Neuroendocrine Stress Axis-Dependence of Duloxetine Analgesia (Anti-Hyperalgesia) in Chemotherapy-Induced Peripheral Neuropathy

doi:10.1523/JNEUROSCI.1691-21.2021

. 2022 Jan 19;42(3):405-415.

doi: 10.1523/JNEUROSCI.1691-21.2021. Epub 2021 Dec 8.

Neuroendocrine Stress Axis-Dependence of Duloxetine Analgesia (Anti-Hyperalgesia) in Chemotherapy-Induced Peripheral Neuropathy

Larissa Staurengo-Ferrari¹, Ivan J M Bonet¹, Dioneia Araldi¹, Paul G Green^{1

2}, Jon D Levine^{3

4}

Affiliations

¹ Department of Oral & Maxillofacial Surgery, Division of Neuroscience, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143.
² Departments of Preventative & Restorative Dental Sciences and Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, California 94143.
³ Department of Oral & Maxillofacial Surgery, Division of Neuroscience, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143 [email protected].
⁴ Department of Medicine, University of California at San Francisco, San Francisco, California 94143.

PMID: 34880120
PMCID: PMC8802923
DOI: 10.1523/JNEUROSCI.1691-21.2021

Neuroendocrine Stress Axis-Dependence of Duloxetine Analgesia (Anti-Hyperalgesia) in Chemotherapy-Induced Peripheral Neuropathy

Larissa Staurengo-Ferrari et al. J Neurosci. 2022.

. 2022 Jan 19;42(3):405-415.

doi: 10.1523/JNEUROSCI.1691-21.2021. Epub 2021 Dec 8.

Authors

Larissa Staurengo-Ferrari¹, Ivan J M Bonet¹, Dioneia Araldi¹, Paul G Green^{1

2}, Jon D Levine^{3

4}

Affiliations

¹ Department of Oral & Maxillofacial Surgery, Division of Neuroscience, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143.
² Departments of Preventative & Restorative Dental Sciences and Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, California 94143.
³ Department of Oral & Maxillofacial Surgery, Division of Neuroscience, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143 [email protected].
⁴ Department of Medicine, University of California at San Francisco, San Francisco, California 94143.

PMID: 34880120
PMCID: PMC8802923
DOI: 10.1523/JNEUROSCI.1691-21.2021

Abstract

Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is the best-established treatment for painful chemotherapy-induced peripheral neuropathy (CIPN). While it is only effective in little more than half of patients, our ability to predict patient response remains incompletely understood. Given that stress exacerbates CIPN, and that the therapeutic effect of duloxetine is thought to be mediated, at least in part, via its effects on adrenergic mechanisms, we evaluated the contribution of neuroendocrine stress axes, sympathoadrenal and hypothalamic-pituitary-adrenal, to the effect of duloxetine in preclinical models of oxaliplatin- and paclitaxel-induced CIPN. Systemic administration of duloxetine, which alone had no effect on nociceptive threshold, both prevented and reversed mechanical hyperalgesia associated with oxaliplatin- and paclitaxel-CIPN. It more robustly attenuated oxaliplatin CIPN in male rats, while it was more effective for paclitaxel CIPN in females. Gonadectomy attenuated these sex differences in the effect of duloxetine. To assess the role of neuroendocrine stress axes in the effect of duloxetine on CIPN, rats of both sexes were submitted to adrenalectomy combined with fixed level replacement of corticosterone and epinephrine. While CIPN, in these rats, was of similar magnitude to that observed in adrenal-intact animals, rats of neither sex responded to duloxetine. Furthermore, duloxetine blunted an increase in corticosterone induced by oxaliplatin, and prevented the exacerbation of CIPN by sound stress. Our results demonstrate a role of neuroendocrine stress axes in duloxetine analgesia (anti-hyperalgesia) for the treatment of CIPN.SIGNIFICANCE STATEMENT Painful chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating dose-dependent and therapy-limiting side effect of many of the cytostatic drugs used to treat cancer (Argyriou et al., 2010; Marmiroli et al., 2017). Duloxetine is the only treatment for CIPN currently recommended by the American Society of Clinical Oncology (Hershman et al., 2014). In the present study, focused on elucidating mechanisms mediating the response of oxaliplatin- and paclitaxel-induced painful peripheral neuropathy to duloxetine, we demonstrate a major contribution to its effect of neuroendocrine stress axis function. These findings, which parallel the clinical observation that stress may impact response of CIPN to duloxetine (Taylor et al., 2007), open new approaches to the treatment of CIPN and other stress-associated pain syndromes.

