Magda Passatore

Influence of sympathetic nervous system on sensorimotor function: whiplash associated disorders (WAD) as a model.

There is increasing interest about the possible involvement of the sympathetic nervous system (SNS) in initiation and maintenance of chronic muscle pain syndromes of different aetiology. Epidemiological data show that stresses of different nature, e.g. work-related, psychosocial, etc., typically characterised by SNS activation, may be a co-factor in the development of the pain syndrome and/or negatively affect its time course. In spite of their clear traumatic origin, whiplash associated disorders (WAD) appear to share many common features with other chronic pain syndromes affecting the musculo-skeletal system. These features do not only include symptoms, like type of pain or sensory and motor dysfunctions, but possibly also some of the pathophysiological mechanisms that may concur to establish the chronic pain syndrome. This review focuses on WAD, particular emphasis being devoted to sensorimotor symptoms, and on the actions exerted by the sympathetic system at muscle level. Besides its well-known action on muscle blood flow, the SNS is able to affect the contractility of muscle fibres, to modulate the proprioceptive information arising from the muscle spindle receptors and, under certain conditions, to modulate nociceptive information. Furthermore, the activity of the SNS itself is in turn affected by muscle conditions, such as its current state of activity, fatigue and pain signals originating in the muscle. The possible involvement of the SNS in the development of WAD is discussed in light of the several positive feedback loops in which it is implicated.

Sympathetic modulation of muscle spindle afferent sensitivity to stretch in rabbit jaw closing muscles

Previous reports showed that sympathetic stimulation affects the activity of muscle spindle afferents (MSAs). The aim of the present work is to study the characteristics of sympathetic modulation of MSA response to stretch: (i) on the dynamic and static components of the stretch response, and (ii) on group Ia and II MSAs to evaluate potentially different effects. In anaesthetised rabbits, the peripheral stump of the cervical sympathetic nerve (CSN) was stimulated at 10 impulses s−1 for 45–90 s. The responses of single MSAs to trapezoidal displacement of the mandible were recorded from the mesencephalic trigeminal nucleus. The following characteristic parameters were determined from averaged trapezoidal responses: initial frequency (IF), peak frequency at the end of the ramp (PF), and static index (SI). From these, other parameters were derived: dynamic index (DI = PF ‐ SI), dynamic difference (DD = PF ‐ IF) and static difference (SD = SI ‐ IF). The effects of CSN stimulation were also evaluated during changes in the state of intrafusal muscle fibre contraction induced by succinylcholine and curare. In a population of 124 MSAs, 106 units (85.4 %) were affected by sympathetic stimulation. In general, while changes in resting discharge varied among different units (Ia vs. II) and experimental conditions (curarised vs. non‐curarised), ranging from enhancement to strong depression of firing, the amplitude of the response to muscle stretches consistently decreased. This was confirmed and detailed in a quantitative analysis performed on 49 muscle spindle afferents. In both the non‐curarised (23 units) and curarised (26 units) condition, stimulation of the CSN reduced the response amplitude in terms of DD and SD, but hardly affected DI. The effects were equally present in both Ia and II units; they were shown to be independent from gamma drive and intrafusal muscle tone and not secondary to muscle hypoxia. Sympathetic action on the resting discharge (IF) was less consistent. In the non‐curarised condition, IF decreased in most Ia units, while in II units decreases and increases occurred equally often. In the curarised condition, IF in group II units mostly increased. The results have important functional implications on the control of motor function in a state of ‘high’ sympathetic activity, like excessive stress, as well as in certain pathological conditions such as sympathetically maintained pain.

Sympathetically-induced development of tension in jaw muscles: the possible contraction of intrafusal muscle fibres.

In rabbits, cats and rats anaesthetized, curarized, with the skull fixed in a stereotaxic apparatus, the peripheral stump of the cervical sympathetic nerve (c.s.n.) was electrically stimulated at frequencies within the physiological range and the isometric tension was recorded at the lower jaw. In a group of experiments the afferent discharges from the jaw elevator muscle spindles was also recorded, in the mesencephalic nucleus of the fifth cranial nerve.Unilateral stimulation of the c.s.n. induced in jaw elevator muscles of rabbits an increase of tension of 5.5±0.5 g (latency: 0.5–2 s, time constant: 2.5–5 s) maintained with little or no decrement until the end of stimulation. This response proved not to be secondary to vasomotor changes since: i) approximately half of it was mediated by the fastest conducting component of the c.s.n. fibres, ii) it was not mimicked by a sudden reduction of blood supply to the muscles, iii) it was unaffected by 10 min bilateral occlusion of both the external and the internal carotid arteries. During c.s.n. stimulation the afferent discharge from spindles belonging to jaw elevator muscles exhibited an increase of firing (often preceded by a transient decrease) lasting throughout the stimulation. Also, the position sensitivity of all the spindle afferents tested was modified by the sympathetic stimulation.The results presented are interpreted to suggest that the sympathetic system may induce an intrafusal muscle fibre contraction in jaw elevator muscles. The possible functional implications are also discussed.

