Bradykinin and Nerve Growth Factor Play Pivotal Roles in Muscular Mechanical Hyperalgesia after Exercise (Delayed-Onset Muscle Soreness)

Shiori Murase,¹ Etsuji Terazawa,^1,2  Fernando Queme,¹ Hiroki Ota,¹ Teru Matsuda,¹ Kenji Hirate,³  Yasuko Kozaki,^1,4 Kimiaki Katanosaka,¹ Toru Taguchi,¹ Hisako Urai,^1,5 , and Kazue Mizumura¹

¹Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan, ²Department of Anesthesiology and Pain Medicine, Gifu University School of Medicine, Gifu 501-1194, Japan, ³Laboratory of Discovery Research, Research Laboratories, Nippon Chemiphar Company, Ltd., Misato 341-0005, Japan, ⁴Department of Pharmacy, Kinjo Gakuin University, Nagoya 463-8521, Japan, and ⁵Department of Sport and Health Sciences, Graduate School of Sport Sciences, Osaka University of Health and Sport Sciences, Osaka 590-0496, Japan

Correspondence should be addressed to Kazue Mizumura, Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan. Email: mizu{at}riem.nagoya-u.ac.jp

Abstract: Unaccustomed strenuous exercise that includes lengthening contraction (LC) often causes delayed-onset muscle soreness (DOMS), a kind of muscular mechanical hyperalgesia. The substances that induce this phenomenon are largely unknown. Peculiarly, DOMS is not perceived during and shortly after exercise, but rather is first perceived after 1 d. Using B₂ bradykinin receptor antagonist HOE 140, we show here that bradykinin released during exercise plays a pivotal role in triggering the process that leads to muscular mechanical hyperalgesia. HOE 140 completely suppressed the development of muscular mechanical hyperalgesia when injected before LC, but when injected 2 d after LC failed to reverse mechanical hyperalgesia that had already developed. B₁ antagonist was ineffective, regardless of the timing of its injection. Upregulation of nerve growth factor (NGF) mRNA and protein occurred in exercised muscle over a comparable time course (12 h to 2 d after LC) for muscle mechanical hyperalgesia. Antibodies to NGF injected intramuscularly 2 d after exercise reversed muscle mechanical hyperalgesia. HOE 140 inhibited the upregulation of NGF. In contrast, shortening contraction or stretching induced neither mechanical hyperalgesia nor NGF upregulation. Bradykinin together with shortening contraction, but not bradykinin alone, reproduced lasting mechanical hyperalgesia. We also showed that rat NGF sensitized thin-fiber afferents to mechanical stimulation in the periphery after 10–20 min. Thus, NGF upregulation through activation of B₂ bradykinin receptors is essential (though not satisfactory) to mechanical hyperalgesia after exercise. The present observations explain why DOMS occurs with a delay, and why lengthening contraction but not shortening contraction induces DOMS.

Correspondence should be addressed to Kazue Mizumura, Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan. Email: mizu{at}riem.nagoya-u.ac.jp

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