Consideration of afferent input timing.
The type of afferent fiber activity corresponds to specific time frames within a stimulation period, with mechanically sensitive afferents responding at the onset of MC, and chemically sensitive afferents responding later (11,12,14). There was no significant difference in peak MAP during the first 12 s of the response (F 3,12 = 2.71; P > 0.05; power = 0.51). Significant differences were found in the last 12 s and the last 6 s responses for MAP at T + 60 min (last 12 s: F 3,12 = 4.33; P < 0.05; last 6 s: F 3,12 = 4.03; P < 0.05). The mean (M ± SEM) of the peak MAP for the ipsilateral side in the last 12 s were T = 0 = 33 mm Hg ± 8, T + 20 = 28 ± 4, T +40 = 21 ± 4, and T + 60 = 15 ± 5. The peak MAP responses at the very end (last 6 s) were T = 0 = 34 mm Hg ± 8, T + 20 = 27 ± 3, T + 40 = 20 ± 2, and T + 60 = 12 ± 5. There were no significant differences in HR observed with any condition.
No differences were found in overall peak MAP (F 3,12 = 2.56, P > 0.05). The afferent timing results also showed no differences in the peak MAP during the first 12 s (F 3,12 = 1.57, P > 0.05). There were significant effects observed on the peak MAP responses during the last 12 s and the last 6 s of the muscle stimulation period at T + 50 min after application (last 12 s: F 3,12 = 3.48, P < 0.05; last 6 s: F 3,12 = 4.29, P < 0.05) on the side on which no TS was applied (Fig. 5). The mean (M ± SEM) of the peak MAP for the contralateral side in the last 12 s were T − 10 = 26 mm Hg ± 6, T + 10 = 27 ± 7, T + 30 = 19 ± 4, and T + 50 min = 10 ± 3. The mean values of the peak MAP for the end response (last 6 s) for T − 10, T + 10, T + 30, and T + 50 min were 23 ± 6, 23 ± 7, 16 ± 5, and 6 ± 2, respectively.
In five control animals, no significant differences in MAP responses were identified during the 60 min of testing. This demonstrates that the AB base was not the cause of the observed attenuation.
The results demonstrate that salicylate-based AB without counterirritant properties can attenuate pressor responses evoked by MC similar to those effects seen with the counterirritants, capsaicin (17), and menthol (19). There was a decrease in the overall peak MAP response at 60 min after application of TS on the ipsilateral side. The time course of the effects from the TS was longer than that seen with counterirritants. Past AB work with counterirritants (17,19) has shown significant overall peak attenuation at 20 min after application, but the response returned to baseline at 40 min after application. This difference in time course may be attributed to the differences in the putative mechanism of action of the active ingredients. Counterirritants produce strong sensory stimulation quickly, with the effects not long lasting. Counterirritants are thought to hyperstimulate and elicit an opiate system response (15,16). Conversely, salicylates must penetrate the skin rather than stimulating its surface, and they are thought to limit the production of prostaglandins through the cyclooxygenase pathways (24).
These differences suggest a delay in the latency of the effects of salicylates versus counterirritants. Furthermore, these differences help explain our previous observations in which a combined product containing counterirritant and salicylate was tested (7). Whereas a combined product had a short latency effect, this was likely attributable to the counterirritant portion of this AB. However, it is likely that the response at 40 min was a combination of a waning counterirritant effect (17) and, perhaps, the beginning of the salicylate effect. In the present study, which examines a pure salicyate effect, it is likely that the effects become statistically significant only at 50-60 min. We and others have theorized that counterirritants act by closure of spinal- and/or brainstem-mediated gate control mechanisms (3,7,17,19). The counterirritant component, which consists of capsaicin, may also deplete afferents of peptides or neurotransmitters (6,10). Salicylates have been shown to penetrate the dermis and to work subcutaneously over time (23,24). It seems likely that the TS penetrated the skin to have some effects on sensory nerve endings through both local penetration and blood-borne routes, presumably on prostaglandin metabolite formation (1). The presence of a contralateral effect certainly could not be attributed to a direct local penetration. Further, the CNS was likely not affected directly by penetration by crossing the blood-brain barrier (18). The most likely remaining route for contralateral effects would, then, be blood-borne effects on peripheral receptors.