Effect of generalised sympathetic activation by cold pressor test on cerebral haemodynamics in healthy humans.

There is no general agreement regarding several aspects of the role of the sympathetic system on cerebral haemodynamics such as extent of effectiveness, operational range and site of action. This study was planned to identify the effect of a generalised sympathetic activation on the cerebral haemodynamics in healthy humans before it is masked by secondary corrections, metabolic or myogenic in nature. A total of 35 healthy volunteers aged 20-35 underwent a 5 min lasting cold pressor test (CPT) performed on their left hand. The cerebral blood flow (CBF) velocity in the middle cerebral arteries and arterial blood pressure were recorded with transcranial Doppler sonography and with a non-invasive finger-cuff method, respectively. The ratio of arterial blood pressure to mean blood velocity (ABP/Vm) and Pulsatility Index (PI) were calculated throughout each trial. CPT induced an increase in mean ABP (range 2-54 mmHg depending on the subject) and only a slight, though significant, increase in blood velocity in the middle cerebral artery (+2.4 and +4.4% on ipsi- and contralateral side, respectively). During CPT, the ratio ABP/Vm increased and PI decreased in all subjects on both sides. These changes began simultaneously with the increase in blood pressure. The increase in ABP/Vm ratio is attributed to an increase in the cerebrovascular resistance, while the concomitant reduction in PI is interpreted as due to the reduction in the compliance of the middle cerebral artery. The results suggest that generalised increases in the sympathetic discharge, causing increases in ABP, can prevent concomitant increases in CBF by acting on both small resistance and large compliant vessels. This effect is also present when a slight increase in blood pressure occurs, which suggests a moderate increase in the sympathetic discharge, i.e. when ABP remains far below the upper limit of CBF autoregulation.

Effect of sympathetic nervous system activation on the tonic vibration reflex in rabbit jaw closing muscles.

1. In precollicular decerebrate rabbits we investigated the effect of sympathetic stimulation, at frequencies within the physiological range, on the tonic vibration reflex (TVR) elicited in jaw closing muscles by small amplitude vibrations applied to the mandible (15‐50 microns, 150‐180 Hz). The EMG activity was recorded bilaterally from masseter muscle and the force developed by the reflex was measured through an isometric transducer connected with the mandibular symphysis. 2. Unilateral stimulation of the peripheral stump of the cervical sympathetic by the TVR, and a marked decrease or disappearance of the ipsilateral EMG activity. No significant changes were detected in the EMG contralateral to the stimulated nerve. Bilateral CSN stimulation reduced by 60‐90% the force reflexly produced by the jaw closing muscles and strongly decreased or suppressed EMG activity on both sides. This effect was often preceded by a transient TVR enhancement, very variable in amplitude and duration, which was concomitant with the modest increase in pulmonary ventilation induced by the sympathetic stimulation. 3. During bilateral CSN stimulation, an increase in the vibration amplitude by a factor of 1.5‐2.5 was sufficient to restore the TVR reduced by sympathetic stimulation. 4. The depressant action exerted by sympathetic activation on the TVR is mediated by alpha‐adrenergic receptors, since it was almost completely abolished by the I.V. administration of either phentolamine or prazosin, this last drug being a selective antagonist of alpha 1‐adrenoceptors. The sympathetically induced decrease in the TVR was not mimicked by manoeuvres producing a large and sudden reduction or abolition of the blood flow to jaw muscles, such as unilateral or bilateral occlusion of the common carotid artery. 5. The effect of sympathetic stimulation was not significantly modified after denervation of the inferior dental arch and/or anaesthesia of the temporomandibular joint, i.e. after having reduced the afferent input from those receptors, potentially affected by CSN stimulation, which can elicit either a jaw opening reflex or a decrease in the activity of the jaw elevator muscle motoneurons. 6. These data suggest that, when the sympathetic nervous system is activated under physiological conditions, there is a marked depression of the stretch reflex which is independent of vasomotor changes and is probably due to a decrease in sensitivity of muscle spindle afferents.

