Small-diameter Muscle Afferents Research Articles

NaV1.9 channels in muscle afferent neurons and axons.

The exercise pressor reflex (EPR) is activated by muscle contractions to increase heart rate and blood pressure during exercise. While this reflex is beneficial in healthy individuals, the reflex activity is exaggerated in patients with cardiovascular disease, which is associated with increased mortality. Group III and IV afferents mediate the EPR and have been shown to express both tetrodotoxin-sensitive (TTX-S, NaV1.6, and NaV1.7) and -resistant (TTX-R, NaV1.8, and NaV1.9) voltage-gated sodium (NaV) channels, but NaV1.9 current has not yet been demonstrated. Using a F--containing internal solution, we found a NaV current in muscle afferent neurons that activates at around -70 mV with slow activation and inactivation kinetics, as expected from NaV1.9 current. However, this current ran down with time, which resulted, at least in part, from increased steady-state inactivation since it was slowed by both holding potential hyperpolarization and a depolarized shift of the gating properties. We further show that, following NaV1.9 current rundown (internal F-), application of the NaV1.8 channel blocker A803467 inhibited significantly more TTX-R current than we had previously observed (internal Cl-), which suggests that NaV1.9 current did not rundown with that internal solution. Using immunohistochemistry, we found that the majority of group IV somata and axons were NaV1.9 positive. The majority of small diameter myelinated afferent somata (putative group III) were also NaV1.9 positive, but myelinated muscle afferent axons were rarely labeled. The presence of NaV1.9 channels in muscle afferents supports a role for these channels in activation and maintenance of the EPR. NEW & NOTEWORTHY Small diameter muscle afferents signal pain and muscle activity levels. The muscle activity signals drive the cardiovascular system to increase muscle blood flow, but these signals can become exaggerated in cardiovascular disease to exacerbate cardiac damage. The voltage-dependent sodium channel NaV1.9 plays a unique role in controlling afferent excitability. We show that NaV1.9 channels are expressed in muscle afferents, which supports these channels as a target for drug development to control hyperactivity of these neurons.

Commentaries on Viewpoint: Could small-diameter muscle afferents be responsible for the ergogenic effect of limb ischemic preconditioning?

Commentaries on Viewpoint: Could small-diameter muscle afferents be responsible for the ergogenic effect of limb ischemic preconditioning?

Could small-diameter muscle afferents be responsible for the ergogenic effect of limb ischemic preconditioning?

originally developed with the aim of protecting cardiac muscle fibers from sustained ischemic insults, local or remote acute ischemic preconditioning (IP) consists of a potent endogenous mechanism that has been shown to protect various tissues and organs against ischemia-reperfusion injury ([16][1

Neural Contributions to Muscle Fatigue

: During exercise, there is a progressive reduction in the ability to produce muscle force. Processes within the nervous system as well as within the muscles contribute to this fatigue. In addition to impaired function of the motor system, sensations associated with fatigue and impairment of homeostasis can contribute to the impairment of performance during exercise. This review discusses some of the neural changes that accompany exercise and the development of fatigue. The role of brain monoaminergic neurotransmitter systems in whole-body endurance performance is discussed, particularly with regard to exercise in hot environments. Next, fatigue-related alterations in the neuromuscular pathway are discussed in terms of changes in motor unit firing, motoneuron excitability, and motor cortical excitability. These changes have mostly been investigated during single-limb isometric contractions. Finally, the small-diameter muscle afferents that increase firing with exercise and fatigue are discussed. These afferents have roles in cardiovascular and respiratory responses to exercise, and in the impairment of exercise performance through interaction with the motor pathway, as well as in providing sensations of muscle discomfort. Thus, changes at all levels of the nervous system, including the brain, spinal cord, motor output, sensory input, and autonomic function, occur during exercise and fatigue. The mix of influences and the importance of their contribution vary with the type of exercise being performed.

