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

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 ϳ1 d. Using B 2 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. B 1 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 B 2 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.

An antinociceptive role for substance P in acid-induced chronic muscle pain

“…administration of neurotrophin 3 reverses the acid-induced hyperalgesia, SP may work through or in parallel with neurotrophin receptors (24). However, neurotrophin (e.g., NGF) receptors also are implicated in mediating hyperalgesia in delayed-onset muscle soreness (48). Further studies should probe whether the antinociceptive effects of SP are blocked by neurotrophin receptor antagonists.…”

Stretching adversely modulates locomotor capacity following spinal cord injury via activation of nociceptive afferents.

“…Delayed onset muscle soreness (DOMS) which is a type of mechanical hyperalgesia, occurs 1 to 2 days after eccentric contractions as a result of nociceptive afferents sensitization in response to release of bradykinin and nerve growth factor. [240] Consistent with the DOMS phenomenon is the following observation: we have never observed any decrements in locomotor function following the initial stretching session in this (Fig. 1) or any of our earlier studies.…”

Visual Analog Scale and Pressure Pain Threshold for Delayed Onset Muscle Soreness Assessment

“…DOMS is characterized by the sensation of a dull, aching pain, usually felt during movement or palpation of the affected muscles, develops within 24 hours after performing exercise, and peaks 1-3 days post-exercise (1,2). The underlying mechanisms of DOMS have not been fully understood, but it has been documented that damage to contractile proteins, intermediate filaments, and/or connective tissue surrounding muscle fibers, and subsequent inflammatory process are associated with it (1,3).…”