This section is to assist people understand the summary of my hypotheses:


if they are not familiar with some basic neuroscience terms and concepts.

A dopamine agonist (AKA "dopamine receptor agonist") is a molecule which occupies and activates dopamine receptors - the molecules on the input terminals of neurons which are normally, in the body, occupied and activated by the neurotransmitter dopamine.  So dopamine itself is a dopamine agonist - an endogenous one since it is produced by the body. 

Dopamine agonist drugs such as Pramipexole are used to treat RLS/PLMD.  They are ingested, pass into the bloodstream, and then into the cerebro-spinal fluid, where they are accepted by dopamine receptor molecules, and activate those molecules just as if they were activated by a real dopamine molecule.

Opioid agonists include the endogenous (produced in the body) endorphins and enkephalins.  Exogenous (from outside the body) opioid agonists include opium, morphine, methadone, codeine and oxycodone.

Agonist molecules with a high affinity for the receptor will tend to stay in the receptor's slot for longer, competing successfully with agonists and antagonists of  lower affinity.

A dopamine antagonist (AKA "dopamine receptor antagonist") is a molecule which is accepted by dopamine receptors, but does not activate the receptor.  As long as it occupies the receptor, the receptor cannot be activated by an agonist molecule.

Promethazine (Phenergan) is, amongst other properties, a dopamine receptor antagonist. 

Naltrexone and Naloxone are opioid antagonists (AKA "opioid receptor antagonists) - they occupy opioid receptors without activating them, and thereby prevent them being occupied and activated by opioid receptor agonists.  A Naloxone injection can save the life of a person suffering from opioid overdose, such as from morphine or heroin.  4-caffeoyl-1,5-quinide is an opioid receptor antagonist present in large quantities in coffee, including decaf. ../../coffee/  It has a relatively high affinity for opioid receptors - comparable with that of Nalaxone.  

I am not aware of any endogenous dopamine or opioid receptor antagonists.

Antagonist molecules with a high affinity for the receptor will tend to stay in the receptor's slot for longer, competing successfully with agonists and antagonists of  lower affinity.

Dopamine is one of the most important neurotransmitters.  It is synthesized from the amino acid tyrosine by the actions of the enzyme tyrosine hydroxylase, which requires an atom of iron and energy input via other co-factor molecules.  The result is L-DOPA, which is quickly and easily converted into dopamine by a second enzyme.

Dopamine has many uses in the central nervous system, most of them in the brain.  Shortage of dopamine somewhere in the nervous system is well recognised as being central to RLS/PLMD pathology, since introducing low levels of dopamine agonists reduces or eliminates symptoms.  Dopamine is used in the brain for motor control, in a system which is disrupted by Parkinson's Disease.  It is also used in reward pathways in the brain.  These pathways are disrupted by cocaine, which blocks the recycling of dopamine from the synapse, leaving more of it in the synapse for longer, which activates the dopamine receptors of the input terminals of the receiving neuron for longer.


"Dopaminergic" describes any molecule, cell etc. which in some way is related to the neurotransmitter dopamine.  A dopaminergic neuron is one which produces the neurotransmitter dopamine at its output terminal. 

Most neurons release a single type of neurotransmitter at their output terminals when they depolarize (fire).  A dopaminergic neuron may have receptors for multiple neurotransmitters on its input terminals.  It may also have dopamine receptors on its input terminals and output terminals, often for negative feedback to self-regulate its activity.

Dopamine receptor and receptors in general
Dopamine receptor molecules are found on the input terminals of some neurons. The D2 subtype of dopamine receptor (there are five subtypes) is a single molecule of protein (made of amino acids, in a particular sequence, which fold into a particular shape) which spans the cell membrane so some parts of the molecule are exposed to the water and molecules in the cerebrospinal fluid (CSF) in which the cell is bathed, while another part of the receptor extends into the fluid inside the cell - the water and other molecules of the cytoplasm.

Dopamine receptors are naturally occupied and activated by dopamine molecules, which are typically released from an output terminal of another neuron, which are directly adjacent (a fraction of a micron - 1/1000 of a millimeter - or so) to the input terminal.  The receptor molecule's external structure has an indentation or "slot" with a particular shape, and with particular hydrophobic (oily, water avoidant) amino acids in some parts of the slot and hydrophilic (water-attracting) amino acids in other parts.  Particular atoms in particular amino acids may have positive and negative electrical charges.

