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. 2018 Jun;19(6):670-677.
doi: 10.1016/j.jpain.2018.01.009. Epub 2018 Feb 9.

Neonatal Handling Produces Sex Hormone-Dependent Resilience to Stress-Induced Muscle Hyperalgesia in Rats

Pedro Alvarez  1 , Paul G Green  2 , Jon D Levine  3
Affiliations

Neonatal Handling Produces Sex Hormone-Dependent Resilience to Stress-Induced Muscle Hyperalgesia in Rats

Pedro Alvarez et al. J Pain. 2018 Jun.

Abstract

Neonatal handling (NH) of male rat pups strongly attenuates stress response and stress-induced persistent muscle hyperalgesia in adults. Because female sex is a well established risk factor for stress-induced chronic muscle pain, we explored whether NH provides resilience to stress-induced hyperalgesia in adult female rats. Rat pups underwent NH, or standard (control) care. Muscle mechanical nociceptive threshold was assessed before and after water avoidance (WA) stress, when they were adults. In contrast to male rats, NH produced only a modest protection against WA stress-induced muscle hyperalgesia in female rats. Gonadectomy completely abolished NH-induced resilience in male rats but produced only a small increase in this protective effect in female rats. The administration of the antiestrogen drug fulvestrant, in addition to gonadectomy, did not enhance the protective effect of NH in female rats. Finally, knockdown of the androgen receptor by intrathecal antisense treatment attenuated the protective effect of NH in intact male rats. Together, these data indicate that androgens play a key role in NH-induced resilience to WA stress-induced muscle hyperalgesia.

Perspective: NH induces androgen-dependent resilience to stress-induced muscle pain. Therefore, androgens may contribute to sex differences observed in chronic musculoskeletal pain and its enhancement by stress.

Keywords: Androgens; hypothalamic-pituitary-adrenal axis; musculoskeletal pain; nociceptor; sex difference; stress-induced pain; water avoidance stress.

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Figures

Figure 1
Figure 1. Sex differences in neonatal handling-induced protection against muscle hyperalgesia produced by water avoidance stress, in adult rats
Baseline muscle mechanical nociceptive thresholds were measured pre-exposure to water avoidance stress (Pre), in naïve (Control) and neonatally handled (NH) adult male (solid bars) and female (open bars) rats. Nociceptive thresholds were also obtained one day after the last exposure to water avoidance stress (Post). (A) Gonad intact rats: a greater protective effect of NH is observed in adult male, gonad intact rats; (B) Gonadectomy attenuates the protective effect of NH on water avoidance stress-induced muscle hyperalgesia, in adult rats. *P < 0.05; ***P < 0.001. Numbers in each bar indicate sample size.
Figure 2
Figure 2. Systemic fulvestrant does not increase the protective effect of neonatal handling in gonadectomized female rats
Neonatally handled female rats gondectomized at postnatal days 24–25, receiving control treatment or fulvestrant, exhibited comparable muscle mechanical nociceptive thresholds 2 weeks after each implant of osmotic pumps delivering the respective treatments. After 10 days of exposure to water avoidance stress (WA) a significant decrease in nociceptive threshold was observed in both experimental groups. ***P < 0.001. Numbers in each bar indicate sample size.
Figure 3
Figure 3. Knockdown of androgen receptor (AR) by intrathecal antisense attenuates the protective effect of neonatal handling in gonad intact adult male rats
Experimental groups did not exhibit differences in mechanical nociceptive threshold at baseline or after 3 intrathecal injections (Post ODN×3) of antisense (AS) or mismatch (MM) oligodeoxynucleotides (ODN). In contrast, the full AS treatment (Post ODN×8) attenuated the protective effect of neonatal handling on water avoidance stress (WA)-induced muscle hyperalgesia in adult male rats. ***P < 0.001. Numbers in each bar indicate sample size.
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