Complex impairment of IA muscle proprioceptors following traumatic or neurotoxic injury

Abstract

The health of primary sensory afferents supplying muscle has to be a first consideration in assessing deficits in proprioception and related motor functions. Here we discuss the role of a particular proprioceptor, the IA muscle spindle proprioceptor in causing movement disorders in response to either regeneration of a sectioned peripheral nerve or damage from neurotoxic chemotherapy. For each condition, there is a single preferred and widely repeated explanation for disability of movements associated with proprioceptive function. We present a mix of published and preliminary findings from our laboratory, largely from in vivo electrophysiological study of treated rats to demonstrate newly discovered IA afferent defects that seem likely to make important contributions to movement disorders. First, we argue that reconnection of regenerated IA afferents with inappropriate targets, although often repeated as the reason for lost stretch-reflex contraction, is not a complete explanation. We present evidence that despite successful recovery of stretch-evoked sensory signaling, peripherally regenerated IA afferents retract synapses made with motoneurons in the spinal cord. Second, we point to evidence that movement disability suffered by human subjects months after discontinuation of oxaliplatin (OX) chemotherapy for some is not accompanied by peripheral neuropathy, which is the acknowledged primary cause of disability. Our studies of OX-treated rats suggest a novel additional explanation in showing the loss of sustained repetitive firing of IA afferents during static muscle stretch. Newly extended investigation reproduces this effect in normal rats with drugs that block Na(+) channels apparently involved in encoding static IA afferent firing. Overall, these findings highlight multiplicity in IA afferent deficits that must be taken into account in understanding proprioceptive disability, and that present new avenues and possible advantages for developing effective treatment. Extending the study of IA afferent deficits yielded the additional benefit of elucidating normal processes in IA afferent mechanosensory function.

Keywords: chemotherapy; mechanotransduction; muscle spindle; sensory encoding; synaptic transmission.

Fig 1

Diagram and data representing selected functions and structures of IA afferent in adult rat. (a and b) This IA afferent is divided, respectively, into peripheral and central portions relative to micropipette recording site in dorsal root near its spinal cord entry zone. (a) IA afferent firing that is produced in response to ramp-hold muscle stretch and that represents the culmination of mechanical transduction followed by action potential encoding and orthodromic conduction. Top trace shows action potentials vertical lines with instantaneous firing rates plotted by superimposed black dots; the bottom trace is muscle length during ramp-hold stretch (ramp 20 mm/s to 3 mm and hold for 1 s). (b) Central IA afferent structures, including central axon collaterals (intra-axonal neurobiotin labeled green) that project in the spinal cord to laminae V/VI, VII, IX where they form synapses (VGluT1) with different populations of neurons (labeled with NeuN). Regions (a and b) are divided to assist discussion of where and how IA afferent demonstrate impairment after peripheral nerve injury and chronic chemotherapy.

Fig 2

Partial disconnection of regenerated IA afferents in the homonymous motor pool. Intracellular records of motoneuron membrane potential during quick stretch (400 m/s; 1 mm) of the homonymous muscle. Representative data collected in terminal study of an anesthetized rat with the muscle re-innervated by its original nerve that was cut and surgically repaired 1 year earlier. EPSPs normally present in all motoneurons were smaller than normal and absent in 2/5 motoneurons.

Fig 3

Chronic oxaliplatin (OX) treatment abbreviates static phase firing without neuropathy. Electromechanical data arranged vertically for one IA afferent sampled in vivo from a control rat and for one IA afferent taken from a rat 5 weeks after injections of OX (1/week for 4 weeks; cumulative dose 70 mg/kg). Firing of the IA afferents (top traces) is shown in response to three different forms of muscle stretch (bottom traces): (a) ramp-hold; (b) triangular; (c) vibration. Action potentials are shown as vertical lines firing at instantaneous firing rates indicated by superimposed black dots. During the static (hold) phase of muscle stretch (a), IA afferents in normal rats typically sustained firing, but those in OX-treated rats rapidly adapted and ceased firing. By contrast, during dynamic (changing length) phases of muscle stretch (a–c), IA afferents were similarly responsive in control and OX-treated rats. Also, IA afferents in both groups displayed high-frequency initial burst firing at the onset of ramp (a) and triangular (b) stretches, and fired with 1 : 1 entrainment to muscle vibration at high frequency (100 Hz) and low amplitude (0.08 mm) (c). (d) Data demonstrate the absence of neuropathy: top traces show that electrically evoked sensory nerve action potentials (SNAPs) recorded from the tail before and after treatment in the OX rat were indistinguishable; the bottom image represents finding that muscle spindles in OX rats were consistently innervated by normal-looking annulospiral endings (stained with PGP9.5).

Fig 4

IA afferent static phase firing restored by muscle vibration. IA afferent repetitive firing was sustained throughout the static (hold) phase of muscle stretch in normal rat (a), but abbreviated in a rat weeks after oxaliplatin (b). Action potentials shown as vertical lines with instantaneous firing rate are indicated by superimposed black dots; muscle length trace for ramp-hold-release stretch is shown in the bottom trace in (b). (c) Same IA afferent as in (b); 100 Hz muscle vibration superimposed on the hold phase of stretch-elicited sustained firing at 100 Hz.

Fig 5

Antiepileptic drugs abbreviate static phase firing. Similar to oxaliplatin (Fig3), afferent responses following acute injection of riluzole and phenytoin fail to maintain repetitive firing during the static phase of muscle stretch (a). Otherwise, IA afferents exhibited normal firing during the dynamic phase of ramp (a) and triangular (b) stretch. Also normal was initial burst firing at onset of ramp (a) and triangular (b) stretch and 1 : 1 firing entrainment to 100 Hz muscle vibration (c).

Fig 6

Mechanosensory model of IA proprioceptor adapted from Bewick & Banks (2014). Neural mechanisms in mechano-transduction and sensory encoding for IA afferent fitted to muscle spindle structure including intrafusal muscle fiber (pink) wrapped by annulospiral ending (green) that extends unmyelinated followed by myelinated axon. Mechano-transduction involves mechano-sensitive sodium channels (MSSC) and metabotropic glutamate receptors (M-GLUR) that act through a phospholipase D (PLD) mechanism to modulate glutamate release from synaptic like vesicles (SLV). Sensory-encoding mechanisms include BK and SK potassium channels activated by Ca²⁺; P/Q- and T-type Ca²⁺ channels; and voltage-gated Na⁺ channels (NaV) including Na⁺ persistent inward current (PIC), which we add to the model based on preliminary findings presented in this report.