Keywords: CIPN; oxaliplatin; paclitaxel; pain; sex differences; stress.

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Figures

**Figure 1.**
Effect of duloxetine on nociceptive threshold. Groups of male and female rats were treated intraperitoneally with duloxetine (10 mg/kg, i.p.) or its vehicle (2% of DMSO plus saline, i.p.), for either 3 or 10 consecutive days. Before treatment (baseline) and 24 h after the last administration of duloxetine (after 3 or 10 d of treatment), mechanical nociceptive threshold was evaluated using the Randall–Selitto paw-withdrawal test. A, Males. Administration of duloxetine did not affect mechanical nociceptive threshold in male rats treated with duloxetine for either 3 or 10 consecutive days compared with the vehicle-treated control group (two-way ANOVA duloxetine vs vehicle: duloxetine × time interaction, F_(2,20) = 1.608, not significant). Data are mean ± SEM; n = 6/group. B, Females. Administration of duloxetine also did not affect mechanical nociceptive threshold in females treated with duloxetine for 3 or 10 consecutive days compared with the vehicle control group (two-way ANOVA, duloxetine vs vehicle: duloxetine × time interaction, F_(2,20) = 2.012, not significant). Data are mean ± SEM; n = 6/group.

**Figure 2.**
Sex difference in duloxetine anti-hyperalgesia for oxaliplatin CIPN. Both male and female rats were treated intraperitoneally with duloxetine or its vehicle, for 10 consecutive days, in prevention and reversal protocols. Prevention protocol: oxaliplatin (2 mg/kg, i.v.) was administered ∼24 hours after the third daily injection of duloxetine or vehicle (day 0). Reversal protocol: treatment with duloxetine or vehicle started 4 days after administration of oxaliplatin (2 mg/kg, i.v.). In both protocols, mechanical nociceptive threshold was evaluated before oxaliplatin administration and again 30 minutes and 1, 4, 7, 11, 14, 21, and 28 d later. Males: A, The magnitude of oxaliplatin-induced hyperalgesia was markedly attenuated in male rats treated with duloxetine (10 mg/kg, i.p.) in the prevention protocol, 30 min and on days 1, 4, 7, and 11 after oxaliplatin administration. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × duloxetine interaction, F_(7,70) = 9.06, p < 0.0001; duloxetine treatment, F_(1,10) = 23.99, p = 0.0006; Bonferroni's multiple *post hoc* comparisons test: ***p < 0.0001, **p = 0.004, *p = 0.018: duloxetine, oxaliplatin group versus vehicle, oxaliplatin group (n = 6/group). B, The magnitude of oxaliplatin-induced hyperalgesia was also markedly attenuated in male rats treated with duloxetine (10 mg/kg, i.p.) in the reversal protocol, on days 7, 11, and 14 after oxaliplatin administration. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × duloxetine interaction, F_(7,70) = 15.25, p < 0.0001; duloxetine treatment, F_(1,10) = 29.10, p = 0.0003; Bonferroni's multiple *post hoc* comparisons test: ***p = 0.003, **p = 0.087 (n = 6/group). Females: C, The magnitude of oxaliplatin-induced hyperalgesia was modestly attenuated in female rats treated with duloxetine, in the prevention protocol, measured on days 1, 4, and 7 after oxaliplatin administration. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × duloxetine interaction, F_(7,70) = 5.54, p < 0.0001; duloxetine treatment, F_(1,10) = 5.047, p = 0.0485; Bonferroni's multiple *post hoc* comparisons test: **p = 0.026 (n = 6/group). D, The magnitude of oxaliplatin-induced hyperalgesia was also modestly attenuated by duloxetine (10 or 20 mg/kg, i.p.) in the reversal protocol, in females, on days 7 and 11. No statistical differences between the two duloxetine doses were detected. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × duloxetine treatment, F_(14,105) = 3.44, p = 0.0001; duloxetine treatment, F_(2,15) = 2.80, p = 0.092; Bonferroni's multiple *post hoc* comparisons test: ***p = 0.0041 (vehicle vs 10 mg/kg duloxetine), **p = 0.0039 (vehicle vs 20 mg/kg duloxetine), *p = 0.0032 (vehicle vs 10 mg/kg duloxetine) (n = 6/group).

