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.

Delayed onset muscle soreness (DOMS) is quite common, but the mechanism for this phenomenon is still not understood; even the existence of muscle tenderness (mechanical hyperalgesia) has not been demonstrated in experimental models. We developed an animal model of DOMS by inducing eccentric contraction (lengthening contraction, ECC) to the extensor digitorum longus muscle (EDL), and investigated the existence of mechanical hyperalgesia in the EDL by means of behavioural pain tests (Randall-Selitto test and von Frey hair test, applied to/through the skin on the EDL muscle) and c-Fos expression in the spinal dorsal horn. We found that the mechanical withdrawal threshold measured with the Randall-Selitto apparatus decreased significantly between 1 and 3 days after ECC, while that measured by von Frey hairs did not. The group that underwent stretching of the muscle only (SHAM group) showed no change in mechanical pain threshold in either test. These results demonstrated that the pain threshold of deep tissues (possibly of the muscle) decreased after ECC. c-Fos immunoreactivity in the dorsal horn (examined 2 days after ECC/SHAM exercise) was not changed by either ECC or compression (1568 mN) to the EDL muscle by itself, but it was significantly increased by applying compression to the EDL muscle 2 days after ECC. This increase was observed in the superficial dorsal horn of the L4 segment of the ipsilateral side, and was clearly suppressed by morphine treatment (10 mg kg −1 , I.P.). These results demonstrated the existence of mechanical hyperalgesia in the muscle subjected to ECC. This model could be used for future study of the neural mechanism of muscle soreness.

The change with age in pain perception in humans and the nociceptive behaviors in animals elicited by noxious stimuli to the skin are not well understood, and little is known about the peripheral neural mechanisms of cutaneous nociception in the aged. We systematically examined cutaneous nociceptor responses and nociceptive behaviors in young (9-14 w) and in aged (127-138 w) Sprague-Dawley rats. C-fiber nociceptors in the skin were identified by mechanical and electrical stimulation, and extracellularly recorded from hind paw skin-saphenous nerve preparations in vitro. In the aged rats, the proportions of mechano-responsive and/or heat-responsive C-nociceptors were significantly lower. The proportion of mechano- and thermo-insensitive units, on the other hand, was significantly increased. In addition, the response threshold to mechanical stimulus tended to be higher and the magnitude of the response tended to be smaller. There were no differences between the two age groups in the response magnitudes of mechano-responsive C-nociceptors to bradykinin, cold or heat. Repetitive electrical stimulation of afferent fibers revealed exaggerated slowing of conduction velocity in mechano-responsive C-fibers in the aged. This showed for the first time that not only receptive properties of afferent terminals but also membrane properties of conducting axons are changed in aged rats. Nociceptive behaviors in response to noxious levels of cold (cold plate test) and heat (Hargreaves' radiant heat test) were facilitated in aged animals, while mechanical sensitivity measured by von Frey hairs remained unchanged. These discrepancies between the changes in peripheral afferents and the behavioral outcomes might be explained by facilitatory changes in the central nervous system.

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Delayed-onset muscle soreness (DOMS) is a common but displeasing event induced by excessive muscle use or unaccustomed exercise and characterized by tenderness and movement-related pain in the exercised muscle. Thermal therapies, either icing or heating applied to muscles immediately after exercise, have been used as therapeutic interventions for DOMS. However, the mechanisms of their analgesic effects, and physiological and metabolic changes in the muscle during thermal therapy, remain unclear. In the present study, we investigated the effects of both thermal treatments on mechanical hyperalgesia of DOMS and physiological and muscle metabolite changes using the rat DOMS model induced by lengthening contraction (LC) to the gastrocnemius muscle. Heating treatment just after LC induced analgesic effects, while rats with icing treatment showed mechanical hyperalgesia similar to that of the LC group. Furthermore, increased physiological responses (e.g., muscle temperature and blood flow) following the LC were significantly kept high only in the rats with heating treatment. In addition, heating treatment increased metabolites involved in the improvement of blood flow and oxidative metabolisms in the exercised muscle. The results indicated that heating treatment just after LC has analgesic effects on DOMS, which might be mediated partly through the improvement of muscle oxidative metabolisms by changes in metabolites and elevated physiological responses. NEW & NOTEWORTHY Physiological effects of thermal therapy in the muscle and its mechanisms of analgesic effects remain unclear. The results indicated that heating, but not icing, treatment just after lengthening contractions induced analgesic effects in the rat muscle. Increases in hemodynamics, muscle temperature, and metabolites such as nicotinamide were more prominent in heating treatment, consistent with improvement of muscle oxidative metabolisms, which might reduce chemical factors to induce mechanical hyperalgesia.

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In this paper, we proposed long-lifetime and high-sensitive measurement using fluorescent intensity by compensation of photo-bleaching with the difference compensation for cell measurement. Photo-bleaching of fluorescence is one of the most crucial factors to cause measurement error in physiological measurement. In our approach, difference of fluorescent intensity between imaging time is compensated using single exponential function to make the difference amount uniform in each imaging time. We evaluated the dependencies of measurable time and the sensitivity by fluorescent lifetime and the decay coefficient of fluorescent lifetime using numerical simulation. From these results, the proposed method has much higher sensitivity and longer measurable time against conventional compensation method of photo-bleaching. By using the proposed method, we demonstrate the photosynthesis activity of single Synechocystis sp. PCC 6803 in the micro chamber with gas barrier layer.