Firing of antagonist small‐diameter muscle afferents reduces voluntary activation and torque of elbow flexors

During muscle fatigue, firing of small-diameter muscle afferents can decrease voluntary activation of the fatigued muscle. However, these afferents may have a more widespread effect on other muscles in the exercising limb. We examined if the firing of fatigue-sensitive afferents from elbow extensor muscles in the same arm reduces torque production and voluntary activation of elbow flexors. In nine subjects we examined voluntary activation of elbow flexors by measuring changes in superimposed twitches evoked by transcranial magnetic stimulation of the motor cortex during brief (2-3 s) maximal voluntary contractions (MVC). Inflation of a blood pressure cuff following a 2-min sustained MVC blocked blood flow to the fatigued muscle and maintained firing of small-diameter afferents. After a fatiguing elbow flexion contraction, maximal flexion torque was lower (26.0 ± 4.4% versus 67.9 ± 5.2% of initial maximal torque; means ± s.d.; P < 0.001) and superimposed twitches were larger (4.1 ± 1.1% versus 1.8 ± 0.2% ongoing MVC, P = 0.01) with than without ischaemia. After a fatiguing elbow extensor contraction, maximal flexion torque was also reduced (82.2 ± 4.9% versus 91.4 ± 2.3% of initial maximal torque; P = 0.007), superimposed twitches were larger (2.7 ± 0.7% versus 1.3 ± 0.2% ongoing MVC; P = 0.02) and voluntary activation lower (81.6 ± 8.2% versus 95.5 ± 6.9%; P = 0.04) with than without ischaemia. After a fatiguing contraction, voluntary drive to the fatigued muscles is reduced with continued input from small-diameter muscle afferents. Furthermore, fatigue of the elbow extensor muscles decreases voluntary drive to unfatigued elbow flexors of the same arm. Therefore, firing of small-diameter muscle afferents from one muscle can affect voluntary activation and hence torque generation of another muscle in the same limb.

A comparison of central aspects of fatigue in submaximal and maximal voluntary contractions

Magnetic and electrical stimulation at different levels of the neuraxis show that supraspinal and spinal factors limit force production in maximal isometric efforts ("central fatigue"). In sustained maximal contractions, motoneurons become less responsive to synaptic input and descending drive becomes suboptimal. Exercise-induced activity in group III and IV muscle afferents acts supraspinally to limit motor cortical output but does not alter motor cortical responses to transcranial magnetic stimulation. "Central" and "peripheral" fatigue develop more slowly during submaximal exercise. In sustained submaximal contractions, central fatigue occurs in brief maximal efforts even with a weak ongoing contraction (<15% maximum). The presence of central fatigue when much of the available motor pathway is not engaged suggests that afferent inputs contribute to reduce voluntary activation. Small-diameter muscle afferents are likely to be activated by local activity even in sustained weak contractions. During such contractions, it is difficult to measure central fatigue, which is best demonstrated in maximal efforts. To show central fatigue in submaximal contractions, changes in motor unit firing and force output need to be characterized simultaneously. Increasing central drive recruits new motor units, but the way this occurs is likely to depend on properties of the motoneurons and the inputs they receive in the task. It is unclear whether such factors impair force production for a set level of descending drive and thus represent central fatigue. The best indication that central fatigue is important during submaximal tasks is the disproportionate increase in subjects' perceived effort when maintaining a low target force.

The influence of pain on masseter spindle afferent discharge

Muscle spindles provide proprioceptive feedback supporting normal patterns of motor activity and kinesthetic sensibility. During mastication, jaw muscle spindles play an important role in monitoring and regulating the chewing cycle and the bite forces generated during mastication. Both acute and chronic orofacial pain disorders are associated with changes in proprioceptive feedback and motor function. Experimental jaw muscle pain also alters the normal response of masseter spindle afferents to ramp and hold jaw movements. 1 It has been proposed that altered motor function and proprioceptive input results from group III muscle afferent modulation of the fusimotor system which alters spindle afferent sensitivity in limb muscles. 2 The response to nociceptive stimuli may enhance or reduce the response of spindle afferents to proprioceptive stimuli. Several experimental observations suggesting the possibility that a similar mechanism also functions in jaw muscles are presented in this report. First, evidence is provided to show that nociceptive stimulation of the masseter muscle primarily influences the amplitude sensitivity of spindle afferents with relatively little effect on the dynamic sensitivity. 3 Second, reversible inactivation of the caudal trigeminal nuclei attenuates the nociceptive modulation of spindle afferents. Finally, functionally identified gamma-motoneurons in the trigeminal motor nucleus are modulated by intramuscular injection with algesic substances. Taken together, these results suggest that pain-induced modulation of spindle afferent responses are mediated by small diameter muscle afferents and that this modulation is dependent, in part, on the relay of muscle nociceptive information from trigeminal subnucleus caudalis onto trigeminal gamma-motoneurons. The implication of these results will be considered in light of current theories on the relationship between jaw muscle pain and oral motor function.