A comparative study of changes operated by sympathetic nervous system activation on spindle afferent discharge and on tonic vibration reflex in rabbit jaw muscles

The effect of sympathetic activation on the spindle afferent response to vibratory stimuli eliciting the tonic vibration reflex in jaw closing muscles was studied in precollicularly decerebrate rabbits. Stimulation of the cervical sympathetic trunk, at frequencies within the physiologic range, consistently induced a decrease in spindle response to muscle vibration, which was often preceded by a transient enhancement. Spindle discharge was usually correlated with the EMG activity in the masseter muscle and the tension reflexly developed by jaw muscles. The changes in spindle response to vibration were superimposed on variations of the basal discharge which exhibited different patterns in the studied units, increases in the firing rate being more frequently observed. These effects were mimicked by close arterial injection of the selective alpha 1-adrenoceptor agonist phenylephrine. Data presented here suggest that sympathetically-induced modifications of the tonic vibration reflex are due to changes exerted on muscle spindle afferent information.

A dual effect of sympathetic nerve stimulation on jaw muscle spindles

In anaesthetized and paralyzed rabbits, electrical stimulation of the cervical sympathetic nerve at physiological frequencies induces in jaw muscle spindle afferents a short-latency decrease or suppression of discharge. This effect is very stereotyped in pattern and is attributed to direct sympathetic innervation of spindles. It is mediated by preganglionic S1-S2 sympathetic fiber groups. A longer-latency facilitatory effect follows, probably vasomotor in origin and mediated by S3-S4 groups. Both responses are eliminated by administration of alpha-adrenergic blocking agents. The latencies, patterns, thresholds, durations and reproducibility of these responses have been studied and the mechanisms possibly involved are discussed.

Cervical sympathetic nerve stimulation can induce an intrafusal muscle fibre contraction in the rabbit

Recent data by Ballard (1978) and by Barker and Saito (1981) about the innervation of muscle spindles by sympathetic nerve fibres (cf. Santini and Ibata, 1971) pose most crucially the problem of the effect and mechanisms of the sympathetic action on muscle spindle behaviour (Hunt et al., 1982; Passatore and Filippi, 1982; further ref. in Staderini and Ambrogi Lorenzini, 1969). In particular, sympathetic terminals were found to be located adjacent to the sensory endings and also in neuroeffective association with both bag and chain intrafusal fibres (Barker and Saito). Consequently the following questions can be posed: 1) is the sympathetic system capable of affecting the activity of the intrafusal muscle fibres? 2) if so, is the effect on spindle output compatible with, and thus presumably secondary to, the action exerted upon intrafusal muscle fibres? 3) what kind of transmitter and receptor are involved? The main results of a series of investigations addressed to answer these questions will be summarized below.

Postsynaptic α1- and α2- adrenoceptors mediating the action of the sympathetic system on muscle spindles, in the rabbit

In anaesthetized and curarized rabbits, the cervical sympathetic nerve (CSN) stimulation induces in jaw elevator muscles a tension response which can be mimicked by the intravenous injection of adrenaline, noradrenaline and phenylephrine. This response, previously described and attributed to the contraction of muscle spindle fibres, is entirely mediated by alpha-adrenoceptors. The administration of phenoxybenzamine (2.5-3.5 mg/kg) markedly inhibits the responses to the sympathetic stimulation and to the injection of adrenergic agonists. Rauwolscine (1 mg/kg) reduces the development of tension induced by both CSN stimulation and noradrenaline injection without significantly affecting the response to phenylephrine. These data suggest the presence of postsynaptic alpha 1- and alpha 2-adrenoceptors in intrafusal muscle fibres. Moreover, the possibility that alpha 2-adrenoceptors may also have an extrasynaptic location is entertained.

Efferent fibers in the cervical sympathetic nerve influenced by light.

Abstract Spontaneous electrical activity of single-fiber preparations isolated from the central stump of the cervical sympathetic nerve has been recorded, the discharge frequency of which was greatly modified by changing the intensity of light reaching the cats eyes. These fibers showed the highest firing frequency during darkness and the lowest in light (sometimes complete inhibition) and a gradation of the response intermediate illumination values. Light stimulations ranged from 0 to 1500 lux. The close correlation between the discharge frequency of these fibers and at the light stimulus intensity suggested that the fibers originated from the Budges ciliospinal center and were directed to the dilatator pupillae muscle. Analysis of these units, besides confirming the intervention of the sympathetic system in the development of the pupillary light reflex, corroborates the hypothesis of a larger participation of sympathetic nerves in the reflex response to darkness than in the response to light. The role of sympathetic nerves in the direct light reflex appeared larger than in the consensual one. The conduction velocities of the light-responsive components were in a range of 6 to 25 m/sec (usually between 10 and 15 m/sec) as determined by (i) the action potential evoked in the single-fiber preparations, (ii) the functional analysis of compound action potentials, and (iii) the use of the antidromic occlusion method on the whole cervical sympathetic nerve. Very small doses of Nembutal (5 mg/kg) greatly decreased the resting discharge of the sympathetic light-responsive fibers and completely abolished the response to darkness.