Spinal opioid receptor-sensitive muscle afferents contribute to the fatigue-induced increase in intracortical inhibition in healthy humans

Abstract

We investigated the influence of spinal opioid receptor-sensitive muscle afferents on cortical changes following fatiguing unilateral knee-extensor exercise. On separate days, seven subjects performed an identical five sets of intermittent isometric right-quadriceps contractions, each consisting of eight submaximal contractions [63 ± 7% maximal voluntary contraction (MVC)] and one MVC. The exercise was performed following either lumbar interspinous saline injection or lumbar intrathecal fentanyl injection blocking the central projection of spinal opioid receptor-sensitive lower limb muscle afferents. To quantify exercise-induced peripheral fatigue, quadriceps twitch force (Q tw,pot ) was assessed via supramaximal magnetic femoral nerve stimulation before and after exercise. Motor evoked potentials and cortical silent periods (CSPs) were evaluated via transcranial magnetic stimulation of the motor cortex during a 3% MVC pre-activation period immediately following exercise. End-exercise quadriceps fatigue was significant and similar in both conditions ( Q tw,pot −35 and −39% for placebo and fentanyl, respectively; P = 0.38). Immediately following exercise on both days, motor evoked potentials were similar to those obtained prior to exercise. Compared with pre-exercise baseline, CSP in the placebo trial was 21 ± 5% longer postexercise (P < 0.01). In contrast, CSP following the fentanyl trial was not significantly prolonged compared with the pre-exercise baseline (6 ± 4%). Our findings suggest that the central effects of spinal opioid receptor-sensitive muscle afferents might facilitate the fatigue-induced increase in CSP. Furthermore, since the CSP is thought to reflect inhibitory intracortical interneuron activity, which may contribute to central fatigue, our findings imply that spinal opioid receptor-sensitive muscle afferents might influence central fatigue by facilitating intracortical inhibition.

Cerebral perturbations during exercise in hypoxia

“…This hypothesis is supported by both the increased motor drive during the first half of a normoxic 5-km cycling time trial performed with impaired cortical projection of opioid-mediated muscle afferents by intrathecal fentanyl injection and the excessive development of locomotor muscle fatigue observed during the time trial (11). Spinal opioid receptor muscle afferents may influence cerebral adaptations to exercise by facilitating intracortical inhibition (45). Consequently, under moderate hypoxic conditions, muscle fatigue may represent a key factor responsible for impaired central drive in hypoxia through enhanced muscle inhibitory afferent signals because of an accelerated development of locomotor muscle fatigue (12,54).…”

Fatigue and Exhaustion in Hypoxia: The Role of Cerebral Oxygenation

“…Quantifying these cortical activity changes during hypoxic exercise would help us identify the specific regions of interest, perhaps even help locate an ''origin'' of central fatigue in the brain. Some early promising work by Hilty et al (2011aHilty et al ( , 2011bHilty et al ( , 2011c indicates that muscle fatigue leads to changes in interaction between mid/ anterior insular, thalamus, and the motor cortex.…”

Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans

“…This stimulus drives much of the cardiovascular response to exercise, a regulatory mechanism termed the "exercise pressor reflex" (9,26,35,38,39). The pharmacologic stimulation of spinal -opioid receptors temporarily inhibits group III/IV muscle afferent feedback to the cardiovascular control centers in the brainstem (25,36) without affecting the force-generating capacity of skeletal muscle (2,22). Taking advantage of this phenomenon, previous studies have addressed the role of the exercise pressor reflex in determining the overall circulatory response to exercise in animals (21,36,44) and humans (1,3).…”