVA followed by Bonferroni post hoc tests were used to compare antisense and mismatch groups over time.
Figure 4.
Figure 4.. Role of glucocorticoid receptor (GR) in oxaliplatin-induced hyperalgesia.
Male and female rats were treated with intrathecal injections of AS-ODN or MM-ODN against GR mRNA, for 10 consecutive days (80 μg/day, 20 μl) in the prevention or reversal protocol. Prevention protocol (A and B): oxaliplatin (2 mg/kg, i.v.) was administered approximately 17 hours after the third intrathecal injection of GR ODN (day 0). Mechanical nociceptive threshold was evaluated before ODN treatment was started and again 30 min and 1, 7, 14, 21, and 28 days after administration of oxaliplatin. (A) The magnitude of oxaliplatin-induced hyperalgesia was significantly attenuated in males treated with ADRB2 AS-ODN, compared with the ADRB2 MM-ODN-treated group. Data shown as mean ± SEM, Treatment F (1,60) = 39.75, Time F (5,60) = 0.5798, Interaction F (5,60) = 9.021, ****P<0,0001: GR AS-ODN vs GR AS-MM (n=6 paws per group). (B) The magnitude of oxaliplatin-induced hyperalgesia was significantly attenuated in females treated with ADRB2 AS-ODN, compared with the ADRB2 MM-ODN-treated group. Data shown as mean ± SEM, Treatment F (1,60) = 112.9, Time F (5,60) = 2.813, Interaction F (6.70) = 5.133, ****P<0,0001, ***P<0,001: GR AS-ODN vs GR AS-MM (n=6 paws per group). Reversal protocol (C and D): intrathecal treatment with GR AS- or MM-ODN started 3 days after intravenous administration of oxaliplatin (2 mg/kg). Mechanical nociceptive threshold was evaluated before oxaliplatin administration, and again 30 min and 1, 7, 14, 21 and 28 days later. (C) The magnitude of oxaliplatin-induced hyperalgesia was significantly reversed in males treated with GR AS-ODN, compared to the GR MM-ODN-treated group. Data shown as mean ± SEM, Treatment F (1,60) = 33.83, Time F (5,60)= 5.483, Interaction F (5,60) = 2.929, ****P<0,0001, **P<0,01, *P<0,05: GR AS-ODN vs ADRB2 GR-MM (n=6 paws per group). (D) The magnitude of oxaliplatin-induced hyperalgesia was significantly reversed in males treated with GR AS-ODN, compared to the GR MM-ODN-treated group. Data shown as mean ± SEM, Treatment F (1,60) = 28.94, Time (5,60), Interaction (5,60) = 4.069, ****P<0,0001, ***P<0,001: GR AS-ODN vs GR AS-MM (n=6 paws per group). Two-way repeated measures ANOVA followed by Bonferroni post hoc tests were used to compare antisense and mismatch groups over time.
Figure 5.
Figure 5.. Effect of chronic administration of stress hormones and unpredictable sound stress on oxaliplatin-induced hyperalgesia.
Male and female rats were submitted to stress levels of epinephrine (osmotic minipumps filled with 5.4 μg/0.25 μL/h of epinephrine), corticosterone (100 mg in pellets), or their combination or exposed to unpredictable sound stress on days 1, 3, and 4. Stress hormone exposure protocol: (A and B): surgery for the implantation of epinephrine-containing osmotic minipumps or corticosterone fused pellets in the interscapular space was performed 24h before intravenous administration of oxaliplatin (2 mg/kg) (day 0). (A) In male rats, exposed to epinephrine or the combination of epinephrine and corticosterone, the magnitude of oxaliplatin-induced hyperalgesia was increased in both phases of oxaliplatin CIPN. Rats exposed to corticosterone alone, exhibited an increase in the magnitude of oxaliplatin-induced hyperalgesia at 30 min and 1 (early phase) and 21 (late phase) days after oxaliplatin administration. Data shown as mean ± SEM Treatment F (3,120) = 86.39; Time (5, 120) = 13.42; Interaction (15, 120) =1.221, ****P<0,0001: epinephrine or epinephrine +corticosterone vs oxaliplatin; **P<0,01, *P<0,05: epinephrine+ corticosterone vs oxaliplatin; ####P<0,0001, #P<0,05: corticosterone vs oxaliplatin, using two-way repeated measures ANOVA followed by Bonferroni post hoc test (n=6 paws per group). (B) When female rats were exposed to corticosterone alone or the combination