**Figure 3.**
Sex difference in the anti-hyperalgesic effect of duloxetine in paclitaxel CIPN. Male and female rats were treated with duloxetine or its vehicle, intraperitoneally, for 10 consecutive days, in prevention and reversal protocols. Prevention protocol: starting ∼24 h after the third dose of duloxetine or vehicle, paclitaxel (1 mg/kg, i.p.) was administered every other day for a total of 4 injections, on days 0, 2, 4, and 6 (1 mg/kg × 4, i.p.). Reversal protocol: treatment with duloxetine or vehicle started 4 days after the last injection of paclitaxel (1 mg/kg × 4, i.p.). Males: A, The magnitude of paclitaxel-induced hyperalgesia was modestly attenuated in male rats treated with duloxetine (10 mg/kg, i.p.) in the prevention protocol, on days 7, 14, and 21. Data are mean ± SEM. Two-way repeated-measures ANOVA, interaction, F_(4,40) = 2.037, p = 0.1075; duloxetine treatment, F_(1,10) = 21.82, p = 0.0009; Bonferroni's multiple *post hoc* comparisons test: ***p = 0.0003, **p = 0.0326, *p = 0.0448 (n = 6/group). B, Paclitaxel-induced hyperalgesia was also transiently attenuated in males treated with duloxetine (10 mg/kg, i.p.) in the reversal protocol, measured on day 14. In contrast, in this protocol, duloxetine (20 mg/kg, i.p.) more strongly attenuated hyperalgesia induced by paclitaxel, in males, on days 11, 14, and 21. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × duloxetine interaction, F_(8,60) = 3.96, p = 0.0008; duloxetine treatment, F_(2,15) = 7.95, p = 0.0044; Bonferroni's multiple *post hoc* comparisons test: **p = 0.0063 (vehicle vs 20 mg/kg duloxetine), *p = 0.0138 (vehicle vs 20 mg/kg duloxetine) (n = 6/group). No statistical differences between the effect of the two duloxetine doses were detected. Females: C, Duloxetine markedly attenuated paclitaxel-induced hyperalgesia in females, on days 7, 11, 14, and 21, in the prevention protocol. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × duloxetine interaction, F_(4,40) = 5.392, p = 0.0014; duloxetine treatment, F_(1,10) = 145.8, p < 0.0001; Bonferroni's multiple *post hoc* comparisons test: ****p < 0.0001, *p = 0.01 (n = 6/group). D, Duloxetine markedly, but transiently, attenuated paclitaxel-induced hyperalgesia in females, in the reversal protocol, on days 14 and 21. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × duloxetine interaction, F_(4,40) = 10.49, p < 0.0001; duloxetine treatment, F_(1,10) = 8.88, p = 0.0138; Bonferroni's multiple *post hoc* comparisons test: ***p = 0.0008, **p = 0.0047 (n = 6/group).

**Figure 4.**
Role of gonadal hormones in response of CIPN to duloxetine. Females: Female rats were submitted to ovariectomy. Four weeks later, oxaliplatin was administered (2 mg/kg, i.v.). Four days after oxaliplatin, rats were treated with duloxetine (reversal protocol) or its vehicle (DMSO 2% plus saline). Mechanical nociceptive threshold was evaluated before oxaliplatin administration and again at 30 minutes, and on days 1, 4, 7, 11, 14, 21, and 28 after intravenous administration of oxaliplatin. A, The magnitude of oxaliplatin-induced hyperalgesia was markedly attenuated by duloxetine in gonadectomized females, in the reversal protocol, on days 7, 14, and 21. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × duloxetine interaction, F_(7,70) = 11.18, p < 0.0001; duloxetine treatment, F_(1,10) = 22.04, p = 0.0008; Bonferroni's multiple *post hoc* comparisons test: ***p = 0.002, **p = 0.003, *p = 0.025 (n = 6/group). Furthermore, the attenuation of hyperalgesia by duloxetine was not significantly different between gonadectomized females and gonadal intact males (two-way repeated-measures ANOVA, days 7-14, female ovariectomy, oxaliplatin, duloxetine group vs male, oxaliplatin, duloxetine group, F_(1,10) = 4.45, not significant). Males: Four weeks after gonadectomy, in males, paclitaxel was administered (1 mg/kg × 4, i.p.). Five days after the last injection of paclitaxel (∼day 11), rats were treated with duloxetine (10 mg/kg, i.p.) (reversal protocol) or its vehicle (DMSO 2% in saline). Mechanical nociceptive threshold was evaluated before the first dose of paclitaxel and again 7, 14, 21, and 28 d after intravenous administration of oxaliplatin. B, The magnitude of oxaliplatin-induced hyperalgesia was fully attenuated in gonadectomized males treated with duloxetine, in the reversal protocol, on days 14 and 21. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × duloxetine interaction, F_(4,40) = 9.213, p < 0.0001; duloxetine treatment, F_(1,10) = 97.72, p < 0.0001; Bonferroni's multiple *post hoc* comparisons test: ****p = 0.0007, **p = 0.0008 (n = 6/group).

