Pharmacological blockade of muscle afferents and perception of effort: a systematic review with meta-analysis

The perception of effort (PE) provides information on task difficulty and influences physical exercise regulation and human behavior. This perception differs from other-exercise related perceptions such as pain. There is no consensus on the role of group III-IV muscle afferents as a signal processed by the brain to generate PE. The aim of this meta-analysis was to investigate the effect of pharmacologically blocking muscle afferents on the PE. Six databases were searched to identify studies measuring the ratings of perceived effort (RPE) during physical exercise, with and without pharmacological blockade of muscle afferents. Articles were coded based on the operational measurement used to distinguish studies in which PE was assessed specifically (effort dissociated) or as a composite experience including other exercise-related perceptions (effort not dissociated). Articles that did not provide enough information for coding were assigned to the unclear group. The effort dissociated group (n=6) demonstrated a slight RPE increase with reduced muscle afferents feedback (standard mean change raw (SMCR), 0.39; 95%CI, 0.13 to 0.64). The group effort not dissociated (n=2) did not reveal conclusive results (SMCR, -0.29; 95%CI, -2.39 to 1.8). The group unclear (n=8) revealed a slight RPE decrease with reduced muscle afferents feedback (SMCR, -0.27; 95%CI, -0.50 to -0.04). The heterogeneity in results between groups reveals that the inclusion of other perceptions than effort in its rating influences the RPE scores reported by the participants. The absence of decreased RPE in the effort dissociated group suggests that muscle afferents feedback is not a sensory signal generating PE.

Ischemic preconditioning of the muscle reduces the metaboreflex response of the knee extensors

Purpose This study investigated the effect of ischemic preconditioning (IP) on metaboreflex activation following dynamic leg extension exercise in a group of healthy participants. Method Seventeen healthy participants were recruited. IP and SHAM treatments (3 × 5 min cuff occlusion at 220 mmHg or 20 mmHg, respectively) were administered in a randomized order to the upper part of exercising leg’s thigh only. Muscle pain intensity (MP) and pain pressure threshold (PPT) were monitored while administrating IP and SHAM treatments. After 3 min of leg extension exercise at 70% of the maximal workload, a post-exercise muscle ischemia (PEMI) was performed to monitor the discharge group III/IV muscle afferents via metaboreflex activation. Hemodynamics were continuously recorded. MP was monitored during exercise and PEMI. Results IP significantly reduced mean arterial pressure compared to SHAM during metaboreflex activation (mean ± SD, 109.52 ± 7.25 vs. 102.36 ± 7.89 mmHg) which was probably the consequence of a reduced end diastolic volume (mean ± SD, 113.09 ± 14.25 vs. 102.42 ± 9.38 ml). MP was significantly higher during the IP compared to SHAM treatment, while no significant differences in PPT were found. MP did not change during exercise, but it was significantly lower during the PEMI following IP (5.10 ± 1.29 vs. 4.00 ± 1.54). Conclusion Our study demonstrated that IP reduces hemodynamic response during metaboreflex activation, while no effect on MP and PPT were found. The reduction in hemodynamic response was likely the consequence of a blunted venous return.

Sympathetic Activation due to Limb Venous Distension Is Preserved during Muscle Metaboreceptor Stimulation

Venous saline infusions in an arterially occluded forearm evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in humans (venous distension reflex). It is unclear if the inputs from metabolically sensitive skeletal muscle afferents (i.e. muscle metaboreflex) would modify venous distension reflex. We hypothesized that muscle metaboreceptor stimulation might augment the venous distension reflex. BP (Finapres), heart rate (ECG), and MSNA (microneurography) were assessed in 18 young healthy subjects. In trial A, saline (5% forearm volume) was infused into the veins of an arterially occluded arm (non-handgrip trial). In trial B, subjects performed 2 min static handgrip followed by post exercise circulatory occlusion (PECO) of the arm. During PECO, saline was infused into veins of the arm (handgrip trial). In trial A, the infusion increased MSNA and BP as expected (both P < 0.001). In trial B, handgrip significantly raised MSNA, BP and venous lactic acid concentrations. Venous saline infusion during PECO further raised MSNA and BP (both P < 0.001). The changes in MSNA (D8.6 ± 1.5 to D10.6 ± 1.8 bursts/min, P = 0.258) and mean arterial pressure (P = 0.844) evoked by the infusion during PECO were not significantly different from those in the non-handgrip trial. These observations indicate that venous distension reflex responses are preserved during sympathetic activation mediated by the muscle metaboreflex.

