НЕЙРОХИМИЯ, 2007, том 24, № 4, с. 297-303
== ТЕОРЕТИЧЕСКИЕ РАБОТЫ =
УДК 612.822.3
A ROLE OF OPIOID RECEPTOR AGONISTS AND ANTAGONISTS IN THE TREATMENT OF PARKINSONGffASE
© 2007 г. I. G. Silkis
Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences
A possible mechanism underlying the role of opioids in the treatment of Parkinson's disease and L-dopa-in-duced dyskinesias is suggested. This role is based on the reorganization of neuronal firing in the motor cortico - basal ganglia - thalamocortical loop in consequence of opioid-mediated LTD induction on the spiny cells of the input basal ganglia nucleus, striatum. Analysis of existing data allowed us assume that striatonigral cells in the striosomes and matrix that release dynorphin mainly express ц and к opioid receptors, respectively, whereas striatopallidal cells that release enkephalin express 5 opioid receptors. Proposed mechanism implies that in addition to agonists of dopamine receptors and antagonists of muscarinic receptors, ц and 5 receptor agonists and/or к receptor antagonists might alleviate parkinsonian symptoms and recover locomotor activity. Recurrent collaterals of striatal spiny cells innervating their dendrites and bodies as well as those of striatal cholinergic interneurons form negative feedback loops that allow opioid peptides and substance P regulate and stabilize striatal output pathways. Therefore, in the absence of activation of D2 and D1 receptors on striatal spiny cells, increased enkephalin concentration and decreased dynorphin and substance P level promote suppression of acetylcholine release (due to modulation of cholinergic interneuron firing through 5 opioid and NK receptors), thus reducing the impact of dopamine deficit on the basal ganglia functioning. Opposite changes in opioid concentrations due to L-dopa treatment and reorganization of activity in the same neuronal loops might reduce dysk-inesias.
Key words: opioids, Parkinson's disease, basal ganglia, synaptic plasticity, dyskinesia.
Abbreviations: BG, basal ganglia; LIDs, L-dopa-induced dyskinesias; LTD, long-term depression; LTP, long-term potentiation; SNr, substantia nigra pars reticulata; GPe and GPi, external and internal parts of the globus pallidus.
INTRODUCTION
Current treatment for Parkinson's disease is based mainly on dopamine replacement therapy. However, the long-term treatment with L-dopa is often associated with the appearance of motor complications, including on-off fluctuations and involuntary movements termed L-dopa-induced dyskinesias (LIDs) [1]. These side effects led to widespread interest in nondopaminergic therapies. Dopamine depletion and disturbances in functioning of the motor part of the basal ganglia (BG) are the major source of Parkinson's disease, but changes in concentration of endogenous opioids, enkephalin and dynorphin, in the BG also plays an essential role in behavioral activity [2]. In particular, action of opioids in the input BG nucleus, striatum, modulates locomotions [3]. Recent findings pointed out that the activation of 5 opioid receptors can represent a novel therapeutic approach to the treatment of Parkinson's disease [4-6]. Mechanisms of action of agonists and antagonists of
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different types of opioid receptors in the improvement of Parkinson's disease are still under debate.
Earlier we proposed a possible mechanism of reorganization of neuronal firing in the motor cortico - BG -thalamocortical loop caused by opioid-mediated modulation of signal transduction through the striatum [7]. (It will be briefly described below.) It follows from this mechanism that the activation of 5 and | opioid receptors and/or inactivation of k opioid receptors on striatal spiny cells might alleviate parkinsonian symptoms and recover locomotor activity. Some of known experimental data support this mechanism. Actually, stimulation of 5 opioid receptors facilitated dopamine-dependent behavioral activity of rats [6, 8-11]. Agonists of 5 opi-oid receptors facilitated dopamine D1 and D2 receptor-dependent contralateral turning in dopamine-lesioned rats [12]. In opposite, 5 and | receptor antagonist naloxone reinstated akinesia [10]. Agonist of 5 receptors prevented akinesia caused by using D2 receptor antagonists for a treatment of other diseases [10]. In opposite, injection of k receptor agonists elicited hypoac-tivity [13], depressed the locomotor activity of adults rats [14], prevented locomotions induced by D1 and D2 receptor activation [15], and significantly decreased the amphetamine-evoked increase in behavior [16]. In accordance with our model, agonists of k receptors lead to effects opposite to those of 5 and | receptor agonists. It was found that the systemic administration of 5 and | receptor agonists enhances convulsions, whereas k
receptor stimulation prevents this effect [17]. Agonist of | receptors, morphine, facilitated rotation of rats with artificial lesion of dopamine input [18], whereas administration of k receptor agonist or 5 receptor antagonist suppressed locomotor activity caused by | receptor agonist [19-22].