**Figure 5.**
Role of neuroendocrine stress axes in the effect of duloxetine on oxaliplatin and paclitaxel CIPN. Adrenalectomized male and female rats were submitted to stable replacement of epinephrine (osmotic minipumps filled with 5.4 μg/0.25 μl/h of epinephrine) and corticosterone (100 mg in pellets). Twenty-four hours after surgical removal of the adrenal glands and implanting epinephrine-containing osmotic minipumps and corticosterone fused pellets, subcutaneously in the interscapular space, oxaliplatin (2 mg/kg, i.v.) or the first dose of paclitaxel (1 mg/kg × 4, i.p.) was administered. Four days after oxaliplatin or after the last dose of paclitaxel, rats were treated with duloxetine (reversal protocol) or its vehicle (DMSO 2% plus saline). Mechanical nociceptive threshold was evaluated before adrenalectomy and implant procedures, and again at 30 minutes, and on days 1, 4, 7, 11, 14, 21, and 28 after intravenous administration replacement. In paclitaxel CIPN, mechanical nociceptive threshold was evaluated before the adrenalectomy and implant procedures and again on days 7, 11, 14, 21, and 28 after the first dose of paclitaxel. Males: A, Duloxetine did not attenuate oxaliplatin-induced hyperalgesia in adrenalectomized male rats implanted with stress hormone compared with vehicle treatment. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × duloxetine interaction, F_(7,70) = 0.42, p = 0.887; duloxetine treatment, F_(1,10) = 3.7, p = 0.083 (n = 6/group). B, Duloxetine did not attenuate paclitaxel-induced hyperalgesia in adrenalectomized stress hormone-implanted male rats compared with vehicle treatment. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × duloxetine interaction, F_(4,40) = 0.412, p = 0.799; duloxetine treatment, F_(1,10) = 0.225, p = 0.646 (n = 6/group). Females: C, Duloxetine did not attenuate oxaliplatin-induced hyperalgesia in adrenalectomized stress hormone-implanted female rats compared with vehicle treatment. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × duloxetine interaction, F_(7,70) = 1.14, p = 0.348; duloxetine treatment, F_(1,10) = 0.534, p = 0.482 (n = 6/group). D, Duloxetine did not attenuate paclitaxel-induced hyperalgesia in adrenalectomized stress hormone-implanted female rats compared with vehicle treatment. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × duloxetine interaction, F_(4,40) = 0.245, p = 0.919; duloxetine treatment, F_(1,10) = 0.00003, p = 0.996 (n = 6/group).

**Figure 6.**
Duloxetine prevents sound stress-induced exacerbation of CIPN. Male and female rats were exposed to unpredictable sound stress for 3 days. Eleven days after the last exposure to sound stress, which corresponds to 3 d before chemotherapy administration (oxaliplatin or paclitaxel, day 0), duloxetine treatment (10 mg/kg, i.p.) was started. Animals were treated with duloxetine for 10 consecutive days. Males: A, Duloxetine prevents the exacerbation of oxaliplatin hyperalgesia induced by sound stress, in males. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × treatment interaction, F_(21,140) = 4.733, p < 0.0001; treatment, F_(3,20) = 55.98, p < 0.0001 (n = 6/group). No significant differences between groups treated with duloxetine and submitted to sham or sound stress were detected. Bonferroni's multiple comparisons test, sham stress versus stress: ^####p = 0.0003, ^###p = 0.002, ^##p = 0.009, ^#p = 0.04; stress + vehicle versus stress + duloxetine: ****p < 0.0001, ***p = 0.0008 (day 11), ***p = 0.0004 (day 14), **p = 0.005, *p = 0.017. Females: B, Duloxetine prevents the exacerbation of paclitaxel hyperalgesia by sound stress, in females. Data are mean ± SEM. Two-way repeated-measures ANOVA, time × treatment interaction, F_(12,80) = 9.58, p < 0.0001; treatment, F_(3,20) = 62.48, p < 0.0001 (n = 6/group). No significant differences between groups treated with duloxetine and submitted to sham or sound stress were detected. Bonferroni's multiple comparisons test, sham stress versus stress: ^####p = 0.0003, ^###p = 0.002, ^##p = 0.009, ^#p = 0.04; stress + vehicle versus stress + duloxetine: ****p < 0.0001, ***p = 0.0008 (day 11), ***p = 0.0004 (day 14), **p = 0.005, *p = 0.017. No significant differences between groups treated with duloxetine and submitted to sham or sound stress were detected.

