Free serotonin in plasma role in triggering myasthenic crisis
It has long been known that NA (noradrenaline)
facilitates neuromuscular transmission and muscle contraction .
The sudden (acute) clinical improvement registered in all our MG
patients during neuropharmacological therapy should be
attributed to the effect of NA released at spinal motoneuron
levels. At this level, NA excites alpha-1 post-synaptic
receptors which facilitate muscular activity. As is implied ,
the CNS controls posture and movements through the activation of
spinal motoneurons which receive noradrenergic excitatory and
serotonergic modulatory axons from medullary and pontine nuclei.
Spinal motoneurons receive thousands of presynaptic excitatory
(NA) and inhibitory (5HT) axons which distribute throughout
their dendritic trees. Noradrenaline excites alpha-1 receptors
whereas serotonin, acting at 5HT-1a receptors, modulates NA
effects at the spinal motoneurons level. In addition, NA
synchronizes the evoked quantal release at neuromuscular
junctions . Noradrenergic axons innervating spinal motoneurons
arise from the locus coeruleus (LC) also called A6-NA and A5-NA
cell groups . Serotonergic axons innervating spinal motoneurons
arise from the medullary raphe pallidus and raphe obscurus
nuclei.
Alpha-2antagonist drugs excite motoneurons by
increasing the firing activity of NA neurons which release
noradrenaline from axons innervating spinal motoneurons. Similar
effects are displayed by buspirone. This drug at low doses
(similar to those employed in anxiety patients) may exert a dual
effect on spinal motoneurons: an excitatory effect by increasing
the release of NA from noradrenergic axons, and an indirect
polysynaptic effect secondary to the reduction of activity of
the medullary raphe nuclei which possess 5HT-1a inhibitory
autoreceptors. The short-lived effect of the alpha2antagonists-induced
release of noradrenaline can be prolonged by the addition of an
inhibitor of NA re-uptake at synaptic level (desipramine,
nortryptiline, protryptiline, doxepin,.
According to all the above, it becomes clear why
neuropharmacological therapy addressed to enhancing central NA
neural transmission triggers an acute and sudden improvement of
muscular strength in MG patients. This phenomenon has been known
since the 1980s decade to neurophysiologists familiar with the
findings obtained in spinal cats. Adrafinil and modafinil (two
alpha1 agonists) trigger acetylcholine release from
motor nerves and facilitate neuromuscular transmission by a
selective action at presynpatic alpha1 receptors
located at that level .
The late and sustained improvement registered in our study would
reflect the role played by the excitatory effect of
noradrenergic innervation at lymphoid organs and the
immunosuppressant effects displayed by plasma serotonin (f-5HT).
It has been exhaustively demonstrated that the regions in which
lymphocytes T cells reside, and through which they recirculate,
receive direct sympathetic neural input. Therefore, the immune
system can be considered “hard-wired” to the brain. Chemical
sympathectomy of adult mice resulted in reduced antibody
responses to T-dependent antigens. These and other
findings demonstrate that the noradrenergic innervation of bone
marrow is functionally dynamic and is responsive to central
activation. Furthermore, these results lend credence to the
premise that neural mechanisms participate in regulating
lymphopoietic cellular events.
Finally, it has been known for several years that
pharmacological enhancement of 5HT metabolism suppresses the
immune response in vivo. This immunosuppression occurs
peripherally, not centrally .
Free serotonin in plasma should also play some important role in
triggering myasthenic crisis since we were able to accelerate
the recovery of several MG patients affected by this severe
complication by administering tianeptine to them. This finding
is consistent with the bronchial constriction effect exerted by
f-5HT in asthmatic patients who were also dramatically improved
by this serotonin-enhancing uptaker drug.