Stimulation of chemosensitive afferents from multifidus muscle does not sensitize multifidus muscle spindles to vertebral loads in the lumbar spine of the cat.

Electrophysiologic recordings from muscle spindle afferents innervating the lumbar multifidus muscle of the cat while loading the L6 vertebra at its spinous process and while exposing the segmentally adjacent lumbar multifidus muscles to algesic and inflammatory mediators. The purpose of this study was to investigate a possible mechanism underlying muscle spasm and pain in the lumbar spine. The hypothesis was tested that stimulation of chemosensitive afferents with receptive endings in the paraspinal muscle increases the discharge of paraspinal muscle spindle afferents during loading of a lumbar vertebra. The presence of such a phenomenon would provide a mechanism by which pain or inflammation could alter segmental lumbar biomechanics and contribute to lumbar spine dysfunction. Muscle pain, tenderness, and altered muscle tone are often associated with musculoskeletal disorders. The literature suggests that stimulation of Group III and IV muscle afferents sensitive to algesic or inflammatory metabolites increases the stretch sensitivity of muscle spindles via a reflex pathway involving gamma-motoneurons. The reflex increase in muscle spindle activity, in turn, reflexly increases the excitability of alpha-motoneurons leading to enhanced muscle tone and the further accumulation of muscle metabolites and subsequent pain. Studies in the cervical spine support this hypothesis. It has not been investigated in the lumbar spine. Single unit activity from muscle spindles in the L6 multifidus muscle were recorded from the cut peripheral end of the L6 dorsal root in alpha-chloralose-anesthetized cats and in decerebrate unanesthetized cats. The L6 vertebra was loaded at its spinous process using a force-feedback motor. Ramp and hold loads were delivered at 25%, 50%, 75%, and 100% body weight. Chemosensitive afferents in the L5 and L7 multifidus muscle were stimulated by bathing (subfascial injection) or infiltrating (intramuscular injection) the L5 and L7 multifidus muscles with bradykinin or capsaicin. Loading the L6 vertebra stimulated muscle spindles in the L6 multifidus muscle. Neither the saline volume control nor bradykinin nor capsaicin injected subfascially or intramuscularly affected the response of L6 multifidus muscle spindles to ramp and hold vertebral loads in the alpha-chloralose-anesthetized cat. In addition, neither saline nor bradykinin nor capsaicin injected intramuscularly affected the activity of L6 multifidus muscle spindles to ramp and hold vertebral loads in the unanesthetized decerebrate cat. These results indicate that stimulation of small diameter muscle afferents in a deep muscle of the lumbar spine does not sensitize muscle spindles to vertebral loads. These data do not support the hypothesis that fusimotor reflexes evoked by chemosensitive muscle afferents contribute to muscle spasm or to changes in muscle tone in the lumbar spine. In addition, the present results do not provide evidence for the pain-spasm-pain cycle in the lumbar spine.

Modulation of jaw muscle spindle afferent activity following intramuscular injections with hypertonic saline

Transient noxious chemical stimulation of small diameter muscle afferents modulates jaw movement-related responses of caudal brainstem neurons. While it is likely that the effect is mediated from the spindle afferents in the mesencephalic nucleus (Vmes) via the caudally projecting Probst's tract, the mechanisms of pain induced modulations of jaw muscle spindle afferents is not known. In the present study, we tested the hypothesis that jaw muscle nociceptors gain access to muscle spindle afferents in the same muscle via central mechanisms and alter their sensitivity. Thirty-five neurons recorded from the Vmes were characterized as muscle spindle afferents based on their responses to passive jaw movements, muscle palpation, and electrical stimulation of the masseter nerve. Each cell was tested by injecting a small volume (250 μl) of either 5% hypertonic and/or isotonic saline into the receptor-bearing muscle. Twenty-nine units were tested with 5% hypertonic saline, of which 79% (23/29) showed significant modulation of mean firing rates (MFRs) during one or more phases of ramp-and-hold movements. Among the muscle spindle primary-like units ( n=12), MFRs of 4 units were facilitated, five reduced, two showed mixed responses and one unchanged. In secondary-like units ( n=17), MFRs of 9 were facilitated, three reduced and five unchanged. Thirteen units were tested with isotonic saline, of which 77% showed no significant changes of MFRs. Further analysis revealed that the hypertonic saline not only affected the overall output of muscle spindle afferents, but also increased the variability of firing and altered the relationship between afferent signal and muscle length. These results demonstrated that activation of muscle nociceptors significantly affects proprioceptive properties of jaw muscle spindles via central neural mechanisms. The changes can have deleterious effects on oral motor function as well as kinesthetic sensibility.