Remarkably, in animal models of Parkinson's disease, repeated L-dopa administration is associated not only with LIDs but also with an enhancement of opioid transmission in the BG [23, 24]. Expression of striatal opioid precursor pre-proenkephalin B increased by 172% in dyskinetic Parkinson's disease patients [25]. Some of experimental data denote that changes in opi-oid transmission could be involved in the genesis of LIDs, but on the other hand, | and 5 receptor antagonist naloxone did not reduce LID [23]. It was proposed that changes in opioid transmission in the BG in response to dopamine denervation and repeated L-dopa therapy might be the part of compensatory mechanisms to prevent motor complications [24]. Initially, this compensation might be sufficient to attenuate the parkinsonian syndrome, but with the repeated L-dopa exposure, it eventually fails [24]. Mechanisms underlying changes in opioid concentrations and compensatory effects are still discussed. The goal of this study was to analyse mechanisms underlying the role of opioids in the treatments of movement disorders and suppression of LIDs.
DISTRIBUTION OF DIVERSE TYPES OF OPIOID RECEPTORS IN THE STRIATUM
In the neostriatum, wherein opioid releasing spiny cells are placed, the density of all types of opioid receptors is much higher than in target structures of these cells, substantia nigra pars reticulata (SNr), external and internal parts of the globus pallidus (GPe and GPi) [26]. The properties and connections of striatal neurons are well known [27, 28]. These connections are schematically represented in figure, a. GABAergic striato-pallidal spiny neurons projecting to the GPe synthesize the opioid peptide enkephalin and give rise to the "indirect" inhibitory pathway through the BG, whereas GABAergic striatonigral spiny neurons innervating the SNr, GPi or the entopeduncular nucleus synthesize dynorphin and substance P and give rise to the "direct" disinhibitory pathway through the BG [29]. Striatoni-gral cells predominantly express dopamine D1 and muscarinic M4 receptors, whereas striatopallidal cells predominantly express D2 and M1 receptors. Very high coexpression of D1 receptors and substance P (9199%) as well as D2 receptors and preproenkephalin A (96-99%) in spiny neurons throughout the caudate-putamen and nucleus accumbens have been demonstrated [30]. The majority of striatonigral cells expressing substance P and | receptors are located in strio-somes, 5 and k receptors are diffusely located in the matrix of striatum [26, 31, 32]. Opioid k receptors were found postsynaptically on dendritic spines and presyn-aptically on glutamatergic and dopaminergic axon ter-
minals [33]. Comparison of existing data allowed us conclude that striatonigral cells in the matrix and strio-somes express k and | receptors receptors, respectively (Table) [7].
Axon collaterals of striatopallidal and striatonigral cells affect cholinergic interneurons through the 5 opi-oid receptors and substance P sensitive NK receptors, respectively [32]. In vivo k receptors are activated predominantly by dynorphin A, 5 receptors - by enkepha-lin and beta-endorphin, | receptors are better affected by beta-endorphin, but to a lesser degree by dynorphin A and enkephalin [34]. Above mentioned data and character of 5 and k receptor localization allowed us assume that opioid receptors located on each type of striatal spiny cells could be better affected by opioid peptides, released from recurrent axon collaterals of the same cell type (figure, a) [7]. The existence of extensive contacts of axons collaterals of spiny neurons with their own dendritic arbor [28, 32] provides the morphological base for such assumption.
MODULATORY ACTION OF OPIOIDS
ON EXCITATORY SYNAPTIC INPUTS TO STRIATAL SPINY CELLS AND BEHAVIORAL EFFECTS
It is commonly assumed that parkinsonian akinesia and rigidity is the consequence of the high activity of GABAergic neurons of the output BG nuclei and subsequent inhibition of thalamic and neocortical cell discharges [35]. Since "direct" and "indirect" pathways through the BG disinhibit and inhibit thalamic cells, respectively (figure, a), synergistic increase in motor activity could be achieved by simultaneous induction of LTD in cortical inputs to striatopallidal cells and LTP in cortical inputs to striatonigral cells of matrix [36]. The sign of modification, LTP or LTD is determined by unitary modification and modulation rules that we proposed earlier (Table) [7]. These rules and knowledge of types of receptors localized on striatal cells allowed us explain why dopamine receptor agonists and acetylcholine muscarinic or adenosine receptor antagonists could be used for the facilitation of motor activity [36].
Action of opioids on p
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