Opioid-mediated muscle afferents inhibit central motor drive and limit peripheral muscle fatigue development in humans

Abstract

We investigated the role of somatosensory feedback from locomotor muscles on central motor drive (CMD) and the development of peripheral fatigue during high-intensity endurance exercise. In a double-blind, placebo-controlled design, eight cyclists randomly performed three 5 km time trials: control, interspinous ligament injection of saline (5K(Plac), L3-L4) or intrathecal fentanyl (5K(Fent), L3-L4) to impair cortical projection of opioid-mediated muscle afferents. Peripheral quadriceps fatigue was assessed via changes in force output pre- versus postexercise in response to supramaximal magnetic femoral nerve stimulation (DeltaQ(tw)). The CMD during the time trials was estimated via quadriceps electromyogram (iEMG). Fentanyl had no effect on quadriceps strength. Impairment of neural feedback from the locomotor muscles increased iEMG during the first 2.5 km of 5K(Fent) versus 5K(Plac) by 12 +/- 3% (P < 0.05); during the second 2.5 km, iEMG was similar between trials. Power output was also 6 +/- 2% higher during the first and 11 +/- 2% lower during the second 2.5 km of 5K(Fent) versus 5K(Plac) (both P < 0.05). Capillary blood lactate was higher (16.3 +/- 0.5 versus 12.6 +/- 1.0%) and arterial haemoglobin O(2) saturation was lower (89 +/- 1 versus 94 +/- 1%) during 5K(Fent) versus 5K(Plac). Exercise-induced DeltaQ(tw) was greater following 5K(Fent) versus 5K(Plac) (-46 +/- 2 versus -33 +/- 2%, P < 0.001). Our results emphasize the critical role of somatosensory feedback from working muscles on the centrally mediated determination of CMD. Attenuated afferent feedback from exercising locomotor muscles results in an overshoot in CMD and power output normally chosen by the athlete, thereby causing a greater rate of accumulation of muscle metabolites and excessive development of peripheral muscle fatigue.

Figure 1. Individual (•) and group mean effects (○) of intrathecal fentanyl on resting neuromuscular functions

Measures were taken before (pre-injection) and ∼10 min after (postinjection) the subarachnoid administration of fentanyl through the vertebral interspace L3–L4. A and B reflect the effects of fentanyl on voluntary muscle activation and maximal voluntary contraction force (MVC; P= 0.85 and P= 0.95, respectively). C and D illustrate the effects of fentanyl on potentiated (Q_tw,pot; P= 0.38) and unpotentiated quadriceps twitch force (Q_tw; P= 0.39), respectively.

Figure 2. Effect of modified somatosensory feedback on neural drive and power output during a 5 km cycling time trial

A, effects of opioid analgesic (intrathecal fentanyl) on group mean integrated EMG (iEMG) of vastus lateralis. Mean iEMG of the vastus lateralis was normalized to the iEMG obtained from pre-exercise MVC manoeuvres performed either without (5K_Plac and 5K_Ctrl) or with intrathecal fentanyl (5K_Fent). Mean iEMG during the pre-exercise MVC manoeuvres on the fentanyl day was not different between pre- versus postfentanyl injection (0.23 ± 0.03 versus 0.24 ± 0.03 V s⁻¹, respectively; P= 0.74). Each point represents the mean iEMG of the preceding 0.5 km section. Mean iEMG during the time trial was significantly increased from the trial with interspinous ligament injection of saline (5K_Plac) to the intrathecal fentanyl trial (5K_Fent; P < 0.05). B, group mean power output during the 5 km time trial with and without impaired afferent feedback. The subjects were required to reach an individual target power output before the race was launched (361 ± 15 W). Group mean power output/time to completion were 330 ± 16 W/7.49 ± 0.14 min and 328 ± 16 W/7.51 ± 0.13 min for 5K_Plac and 5K_Fent, respectively (P= 0.82 and P= 0.65, respectively). *P < 0.05, 5K_Fentversus 5K_Plac; n= 8 subjects.

Figure 3. Individual (•) and group mean effects (○) of 5 km time trial without (control trial and placebo trial) and with intrathecal fentanyl (fentanyl trial) on potentiated quadriceps twitch force (Q_tw,pot)

Exercise performance was similar between 5K_Ctrl and 5K_Plac (7.49 ± 0.14 and 7.49 ± 0.14 min, respectively; P= 0.75), which was also reflected in similar exercise-induced reductions in Q_tw,pot from before to 3 min after the time trial (intraclass correlation coefficient = 0.95, P= 0.26). Despite a similar overall exercise performance (7.51 ± 0.13 min), end-exercise quadriceps fatigue was significantly exacerbated following 5K_Fentversus 5K_Plac (P < 0.001).

Figure 4. Physiological responses to a 5 km cycling time trial without (5K_Ctrl and 5K_Plac) and with (5K_Fent) partly blocked somatosensory neural feedback from the fatiguing locomotor muscles

Group mean performance (average power output/time to completion) was similar in all trials (329 ± 16 W/7.49 ± 0.14 min, 330 ± 16 W/7.49 ± 0.14 min and 328 ± 16 W/7.51 ± 0.13 min for 5K_Ctrl, 5K_Plac and 5K_Fent, respectively; n= 8 subjects).