Effects of neurochemically excited group III–IV muscle afferents on motoneuron afterhyperpolarization

When humans voluntarily and maximally contract a muscle under isometric conditions, the average firing rate of motor units decreases from an initially high value over several tens of seconds. The mechanisms underlying the rate reduction are probably manifold. One mechanism could involve changes in the motoneuron afterhyperpolarization, and another reflex effects of group III–IV muscle afferents that are excited during developing muscle fatigue. It appears possible that changes in motoneuron afterhyperpolarization are mediated by these afferent inputs. We therefore studied effects on motoneuron afterhyperpolarization of small-diameter muscle afferents excited by intra-arterially injected metabolites such as bradykinin and serotonin. In decerebrate and mostly spinalized cats, lumbosacral α-motoneurons were recorded intracellularly. Current pulses were injected to test for input resistance and elicit action potentials and afterhyperpolarizations. Afterhyperpolarizations were averaged from 10 successive stimulus repetitions. Measurements were taken of afterhyperpolarization amplitude, half-width and area; and exponential functions were fitted to the afterhyperpolarization decay phase to determine afterhyperpolarization decay time-constants. In selected cases, the entire afterhyperpolarization trajectory was fitted with a sum of two exponentials to assess more precisely changes in afterhyperpolarization trajectory. Small catheters were inserted into side-branches of the sural artery and the accompanying vein to apply substances like bradykinin, serotonin and KCl to the calf muscles. Concentrations were in the range of those used by other workers. Intra-arterial injection of bradykinin and serotonin usually decreased blood pressure, which may at times have affected mean motoneuron membrane potentials. Afterhyperpolarization amplitude usually changed with membrane potential in a way expected from ensuing changes in driving potential. Whenever excitation of group III–IV muscle afferents caused moderate to strong increases in motoneuron synaptic noise, afterhyperpolarization amplitudes were reduced, usually in parallel to decreases in input resistance. Afterhyperpolarization half-widths were mostly unaffected, but occasionally decreased. There was a significant trend for afterhyperpolarization decay time-constants to increase during increased synaptic noise, this increase being inversely correlated with the reduction in afterhyperpolarization amplitude. The reduction in input resistance was associated with a decrease in the membrane time-constant, which could therefore not account for the prolongation of the afterhyperpolarization decay time-constant. The afterhyperpolarization area decreased, indicating that the reduction of afterhyperpolarization amplitude outweighed the prolongation of afterhyperpolarization decay time-constant.During a prolonged fatiguing muscle contraction group III–IV afferents become increasingly excited, produce augmenting synaptic inputs in motoneurons, and will change afterhyperpolarization properties. On average, these changes per se tend to diminish the effect of afterhyperpolarization on motoneuron discharge.

Changes in motor cortical excitability during human muscle fatigue.

