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
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
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
I am not aware of any endogenous dopamine or opioid receptor
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
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
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.
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
The Wikipedia article on the D2
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
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
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
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,
Endogenous opioids are a molecules the body produces which occupy
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
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.
PLMD and PLMS
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.
Legs Syndrome, a diagnostic category primarily concerning
sensations and urges to move the legs, or the arms.
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
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
As a verb,
the pre-synaptic neurons are said to "synapse with" the post-synaptic