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References

1. Adam EK (2006) Transactions among adolescent trait and state emotion and diurnal and momentary cortisol activity in naturalistic settings. Psychoneuroendocrinology 31:664–679. 10.1016/j.psyneuen.2006.01.010 - DOI - PubMed
1. Adam EK, Kumari M (2009) Assessing salivary cortisol in large-scale, epidemiological research. Psychoneuroendocrinology 34:1423–1436. 10.1016/j.psyneuen.2009.06.011 - DOI - PubMed
1. Adam EK, Sutton JM, Doane LD, Mineka S (2008) Incorporating hypothalamic-pituitary-adrenal axis measures into preventive interventions for adolescent depression: are we there yet. Dev Psychopathol 20:975–1001. 10.1017/S0954579408000461 - DOI - PubMed
1. Adam EK, Quinn ME, Tavernier R, McQuillan MT, Dahlke KA, Gilbert KE (2017) Diurnal cortisol slopes and mental and physical health outcomes: a systematic review and meta-analysis. Psychoneuroendocrinology 83:25–41. 10.1016/j.psyneuen.2017.05.018 - DOI - PMC - PubMed
1. Alvarez P, Ferrari LF, Levine JD (2011) Muscle pain in models of chemotherapy-induced and alcohol-induced peripheral neuropathy. Ann Neurol 70:101–109. 10.1002/ana.22382 - DOI - PMC - PubMed

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[1] Adam EK (2006) Transactions among adolescent trait and state emotion and diurnal and momentary cortisol activity in naturalistic settings. Psychoneuroendocrinology 31:664–679. 10.1016/j.psyneuen.2006.01.010 - DOI - PubMed

[2] Adam EK (2006) Transactions among adolescent trait and state emotion and diurnal and momentary cortisol activity in naturalistic settings. Psychoneuroendocrinology 31:664–679. 10.1016/j.psyneuen.2006.01.010 - DOI - PubMed

[3] Adam EK, Kumari M (2009) Assessing salivary cortisol in large-scale, epidemiological research. Psychoneuroendocrinology 34:1423–1436. 10.1016/j.psyneuen.2009.06.011 - DOI - PubMed

[4] Adam EK, Kumari M (2009) Assessing salivary cortisol in large-scale, epidemiological research. Psychoneuroendocrinology 34:1423–1436. 10.1016/j.psyneuen.2009.06.011 - DOI - PubMed

[5] Adam EK, Sutton JM, Doane LD, Mineka S (2008) Incorporating hypothalamic-pituitary-adrenal axis measures into preventive interventions for adolescent depression: are we there yet. Dev Psychopathol 20:975–1001. 10.1017/S0954579408000461 - DOI - PubMed

[6] Adam EK, Sutton JM, Doane LD, Mineka S (2008) Incorporating hypothalamic-pituitary-adrenal axis measures into preventive interventions for adolescent depression: are we there yet. Dev Psychopathol 20:975–1001. 10.1017/S0954579408000461 - DOI - PubMed

[7] Adam EK, Quinn ME, Tavernier R, McQuillan MT, Dahlke KA, Gilbert KE (2017) Diurnal cortisol slopes and mental and physical health outcomes: a systematic review and meta-analysis. Psychoneuroendocrinology 83:25–41. 10.1016/j.psyneuen.2017.05.018 - DOI - PMC - PubMed

[8] Adam EK, Quinn ME, Tavernier R, McQuillan MT, Dahlke KA, Gilbert KE (2017) Diurnal cortisol slopes and mental and physical health outcomes: a systematic review and meta-analysis. Psychoneuroendocrinology 83:25–41. 10.1016/j.psyneuen.2017.05.018 - DOI - PMC - PubMed

[9] Alvarez P, Ferrari LF, Levine JD (2011) Muscle pain in models of chemotherapy-induced and alcohol-induced peripheral neuropathy. Ann Neurol 70:101–109. 10.1002/ana.22382 - DOI - PMC - PubMed

[10] Alvarez P, Ferrari LF, Levine JD (2011) Muscle pain in models of chemotherapy-induced and alcohol-induced peripheral neuropathy. Ann Neurol 70:101–109. 10.1002/ana.22382 - DOI - PMC - PubMed

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Neuroendocrine Stress Axis-Dependence of Duloxetine Analgesia (Anti-Hyperalgesia) in Chemotherapy-Induced Peripheral Neuropathy

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Neuroendocrine Stress Axis-Dependence of Duloxetine Analgesia (Anti-Hyperalgesia) in Chemotherapy-Induced Peripheral Neuropathy

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