of corticosterone and epinephrine, an increase in the magnitude of oxaliplatin-induced hyperalgesia was observed. The magnitude of oxaliplatin-induced hyperalgesia was not affected by epinephrine exposure. Data shown as mean ± SEM Treatment F (3,120) = 51.27; Time (5, 120) = 3.397; Interaction (15, 120) =1.007, ####P<0,0001, ##P<0,01: corticosterone vs oxaliplatin or corticosterone plus epinephrine vs oxaliplatin; #P<0,05: corticosterone plus epinephrine vs oxaliplatin, using two-way repeated measures ANOVA followed by Bonferroni post hoc test (n=6 paws per group). For the sound stress protocol (C and D): oxaliplatin (2 mg/kg, i.v.) was administered (day 0) 14 days after the last exposure to sound stress. Mechanical nociceptive threshold was evaluated before and again 30 min and 1, 7, 14, 21 and 28 days after oxaliplatin. (C) In male rats exposed to sound stress, the magnitude of oxaliplatin-induced hyperalgesia was increased at 30 min and 1, 7, 14 and 21 days after oxaliplatin administration. Data shown as mean ± SEM, Treatment F (1,48) = 81, Time F (5,48) = 18.05, Interaction (5,48) = 6.293, ****P<0,0001, ***P<0,001, **P<0,001: sound stress oxaliplatin vs sham stress oxaliplatin, (n=6 paws per group), using two-way repeated measures ANOVA followed by Bonferroni post hoc tests (n=6 paws per group). (D) The magnitude of oxaliplatin-induced hyperalgesia was increased in female rats exposed to sound stress at 30 min and 1, 7 and 14 days after oxaliplatin administration. Data shown as mean ± SEM, Treatment F (1,60) = 20.6, Time F (5,60) = 15.71, Interaction (5,60) = 2.367, *P<0,05: sound stress oxaliplatin vs sham stress oxaliplatin, using two-way repeated measures ANOVA followed by Bonferroni post hoc tests (n=6 paws per group).
Figure 6.
Figure 6.. Effect of neonatal limited bedding (NLB) and neonatal handling (NH) on oxaliplatin-induced hyperalgesia.
Rats were exposed neonatally to either NLB (stress, upper panels, A and B) or NH (resilience, lower panels, C and D) protocols and, approximately 8 weeks later oxaliplatin (2 mg/kg, i.v.) (day 0) was administered. Mechanical nociceptive threshold was evaluated before and again 30 min and 1, 7, 14, 21 and 28 days after oxaliplatin. (A) The magnitude of oxaliplatin-induced hyperalgesia in NLB male rats did not differ when it was compared with control adult rats that received oxaliplatin. Data shown as mean ± SEM, Treatment F (1,60) = 5.97, Time F (5,60) = 6.306, Interaction F (5,60) =1.747, using 2-way repeated measures ANOVA followed by Bonferroni post hoc test (n=6 paws per group). (B) The magnitude of oxaliplatin-induced hyperalgesia was significantly enhanced in female rats submitted to the NLB protocol, when compared with control adult rats that received oxaliplatin. Data shown as mean ± SEM, Treatment F (1,60) = 167.6, Time F (5,60) = 4.55, Interaction F (5,60) = 2.159, ****P<0,0001, *P<0,05: NLB, oxaliplatin vs oxaliplatin, using two-way repeated measures ANOVA followed by Bonferroni post hoc test (n=6 paws per group). (C) Male rats submitted to the NH protocol showed significant attenuation in oxaliplatin-induced hyperalgesia when compared with control adult rats that received oxaliplatin. Data shown as mean ± SEM, Treatment (1,60) = 279.7, Time F (5,60) = 0.8117, Interaction F (5,60) = 3.681, ****P<0,0001, ***P<0,001: NH, oxaliplatin vs oxaliplatin, using 2-way repeated measures ANOVA followed by Bonferroni post hoc test (n=6 paws per group). (D) Female rats submitted to the NH protocol showed a marked attenuation in oxaliplatin-induced hyperalgesia when compared with control adult rats that received oxaliplatin. Data shown as mean ± SEM, Treatment (1,60) = 89.65, Time F (5,60) = 1.862, Interaction F (5,60) = 1.68, ****P<0,0001, ***P<0,001, **P<0,01, *P<0,05 : NH, oxaliplatin vs oxaliplatin, using 2-way repeated measures ANOVA followed by Bonferroni post hoc test (n=6 paws per group).
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