The structure of the slot is such that a dopamine molecule, in the correct orientation, is attracted into it.  So when a dopamine molecule in solution in the CSF is near this slot, it may be attracted into it.  The dopamine molecule has a high affinity for the slot due to the close match between its hydrophilic and hydrophobic parts, and its positive and negatively charged atoms and corresponding features in the slot.

Thermal motion (heat energy in solids and liquids is the rapid random vibratory motion of electrons, atoms and molecules) will eventually eject the dopamine molecule, leaving the receptor slot empty and ready to attract another matching molecule. 

The dopamine molecule is the natural "ligand" of the dopamine receptor.  The dopamine molecule both occupies and activates the receptor, by slightly changing the shape of the receptor.  There are several mechanisms by which receptors, in general, can alter the voltage inside their part of the input terminal of the neuron.  The D2 receptor's slight change in shape causes its internal section to facilitate complex chemical reactions in the cytoplasm.  This Wikipedia article on G-protein coupling describes, in general, the process by which receptors such as D2  facilitate these chemical reactions when they change shape:


A receptor's slot can attract molecules with similar shapes to dopamine.  Different molecules have different affinities for the receptors.  Some occupy and activate the receptor - these are agonists. Others occupy and do not activate the receptor - these are antagonists.

The Wikipedia article on the D2 receptor:


lists over a dozen agonists, in addition to dopamine itself - including two which are used to treat RLS/PLMD: Pramipexole and Ropinerole.  The exact type of dopamine receptor which are apparently lacking dopamine in RLS/PLMD has not been identified.  Nor has their location.  It is possible that there are more than one type of neuron involved, and each type of neuron may have more than one type of dopamine receptor. 

The D2 receptor, when activated, creates a more negative voltage in its part of the input terminal, which reduces the chance that the neuron will depolarize (fire).  So D2 receptors are inhibitory.  The same input terminal will probably have receptors for neurotransmitters other than dopamine, and there will be adjacent output terminals of other neurons which release these neurotransmitters.  If those other receptors are excitatory, activation of the D2 receptors in this input terminal will counter, and perhaps, block their excitatory influence on the rest of the neuron.

An interneuron is a loose term for a neuron which spans only a short distance, in contrast to one which spans across the brain, down the spinal cord, or from the spinal cord to a distant muscle.

Interneurons are typically involved in receiving both excitatory and inhibitory inputs from sensory neurons and other interneurons. Their output terminals typically drive other interneurons; motor neurons to the muscles; or, the ascending neurons to the brain which report pain and other sensations.

A nerve cell.  Some cells in the brain and spinal cord perform support functions for the neurons.  Neurons exist in the brain, spinal cord and extend to the sensory regions such as the skin, retina, inner ear and to the motor output section: muscles.  Some neurons in the brain and spinal cord are small and the distance between their input terminals and output terminals may be a millimeter or less.  Other neurons are very long.  Upper motor neurons accept input signals in the top centre of the brain (the motor cortex) and extend all the way down to a control centre in the spinal cord.  For the arm muscles this is below the neck. For the leg muscles it is near the base of the spinal cord, which is somewhat higher than the base of the spine. 

At these spinal cord "control centers", the output terminals of the upper motor neurons synapse with the input terminals of lower motor neurons. The lower motor neurons' output terminals are within the muscles they drive.  There may be a hundred or more parallel upper motor neurons for a particular muscle.  Each such neuron is a single cell and spans a fraction of a metre.  (Consider the distance from a giraffe's brain to the base of its spine - these would be single cells about 3 metres long.)  The lower motor neurons may be very long as well, and there may be hundreds or more, in parallel, per muscle.

Neurons either fire or they don't - the "firing" is called "depolarization" and involves a fraction of a volt drop in the internal voltage of the cell, which propagates at high speed from the junction of the input terminals right to the end of one or more (perhaps hundreds) output terminals.  This is all a single cell.

While communication within the neuron is electrical, their signaling to other neurons involves releasing neurotransmitters from their output terminals, which are placed right next (tiny fractions of a mm) to the input terminals of other neurons.  The receptor molecules in the cell-walls of the input terminals accept molecules of particular neurotransmitters and when this happens, they alter the voltage inside the input terminal.  A positive voltage change excites the neuron and a negative voltage change inhibits it.  The voltage inside a rest state (not depolarizing) neuron is typically -70 millivolts.  At some point in the receiving neuron, the voltages of various input terminals are averaged, and if the average exceeds a certain threshold voltage, the neuron depolarizes (fires), with a brief electrical pulse inside the neuron, temporarily taking the voltage to 0 volts, or slightly positive.  This pulse makes all the neuron's output terminals release their particular neurotransmitter molecules.