TRPV1 (Transient Receptor Potential Vanilloid 1) Sensitization of Skeletal Muscle Afferents in Type 2 Diabetic Rats With Hyperglycemia

The blood pressure response to exercise is exaggerated in type 2 diabetes (T2D). However, the underlying mechanisms remain unclear. It is hypothesized that one mechanism mediating the potentiated cardiovascular response in T2D is the sensitization of chemically sensitive afferent neurons by activation of metaboreceptors. To test this hypothesis, we examined TRPV1 (transient receptor potential vanilloid 1)-induced cardiovascular responses in vivo and muscle afferent discharge ex vivo in T2D rats. Additionally, TRPV1 and PKC (protein kinase C) protein levels in dorsal root ganglia subserving skeletal muscle were assessed. For 14 to 16 weeks, Sprague-Dawley rats were given either a normal diet (control) or a high-fat diet in combination with a low dose (35 and 25 mg/kg) of streptozotocin (T2D). Administration of capsaicin, TRPV1 agonist, in hindlimb evoked significantly greater increases in mean arterial pressure and renal sympathetic nerve activity in decerebrated T2D than control. In a muscle-nerve preparation, the discharge to capsaicin exposure in group IV afferents isolated from T2D was likewise significantly augmented at a magnitude that was proportional to glucose concentration. Moreover, the discharge to capsaicin was potentiated by acute exposure of group IV afferents to a high-glucose environment. T2D showed significantly increased phospholyrated-TRPV1 and -PKCα levels in dorsal root ganglia neurons as compared with control. These findings suggest that group IV muscle afferents are sensitized by PKC-induced TRPV1 overactivity in early stage T2D with hyperglycemia and, thereby, may contribute to the potentiated circulatory response to TRPV1 activation in the disease.

Modulation of Muscle Pain Is Not Somatotopically Restricted: An Experimental Model Using Concurrent Hypertonic-Normal Saline Infusions in Humans

We have previously shown that during muscle pain induced by infusion of hypertonic saline (HS), concurrent application of vibration and gentle brushing to overlying and adjacent skin regions increases the overall pain. In the current study, we focused on muscle-muscle interactions and tested whether HS-induced muscle pain can be modulated by innocuous/sub-perceptual stimulation of adjacent, contralateral, and remote muscles. Psychophysical observations were made in 23 healthy participants. HS (5%) was infused into a forearm muscle (flexor carpi ulnaris) to produce a stable baseline pain. In separate experiments, in each of the three test locations (n = 10 per site)—ipsilateral hand (abductor digiti minimi), contralateral forearm (flexor carpi ulnaris), and contralateral leg (tibialis anterior)—50 μl of 0.9% normal saline (NS) was infused (in triplicate) before, during, and upon cessation of HS-induced muscle pain in the forearm. In the absence of background pain, the infusion of NS was imperceptible to all participants. In the presence of HS-induced pain in the forearm, the concurrent infusion of NS into the ipsilateral hand, contralateral forearm, and contralateral leg increased the overall pain by 16, 12, and 15%, respectively. These effects were significant, reproducible, and time-locked to NS infusions. Further, the NS-evoked increase in pain was almost always ascribed to the forearm where HS was infused with no discernible percept attributed to the sites of NS infusion. Based on these observations, we conclude that intramuscular infusion of HS results in muscle hyperalgesia to sub-perceptual stimulation of muscle afferents in a somatotopically unrestricted manner, indicating the involvement of a central (likely supra-spinal) mechanism.