Download descending projections from the trigeminal ganglion and

Trakia Journal of Sciences, Vol.1, No 1, pp 5-14, 2003
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Review Article
DESCENDING PROJECTIONS FROM THE TRIGEMINAL GANGLION
AND MESENCEPHALIC TRIGEMINAL NUCLEUS
Nikolai Lazarov1* and Kamen Usunoff2
1
Department of Anatomy, Faculty of Medicine, Trakia University, Stara Zagora, Bulgaria
2
Department of Anatomy and Histology, Medical University, Sofia, Bulgaria
ABSTRACT
The overview is an updated survey of our current knowledge about the trigeminal primary afferent
neurons involved in the somatosensory processing from the orofacial region. The types of neurons,
located in the trigeminal ganglion (TG) and mesencephalic trigeminal nucleus (MTN), are reviewed.
Critically evaluating recent literature, the topics covered by the ongoing studies include the trigeminal
descending connectivity with special emphasis on newly discovered efferent projections. Their
chemical neuroanatomy under normal and abnormal conditions is also discussed. We provide data that
TG and MTN neurons have similarities and differences in their neurochemical content. On the one
hand, both central and peripheral trigeminal primary afferent neurons express, indeed to a varying
degree, classical transmitters. Taken together with the existing neuroanatomical and
electrophysiological data, the results give strong evidence for the occurrence of both excitatory and
inhibitory transmission in the trigeminal sensory system. On the other hand, TG cell bodies contain
certain neuropeptides while MTN neuronal somata lack peptide neuromessengers. We also show that
the TG and MTN receive catecholaminergic, serotonergic, nitrergic and peptidergic innervation. The
levels of transmitter substances vary according to the environmental conditions. The hodological and
neurochemical studies we have summarized here enhance our understanding of the peripheral
somatosensory reflex patterns. For a more thorough presentation of data the reader is referred to
previous reviews and references therein.
Key words: Mesencephalic trigeminal nucleus, Peripheral projections, Primary sensory neurons,
Primary trigeminal afferents, Trigeminal ganglion
INTRODUCTION
It is a longstanding view that primary sensory
neurons transmit information to the central
nervous system (CNS). from a variety of
sensory receptors in the periphery. Trigeminal
primary afferent neurons are involved in the
somatic sensory innervation of the oral-facial
region through the trigeminal nerve.
Therefore, the trigeminal pathway has proved
to be a useful system for studies on the
interactions between the periphery and the
CNS (for reviews see 21, 41). On the other
hand, the study of trigeminal efferent
connectivity has become increasingly
important for the understanding of their
*Correspondence to: Nikolai Lazarov PhD, DSc Vice
Dean for Research, Faculty of Medicine, Trakia
University, 6003 Stara Zagora, Bulgaria
E-mail: [email protected]
neurochemistry and plasticity in health and
disease (52).
The trigeminal system is a well-defined
sensory system that has been studied
extensively in mammals and birds. It
comprises two populations of primary sensory
neurons, the trigeminal ganglion (TG) and
mesencephalic trigeminal nucleus (MTN),
their peripheral and central target fields and
subsequent projections in the CNS (Table 1).
The neurofunctional organization of the TG
and MTN may depend not only on the
phylogenetically different migration of the
respective primary afferent neurons, but may
also reflect the existence of distinct peripheral
target fields of the trigeminal branches.
For many years, pseudounipolar sensory
neurons located in the TG and MTN are
thought to lack dendrites and possess only an
axonal process (62).
Trakia Journal of Sciences, Vol.1, No 1, 2003
5
N. LAZAROV and K. USUNOFF
Table 1. Cell size, Sensory Functions, Embryonic Origins and Peripheral Target Fields of Trigeminal Primary Afferent
Neurons.
Population
Cell size
Sensory function
Derivation
MTN
Large
diameter Proprioception
Neural crest
(Pseudounipolar)
TG
Small diameter
(Multipolar)
Small diameter
Large diameter
Interneurons?
Nociception
Thermoreception
Proprioception
Mechanoreception Ectodermal
placode
The single axon divides into a peripheral
and a central branch, which terminate in a
variety of structures in the orofacial region
and the central nuclei in the brainstem,
respectively. Axon collaterals bearing en
passant and terminal boutons emerge from the
peripheral process of centrally displaced
ganglionic MTN neurons and terminate into
the region of the trigeminal motor nucleus
(23) making monosynaptic excitatory
connections with jaw-closing motoneurons
(12, 82). It is also believed that peripheral
axons of the MTN neurons possess the same
conduction velocity as those of low-threshold
mechanoreceptive afferent neurons in the TG
(9).