1. The excitability of the motor cortex was investigated during fatiguing con of the elbow flexors in human subjects. During sustained contractions at 30 and 1 voluntary force (MVC), the short-latency electromyographic responses (EMG) evoke brachii and brachioradialis by transcranial magnetic stimulation increased in si EMG in the elbow flexors following the evoked muscle potential (silent period), duration during a sustained MVC but not during 30% MVCs nor during a sustained M muscle (adductor pollicis). 2. When the blood supply to brachioradialis was blocked with sphygmomanometer cuff sustained MVC, the changes in EMG responses to transcranial stimulation rapidly control values, This suggests that changes in these responses during fatigue wer small-diameter muscle afferents. 3. Tendon vibration during sustained MVCs indicated that the changes in the resp cortial stimulation were not mediated by reduced muscle spindle inputs. 4. Muscle action potentials evoked in brachioradialis by electrical stimulation cervicomedullary junction did not increase in size during sustained MVCs. Thus, cortically evoked responses during sustained MVCs reflects a change in cortical Although the silent period following cervicomedullary stimulation lengthened, it substantially shorter than the cortically evoked silent period. 5. The altered EMG responses to transcranial stimulation during fatigue suggest exitation and increased inhibition in the motor cortex. As these changes were un manipulation of afferent input they presumably result from intrinsic cortical pr altered voluntary drive to the motor cortex.

Changes in fusimotor discharge rate provoked by isotonic fatiguing muscle contractions in decerebrate cats

Changes in discharge rate of 26 fusimotor neurones to medial gastrocnemius muscle were studied during isotonic fatiguing contractions of lateral gastrocnemius and soleus muscles in decerebrate cats. Muscle contractions were elicited by either continuous or repetitive electrical stimulation of the muscle nerves. The muscles were considered to be fatigued when, against a load equal to one third of the tension developed at the onset of an isometric contraction, i.e. to the tension indicating isometrically-induced fatigue, they returned to the length at which the isometric contraction was elicited. At the onset of muscle contraction an increase in discharge rate, lasting for 5–220 s, occurred in all except one of the neurones. In 73% of the units a late increase developed in addition in parallel with muscle fatigue outlasting the contraction for 5–180 s. All but one of the remaining neurones exhibited a short lasting burst of spike discharges coincident with the end of contraction. Enhancement of the late increase by muscle ischaemia indicates contribution of chemosensitive small-diameter muscle afferents, while the short lasting burst is supposed to be elicited rather by the mechanosensitive units sensitized by metabolic products liberated during contraction and/or fatigue. Differences of the fusimotor reflex responses to isotonic vs. isometric contraction and/or fatigue and their possible functional role are discussed.

The sensation of effort co-varies with reflex effects on the motoneurone pool: Evidence and implications

Much evidence suggests that signals related to the motor command or effort contribute to sensations of force and of lifted weight. Consistent with this view, evidence is reviewed that reflex effects on alpha motoneurone pools lead to corresponding changes in perceived motor command or effort. For example, spinal reflex inhibition of the alpha motoneurone pool of first dorsal interosseous muscle produces an increase in perceived heaviness of weights lifted by that muscle. Reflex changes produced by small-diameter muscle afferents during muscle fatigue may also inhibit motoneurone pool and contribute to the increased command or effort required in fatiguing work. These findings have a number of implications for the assessment of perceived motor commands both under control circumstances and in the workplace. One corollary is that estimates of subjective effort for a particular repetitive task cannot be made independently of the reflexes associated with it.

Reflex effects on γ fusimotor neurones of chemically induced discharges in small-diameter muscle afferents in decerebrate cats

The effects on fusimotor discharge rate of algesic agents (bradykinin, potassium chloride, histamine, 5-hydroxytryptamine) and lactic acid, applied by close arterial injection into triceps surae muscles, were investigated in decerebrate cats. Fusimotor discharge was recorded from filaments dissected free from otherwise intact nerves to the triceps muscles. The substances applied induced an increase in discharge rate of spontaneously active γ fusimotor neurones as well as a recruitment of previously silent ones. Skeletomotor discharges and/or muscle tension changes occurred only occasionally. The increase in fusimotor discharge rate was not always completely abolished by severing the nerves to triceps. What remained was a short-lasting burst at the very onset of blood-pressure fall. It was concluded that the increase in fusimotor discharge rate was mainly, but not solely, elicited reflexly by discharges from Group III and/or IV muscle afferents sensitive to algesic agents. An elevated fusimotor activity might be expected to accompany muscle inflammation and/or trauma when these agents are liberated in muscle tissue. The increase in fusimotor discharge rate elicited by lactic acid injections indicates that the fusimotor system might also be involved in neural processes of muscular fatigue.

Positive dorsal root potentials produced by stimulation of small diameter muscle afferents

Positive dorsal root potentials produced by stimulation of small diameter muscle afferents