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. 2019 Sep 18;4(5):e782.
doi: 10.1097/PR9.0000000000000782. eCollection 2019 Sep-Oct.

Unpredictable stress delays recovery from exercise-induced muscle pain: contribution of the sympathoadrenal axis

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

Unpredictable stress delays recovery from exercise-induced muscle pain: contribution of the sympathoadrenal axis

Pedro Alvarez et al. Pain Rep. .

Abstract

Introduction: Although stress is a well-establish risk factor for the development of chronic musculoskeletal pain, the underlying mechanisms, specifically the contribution of neuroendocrine stress axes, remain poorly understood.

Objective: To evaluate the hypothesis that psychological stress-induced activation of the sympathoadrenal stress axis prolongs the muscle pain observed after strenuous exercise.

Methods: Adult male Sprague-Dawley rats were exposed to unpredictable sound stress and eccentric exercise. The involvement of the sympathoadrenal stress axis was evaluated by means of surgical interventions, systemic administration of epinephrine, and intrathecal β2-adrenergic receptor antisense.

Results: Although sound stress alone did not modify nociceptive threshold, it prolonged eccentric exercise-induced mechanical hyperalgesia. Adrenal medullectomy (ADMdX) attenuated, and administration of stress levels of epinephrine to ADMdX rats mimicked this effect of sound stress. Knockdown of β2-adrenergic receptors by intrathecal antisense also attenuated sound stress-induced prolongation of eccentric exercise-induced hyperalgesia.

Conclusion: Together, these results indicate that sympathoadrenal activation, by unpredictable sound stress, disrupts the capacity of nociceptors to sense recovery from eccentric exercise, leading to the prolongation of muscle hyperalgesia. This prolonged recovery from ergonomic pain is due, at least in part, to the activation of β2-adrenergic receptors on muscle nociceptors.

Keywords: Adrenal medulla; Delayed-onset muscle soreness; Nociceptor; Rat; β2-adrenergic receptor.

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Conflict of interest statement