The TG mainly innervates mechanoreceptors, thermoreceptors and nociceptors in
the face, oral and nasal cavities while the
MTN mainly supplies proprioceptors in the
masticatory muscles. In addition, findings in
experimental
animals
suggest
that
pseudounipolar neurons in the TG are
topically distributed: the cell bodies sending
axons to the ophthalmic, maxillary and
mandibular nerves are located in the
anteromedial, middle and posterolateral
portions of the ganglion, respectively (39, 40,
53). Microdissection studies (25, 34) imply
that such an organization is also present in
man. Differential somatotopic distribution of
the cell bodies has also been described in the
MTN. In fact, jaw muscle afferent MTN
neurons are more evenly dispersed throughout
6
Neural crest
Innervation
Masticatory muscle
spindles;
A subset of:
 Extraocular muscle
spindles,
 Periodontal ligament
fibers,
 Dental pulp
Facial skin,
Eye, Cornea,
Mucosa of paranasal
sinuses
Nasal and oral cavity
Teeth and periodontium
Vibrissae
Exteroceptive
mechanoreceptors in the
skin
the whole length of the nucleus, whereas
periodontal receptor afferent MTN neurons
are restricted to its caudal part (13, 29, 35,
59).
Despite the considerable advances made in
our understanding of the peripheral
connectivity of the trigeminal sensory system,
many important and fundamental keyquestions such as the somatosensory
innervation of structures which are unique to
the trigeminal region (e.g. tooth pulp,
periodontal ligament, tongue, oral mucosa,
cornea and temporomandibular joint) remain
unanswered. Besides, it is still of certain
interest to establish whether central and
peripheral trigeminal primary afferent neurons
utilize one and the same neuroactive
substance for chemical transmission. This is a
significant issue since the transmitter content
of different neuronal populations often
correlates well with their target projections
(18). Hence, to solve the puzzle of the
neurochemical organization of descending
trigeminal pathways, there are still some
contradictory matters to be settled.
This review, which is not designed to be
exhaustive, focuses on recent advances in
neurobiological research of descending
projections of the central and peripheral
trigeminal primary afferent neurons. It
provides an overall account of their
neurochemistry, with a particular emphasis on
critical evaluation of a few controversial
points in the extant literature.
Trakia Journal of Sciences, Vol.1, No 1, 2003
N. LAZAROV and K. USUNOFF
TG EFFERENT CONNECTIONS AND
THEIR NEUROCHEMISTRY
The distribution of the peripheral branches of
the trigeminal nerve in mammals, as well as
their communication with gustatory and
autonomic nerve fibers was already well
known at the beginning of the twentieth
century (19). Since then it has been studied
through in a great detail (5, 44, 51, 69, 71, and
the references therein). A survey of the
literature reveals that each of these nerves has
its own peripheral innervation area. Briefly,
the ophtalmic nerve innervates the forehead,
upper eyelid, cornea, conjunctiva, dorsum of
the nose, and the mucosa of frontal, ethmoid
and sphenoid sinuses, and the anterior portion
of the nose; the maxillary nerve supplies the
upper lip, lateral portions of the nose, the
lower eyelid and the infraorbital region, the
anterior temple, most of the mucous
membranes of the nose and the paranasal
sinuses, of the upper jaw and the roof of the
mouth, as well as the upper dental arch; the
mandibular nerve innervates the lower lip, the
chin, the posterior portion of the cheek, the
temple, the mucous membranes of the lower
jaw, the floor of the mouth, the anterior twothirds of the tongue, as well as the lower
dental arch. All three divisions of the
trigeminal nerve innervate the dura mater of
the anterior and middle cranial fossa and the
cerebellar tentorium (for reviews see 6, 86,
87). Moreover, there are recent data showing
that branching fibers of the TG cells innervate
both the dental pulp and periodontal ligament
in cats (56). The sensory root (the portio
major) of the trigeminal nerve arises as the
central branches of TG neurons and enters the
brainstem along the motor root by passing
though the brachium pontis. In addition,
motor axons travel in the mandibular nerve to
the masticatory muscles forming the so-called
portio minor (radix motoria).
The trigeminal system receptors cover a
broad spectrum: free nerve endings,
lanceolate, Ruffini and Ruffini-like receptors,
simple cylindrical end-bulbs, Merkel cells,
Golgi-Mazzoni receptors, Meissner and
Meissner-like corpuscles (see 20, 32 for
reviews of ”classic” papers; more recent
literature is comprehensively reviewed by 88).
Kadanoff et al. (37) carried out a broad
comparative study of the encapsulated sensory
nerve endings in the hairless part of the lips
(rodents, carnivores, ruminants, primates,
including apes and man). Their results
strongly support the notion that the
complexity of the sensory corpuscles is a
quantitative evolutionary improvement since
the most complicated receptors are to be
observed in various primates, apes and man.
Thus, the distribution of the peripheral
branches of the ophthalmic, maxillary and
mandibular nerves has already been well
documented. Considerably less is known
about their chemical neuroanatomy. Up to
date, a variety of classical and peptide
transmitters have been associated with subsets
of TG neurons.
Glutamate (GLU) is the major transmitter
of TG neurons (38, 48, 80, 83). Interestingly,
primary afferents innervating the tooth pulp
possess
GLU-immunoreactivity
(3).