The effects were also apparent during the last 12 s of the MC stimulus, indicating that the effects of TS may target group IV afferents, which are stimulated by chemical events (11). This selectivity to chemical processes and events was also evident, with the significant reduction of mean peak MAP during the last 6 s of the response. This time period was chosen to further ensure that the responses would be mediated largely by group IV afferents. It is known that the cyclooxygenase pathway and prostaglandins contribute to pressor responses evoked by MC (25). Furthermore, cyclooxygenase blockade has been shown to attenuate the responses of group IV muscle afferents to static MC (20). This selectivity for chemical events is further supported by the lack of attenuation seen during the initial 12 s of the MC stimulus, which, in turn, is thought to be primarily activating group III afferents, which signal largely mechanical events. It is known that group III sensitivity can be affected by prostaglandin levels, because their responses increase when exposed to arachidonic acid (prostaglandin precursor) (21). Thus, it is somewhat surprising that no changes were observed during the first 12 s of the response to MC. However, taken together, these data clearly show that the TS-based AB can have attenuation effects, which are likely related to an effect of cyclooxygenase inhibition.
The significant contralateral effects on the last 12 s of the response on the contralateral side were unlike the results from the counterirritant studies in which no significant contralateral effects were identified. There were only attenuation effects seen in the last 12 s (chemical) of the contralateral response. This also supports the proposed mechanism of action of salicylate-based AB, acting on chemical events such as prostaglandin metabolite formation. There were no significant effects identified on portions of the response thought to be mediated by nonchemical events. As previously mentioned, these results suggest that, at least in part, the TS affected the contralateral side by being blood borne to the contralateral limb.
On the basis of the work of Dawson etal. (5), in humans it is unlikely that the attenuations could be attributable to changes in overall limb blood flow. However, another factor in these observations could be localized skin blood flow. It has been reported to increase three to four times with AB application (22), which would seem to be an effect of topically applied AB products. Skin blood flow changes could alter or compound the behavior of sensory receptors. It is well known that changes in skin temperature (determined in part by skin blood flow) can lead to changes in sensory circuits and may even lead to analgesic effects (3). However, AB does not lead to temperature changes (26).
Although there were significant contralateral effects on the TS cats, there were no changes in the responses of the control cats that had the AB minus the active ingredient TS for the 60-min time course. Thus, it is likely that the effects were from the TS and not simply the condition of the cats through the longer experiment.
Type of pain and analgesic balms.
The time course and presence of effects in the TS cats in the present study are also important for practical reasons. It seems that the different active ingredients used in AB may target different portions of the response and at different latencies. Both capsaicin and menthol effects are quickly demonstrated by the attenuation of the overall peak responses at 20 min but are not long lasting, with responses returning to baseline levels at 40 min after application. These data, with the longer effects seen with the combination product (1% CAP, 12.5% methyl salicylate) at 40 min (7), 50 min (5), and the results from the present study with TS effects at 50 min and 60 min, seem to indicate that formulations could be developed to produce both immediate and long-lasting effects from AB. Also, products may be potentially developed to target specific afferents and pain, using the knowledge of the portion of the response the active ingredient effects. The last 12 s of the response to MC thought to be mediated by group IV afferents has been shown to be responsive to AB along with overall responses. Although the first 12 s of the response (group III) has not been significantly attenuated with any AB, capsaicin decreased the first 12-s responses from 20.7 ± 3.6 mm Hg initially to 12.7 ± 2.6 mm Hg at 20 min after application (17). The future may hold the tailoring of AB to specific types of pain conditions.
We conclude that the pressor responses caused by activation of group III and IV muscle afferents can be significantly attenuated by the application of AB containing the active ingredient TS. Changes in peak MAP induced by static ipsilateral MC were significantly attenuated at 60 min. This time course of action differs considerably in comparison with our previous work, which investigated specific counterirritants (17,19). However, the data seem consistent with those observed in an experiment in which a combination of counterirritant and salicylate was tested (7). It is likely that TS exerts its effects through an inhibition of cyclooxygenase-specifically, COX-2. This further suggests that the effects from TS are slower to develop and, thus, take effect when the counterirritant effects are waning.
We gratefully acknowledge Chattem Inc. for providing the inactive control substance used in this study. This research was supported in part by National Heart, Lung and Blood Institute grants HL 37400 and the University of Illinois Athletic Training Research Fund.
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Keywords:©2007The American College of Sports Medicine
SALICYLATES; THERAPEUTIC MODALITIES; PAIN; NSAID