Spinal Cord, Dopamine, Opiates, and Restless Legs Syndrome

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Chapter 14 Spinal Cord, Dopamine, Opiates, and Restless Legs Syndrome

Restless legs syndrome (RLS) leads to abnormal limb sensations and periodic limb movements (PLMS). Due to the excellent responses to treatment with dopaminergic and opioidergic agents, an involvement of both dopamine and opioid receptors is highly likely. The spinal cord plays an essential role as the final common pathway in the generation of PLMS. Here we review anatomical and physiologic evidence contributing to PLM generation in the spinal cord and the involvement of the opioid and dopamine system. The bulk of early studies, mainly by the Lundberg group (for refs. see Schomburg1), investigated dopaminergic influence on the spinal cord in greater detail decades ago, with the interest in this research declining somewhat at the end of the last century. Modern techniques have led to a renewed interest in this subject. Two studies involving dopamine D3 receptor knockout mice (D3KO)2,3 sought to explain how impaired D3 activity could contribute to this sleep disorder. The aim of this review is to summarize neurophysiologic data regarding the role of spinal dopamine and opioids against the background of the symptomatology of RLS.

Spinal Structures

The spinal cord provides the primary input stage for sensory afferents and the final output stage for PLMS. At this stage it is possible, in principle, to reduce sensory complaints such as those in RLS by active movements. This is a necessary condition to explain the cessation of symptoms (i.e., that they cease with movement) and, vice versa, the dominance of symptoms in periods of rest.

Incoming sensory afferents and the motoneuron system are interconnected by the spinal interneuronal system, which is responsible for the generation of simple reflex movements as well as complex motor patterns ranging from tonic to phasic movements and from a co-contraction of antagonistic muscles to the coordinated patterning of locomotor activity (for a review, see Schomburg1). The activity of these interneurons, like the activity of all spinal interneurons and the activity of spinal nociceptive neurons in the dorsal horn, is modulated by descending pathways with both inhibitory and excitatory components.4 During normal voluntary movements, reafferent sensory input continuously converges on the spinal circuits that are activated by these descending motor commands; this locus may serve as the anatomical correlate for the earliest suppression of reafferent sensory input5 (Fig. 14-1). Also, presynaptic inhibition of spinal afferents produced by descending commands may effectively reduce synaptic transmission at the initial synapse.6

All these interactions have to be generated quickly, and they depend on immediate motor requirements, that is, on the phase and condition (including possible external disturbances) of a movement and the position of the trunk and limbs. This so-called state-dependent modulation of neurotransmission is an important tool to adapt the spinal interneuronal systems to the requirements of performing movement in response to the existing conditions. Under conditions of disturbed descending control, such as in spasticity after a stroke, identical—or subthreshold peripheral—input becomes itself capable of inducing muscle contractions. In contrast, such as under normal conditions, reflexogenic activation is largely downregulated to prevent inappropriate reflexogenic movements from the continuously activated peripheral receptors. In this downregulated situation, the activity of individual receptor systems is generally unable to evoke reflexogenic movement. If at all, a distinct multisensorial convergence of different receptor systems is required to elicit a movement.7 During sleep, in particular during rapid eye movement (REM) sleep, state-dependent modulation is further downregulated to preclude any unwanted movements during dreaming.

Of all possible spinal structures involved, the spinal flexor reflex afferent (FRA) system and a disturbance of its supraspinal control seem to play the crucial role in the generation of PLMS. The FRA system encompasses the following features:

Dopamine in the Spinal Cord

The spinal cord is virtually devoid of dopaminergic cell bodies. The major source of the spinal dopaminergic projection into the dorsal horns and intermediolateral tracts is area A11.10 The behavioral effects of a first animal model on A11 lesion have not been convincing, most likely because the A11 neurons are spread over a comparatively large area and an isolated lesion appears to be very difficult to achieve.11 Nevertheless, an additional intriguing argument in favor of an A11 lesion as a source for RLS is its anatomical location close to the suprachiasmatic nucleus, which largely controls circadian rhythms and which could explain its predominance at night. The RLS-A11 hypothesis would require a rather selective neurodegeneration of A11 with increasing age and a concomitant reduction in the descending modulation of the dorsal horn or other related structures in the spinal cord.12

Because no RLS animal model is readily available, most data have been obtained in the course of pain studies. Dopamine may ameliorate chronic pain. In rats, intrathecal administration of the dopamine agonist apomorphine produced an analgesia that was antagonized by the prior intrathecal administration of a dopamine receptor antagonist but not by the administration of α2, serotonin, or opiate antagonists.13 Further data beyond the scope of this review confirm the antinociceptive effects of dopamine D2 receptors (for the most detailed review, see Millan10), probably via a direct inhibitory action at either the nociceptive-responsive primary afferent fiber terminals or projection neurons. An inhibitory influence of presynaptic dopamine D2 receptors on Ca2+ currents provides a potential mechanism for a presynaptic reduction of release from primary afferent fiber terminals in the dorsal horn.14 Also, L-DOPA inhibits the early flexor reflex, regardless of whether it is evoked by nociceptive or nonnociceptive afferents.15

State dependence usually depends on dopaminergic stimulation, but there are contrary cases. For example, in acute phase–dependent (during locomotion)1619 or limb position–dependent20 reflex transmission, dopamine is not primarily involved.

The influence of dopamine on the spinal cord is best investigated in the spinalized cat. The findings in spinalized cats are transferable to the intact animal in principle, but in the intact cat, they are under strong supraspinal control. Thus, in the spinalized animal, the functional state of a spinal cord free of predominantly inhibitory supraspinal control can be studied not only in isolation but also in a disinhibited, and thus enhanced, functional state.

Within a medium range of spinal dopamine concentration in the spinalized and paralyzed cat, locomotor activity (“fictive locomotion”; i.e., neuronal rhythmic activity resembling locomotor pattern without real movements in paralyzed animals) can be induced. During fictive locomotion, motoneurons can develop a bistable firing characteristic, caused by their membrane potentials switching between two levels. This state is induced by L-DOPA. Depolarization during active phases was characterized by stable fixed levels and could partly be initiated by excitatory inputs and terminated by inhibitory inputs.21 Similar bistable characteristics have been postulated for RLS.22 It appears, however, unlikely that an L-DOPA–induced bistability is related to the PLM-associated firing pattern in RLS, because L-DOPA suppresses PLM instead of inducing such bursting. However, this is not a direct motoneuronal effect but has to be regarded as a consequence of the L

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