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Figures

Figure 1.
Figure 1.
Preexposure to sound stress prolongs eccentric exercise-induced mechanical hyperalgesia. (A) The experimental protocol used to study muscle nociceptive threshold in rats submitted to unpredictable sound stress on days 1, 3, and 4. After assessment of baseline nociceptive threshold sound stress (SS) rats and naive (control) rats were submitted to eccentric exercise 1 (SS 1 day) or 14 (SS 14 days) days after the last sound stress session. The nociceptive threshold was then measured in the ipsilateral gastrocnemius muscle, up to day 20 after eccentric exercise. (B) Two-way ANOVA showed significant effects for treatment (F2,15 = 61.07, P < 0.001), time (F7,105 = 446.9, P < 0.001), and treatment by time interaction (F14,105 = 30.54, P < 0.001). Post hoc analysis revealed significant differences between control rats and SS 1 day rats from day 3 (P < 0.05) to day 20 (P < 0.001) after eccentric exercise. Significant differences between control rats and SS 14 days rats were observed, from day 2 (P < 0.05) to day 20 (P < 0.001) after eccentric exercise. Significant differences between SS 1 day and SS 14 days rats were observed only in days 3 (P < 0.05) and 5 (P < 0.001) after eccentric exercise. *P < 0.05; ***P < 0.001 (Naive vs SS 14 days); ###P < 0.001 (Naive vs SS 1 day). ANOVA, analysis of variance.
Figure 2.
Figure 2.
Adrenal medullectomy attenuates the prolongation of eccentric exercise-induced muscle hyperalgesia by sound stress. (A) Timing of the experimental protocol used to study muscle nociceptive threshold after surgical excision of the adrenal medulla (ADMdX) or sham procedure in control rats. Five weeks after surgery, after assessment of baseline nociceptive threshold measured in the ipsilateral gastrocnemius muscle (time point −1), rats were submitted to unpredictable sound stress on days 1, 3, and 4. One day after the last SS session, nociceptive threshold was assessed (time point 0) and thereafter rats were submitted to eccentric exercise and the nociceptive threshold measured up to day 20 after eccentric exercise. (B) Two-way ANOVA showed significant effects for treatment (F2,15 = 48.35, P < 0.001), time (F8,120 = 423.95, P < 0.001), and treatment by time interaction (F16,120 = 27.96, P < 0.001). Post hoc analysis revealed significant differences between control (sham) rats + sound stress (SS) and ADMdX + SS rats, from day 1 (P < 0.05) to day 20 (P < 0.001) after eccentric exercise. Of note, nociceptive responses of ADMdX rats are similar to those displayed by naive (control) rats (Fig. 1B), suggesting that excision of the adrenal medulla does not modify, by itself, the nociceptive responses to eccentric exercise. *P < 0.05; ***P < 0.001 (Sham + SS vs ADMdX); #P < 0.05, ##P < 0.01, ###P < 0.001 (Sham + SS vs ADMdX + SS). ANOVA, analysis of variance.
Figure 3.
Figure 3.
Administration of stress levels of epinephrine prolongs eccentric exercise-induced muscle hyperalgesia. (A) Experimental protocol used to study muscle nociceptive threshold after the administration of stress levels of epinephrine or saline, alone or in combination with unpredictable sound stress (SS), in ADMdX rats. Two weeks after osmotic pumps containing epinephrine or saline were implanted, ADMdX rats were submitted to sound stress (SS + Epinephrine; SS + Saline) or sham procedure (Epinephrine) on days 1, 3, and 4. One day after the last sound stress session, they were submitted to eccentric exercise and the nociceptive threshold measured in the ipsilateral gastrocnemius muscle up to day 20 after eccentric exercise. (B) Two-way ANOVA showed significant effects for time (F8,120 = 394.7, P < 0.001), treatment (F2,15 = 34.11, P < 0.001), or treatment by time interaction (F16,120 = 10.30, P = 0.7497). Post hoc analysis revealed significant differences between control rats receiving saline and rats receiving epinephrine alone (Epinephrine) from day 3 to day 20 after eccentric exercise (P < 0.001) and between control rats (SS + Saline) and rats receiving epinephrine plus sound stress (SS + Epinephrine) from day 3 to day 15 after eccentric exercise (P < 0.001). No significant differences between rats receiving epinephrine alone (Epinephrine) and rats receiving epinephrine plus sound stress (SS + Epinephrine) were observed at any time point after eccentric exercise (P > 0.05). **P < 0.01; ***P < 0.001 (SS + Saline vs Epinephrine); ###P < 0.001 (SS + Saline vs SS + Epinephrine). ANOVA, analysis of variance.
Figure 4.
Figure 4.
Nociceptor expression of the β2-AR is necessary for sound stress-induced prolongation of eccentric exercise-induced muscle hyperalgesia. (A) Timing of the experimental protocol used to assess muscle nociceptive threshold after antisense oligodeoxynucleotide (AS ODN) and mismatch oligodeoxynucleotide (MM ODN) treatments, followed by exposure to unpredictable sound stress and eccentric exercise. After measurement of baseline nociceptive threshold (time point −3), rats received daily i.t. injections of AS ODN or MM ODN, for 3 days and their nociceptive threshold assessed one day after the last ODN injection (time point 0) and submitted to sound stress. One day after the last sound stress session, rats' nociceptive thresholds were measured (time point SS) and they were submitted to eccentric exercise (EE). To provide continuous knockdown of β2-AR, after the third daily injection, ODN injections were administered every other day, for a total of 15 injections. (B) Although devoid of a significant effect on nociceptive threshold, the AS ODN treatment directed against β2-AR produced significant attenuation of the prolongation of eccentric exercise hyperalgesia produced by sound stress. Indeed, two-way ANOVA showed significant effects for treatment (F1,10 = 53.98, P = 0.0001), time (F9,90 = 331.79, P < 0.0001), and interaction (F9,90 = 10.12, P < 0.0001). The Bonferroni multiple-comparisons test revealed significant differences between AS ODN and MM ODN treated rats from day 2 to day 20 after eccentric exercise. *P < 0.05; **P < 0.01; ***P < 0.001. ANOVA, analysis of variance.
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