So the nervous system is in some senses digital - neurons either fire or they don't.  Proportional signals are represented by the rate of firing, and some neurons can fire repeatedly, such as a hundred times a second.


Neurotransmitters are, broadly speaking, molecules which are released by the output terminals of neurons when they depolarize, and which are quickly accepted by receptors on nearby input terminals of other neurons.  They both occupy and activate the receptor molecule - and this activation may increase or decrease the chance of the recipient neuron firing, depending on the nature of the receptor molecule.

There are dozens of neurotransmitters, such as acetylcholine, adenosine, glutamate, histamine, serotonin, dopamine and glycine.  Glycine is an amino acid - the same as is used in protein.  Dopamine is produced from the amino acid tyrosine. 

Any molecule which is accepted by a class of receptor molecules known as opioid receptors.  They are named because the first molecules which were discovered to occupy them were opium and related molecules, from the opium poppy.  The term "opioid" on its own typically means an exogenous (from outside the body) molecule which occupies and activates opioid receptor molecules.  These are mainly opioid drugs such as morphine, hydrocodone etc. 

Endogenous opioids are a molecules the body produces which occupy and activate opioid receptors.  Opioid receptors in the spinal cord and brain are involved in reducing sensitivity to painful stimuli and in the generation of euphoria.

Any molecule which occupies and activates opioid receptors is known as an opioid receptor agonist, or "opioid agonist" for short. 

An opioid receptor antagonist, or "opioid antagonist" is a molecule which occupies an opioid receptor without activating it.  This prevents the receptor from being activated by any opioid receptor agonists which would otherwise fall into the receptor's molecular recognition slot.

The endogenous opioid agonists such as endorphins and enkephalins are not ordinarily considered to be neurotransmitters, because typically the source of these compounds is distant from their receptors.  Endogenous opioids may be released in one part of the body and affect receptors in other parts of the body minutes or hours later, with the compounds remaining in circulation for hours or days.  The endogenous opioids typically go into solution in the blood and cerebro-spinal fluid and so reach receptors in distant parts of the nervous system.  So the effects of opioids are non-localized - rather like a hormone - while a neurotransmitter in a synapse has a very localized effect and can generate its effect within a few milliseconds.

Opioids may travel large distances and be present in large total quantities, so it may take hours or days for them to be metabolized.  While opioid release may lead to effects perhaps within seconds, it is more likely to be minutes before the effects appear.  This is very different from neurotransmitters in a synapse, which can be released, activate the receptor, pop out of the receptor and be recycled back into the output terminal which just released them, in a small fraction of a second.

The distinction between these two modes of operation is not entirely clear, since some neurotransmitters leave the synapse they were released into and drift into the receptors in other nearby synapses, and because opioids are sometimes released close to the opioid receptor sites.


Periodic Limb Movement Disorder / Syndrome.  A diagnostic category concerning involuntary limb movements, more typically of the legs, when resting or when awake.  The limb movements typically repeat after 20 to 40 seconds, rather than being continuous or occurring in a random fashion.  A "PLM" is a period limb movement.


Restless Legs Syndrome, a diagnostic category primarily concerning sensations and urges to move the legs, or the arms.


Restless Limbs Sensorimotor Disorder is the term which I propose be used to identify the single disorder underlying RLS and PLMD.  I am proposing a set of hypotheses for the etiology (detailed causative mechanisms) for that disorder in rlsd/ ../ and in the PDF document I sent to researchers.  However, even if I wasn't proposing such a set of etiological hypotheses and even if there was no recognised etiology, I would still argue for RLSD to be the name of what is clearly a single underlying disorder.

As a noun: the point at which output terminals of one or more ("pre-synaptic") neurons almost touch the input terminal of another ("post-synaptic") neuron.  The synapse is a small zone in which neurotransmitters are released by the output terminals, where they quickly find their way to specific receptor molecules on the input terminal, and where they are typically ejected from the receptors and recycled back into the output terminal.

There is typically no electrical connection between the neurons - just the chemical  signaling, which can be disrupted by other molecules drifting into the synapse area from  distant sources, and occupying receptor molecules, with or without  activating them.

As a verb, the pre-synaptic neurons are said to "synapse with" the post-synaptic neuron. 

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© 2011 Robin Whittle   Melbourne Australia