Furthermore, data from previous studies have
shown that a number of TG neurons and some
of their processes may be of a gammaaminobutyric acid (GABA) ergic nature (80,
81). Presently, there is considerable
experimental evidence suggesting that
excitatory amino acid(s) could be the
transmitter(s) of large myelinated nonnociceptive primary afferents whereas GABA
is probably the mediator of smaller trigeminal
neurons. Whether GLU is a nociceptive
transmitter released by trigeminal afferent
terminals, as originally postulated by Watkins
and Evans (91), is still a matter of debate. On
the other hand, a number of previous studies
have revealed that the TG contains nitric
oxide
synthase
(NOS)-immunoreactive
neurons, mainly within its ophthalmic
division, and some of them supply the
cerebral arteries (60) or project to the cochlea
(68). Besides, certain negative large TG
perikarya are completely enveloped by
nitrergic
baskets
(50).
Conversely,
immunohistochemical evidence has suggested
that TG neurons do not utilize catecholamines
as possible neurotransmitters but are under the
influence of monoaminergic afferent fibers of
presumable sympathetic origin (48). In
addition, a strikingly broad spectrum of
neuropeptides has been demonstrated in the
TG neurons and their efferent projections:
substance P (SP), calcitonin gene-related
peptide (CGRP), cholecystokinin (CCK),
somatostatin (SOM), vasoactive intestinal
polypeptide
(VIP),
galanin
(GAL),
neuropeptide Y (NPY), and bombesin (22, 26,
31, 33, 36, 42, 45, 46, 48, 66, 84, 85).
It is now well known that peripheral nerve
damage evokes dynamic alterations in the
levels of expression of neuropeptides and their
receptors in the projection areas of injured
axons, a phenomenon called chemical
plasticity (30). For example, after axotomy of
the inferior alveolar nerve, there is a marked
reduction in the total SP and CGRP
Trakia Journal of Sciences, Vol.1, No 1, 2003
7
N. LAZAROV and K. USUNOFF
expression in TG neurons (24). Likewise, the
release of SP within the TG is largely
increased by peripheral inflammation (58). In
contrast, the NPY and VIP levels are
dramatically up-regulated in axotomized TG
neurons, thus contributing to the survival of
affected neurons in the adaptive processes
following nerve injury (27, 72, 89).
Furthermore, alterations in the levels of
expression of neurotrophins and their
receptors as a consequence of peripheral nerve
lesion have been documented. Indeed, both
high (TrkA) and low (p75) affinity
neurotrophin receptor transcripts in the TG
neurons have been shown to increase after
tooth injury (93). These findings, together
with the demonstrated co-expression of Trk
receptors with SP and CGRP in a population
of small trigeminal primary afferent neurons
(67), have led to the suggestion that
neurotrophins might be part of a molecular
mechanism for mediating nociception.
MTN EFFERENT CONNECTIONS AND
THEIR NEUROCHEMISTRY
The main peripheral projections of the MTN
have already been identified (for a review see
47) and, therefore, only a few further points
need to be mentioned here. In the mammalian
trigeminal system, the distally directed axonal
processes of MTN neurons leaving the pons in
the motor root of the trigeminal nerve (portio
minor), reach the masticatory and extrinsic
eye muscle spindles (1, 15, 35, 74, 82) as well
as a subset of the periodontal ligament
mechanoreceptors,
especially
those
innervating the apical roots of the molar and
incisor teeth (10, 75). These studies suggest
that, in accordance with earlier physiological
observations (13, 17, 35), MTN neurons
project distally in all the three principal
subdivisions of the trigeminal nerve.
Recently, it has also been demonstrated that in
the rat MTN neurons simultaneously
innervate both the masseter muscle spindles
and periodontal ligaments by collaterals of
their peripheral processes (95). The
neurophysiological data, obtained in patients
treated surgically for the relief of trigeminal
neuralgia, indicate that the fibers from
spindles of mastictory muscles, which are
traditionally thought to travel in the motor
root, pass instead in the sensory root (61). It is
also known that peripheral axons of MTN
periodontal afferents pass through motor or
sensory roots of the trigeminal nerve (76).
Yet, it remains to be clarified whether MTN
fibers subserve not only masticatory muscle
8
reflex mechanisms but may also convey
impulses of other sensory modalities.
Until now, many authorities have
expressed divergent views about the
projections of extraocular muscle afferents in
cats where extrinsic eye muscles are presumed
to be spindleless (for a review see 78). It has
been claimed by some authors (63, 64), that
the cells subserving extraocular muscle
proprioception in the cat are located only in
the TG. Others agree on the dual localization
of their cell bodies in both the TG and the
caudal part of the MTN (1, 7). The latter
assumption can no longer be doubted, in view
of the occurrence of atypical muscle spindles
and stretch endings in the extraocular muscles
in the cat (4).
The origin of the proprioceptive
innervation of the other muscles of the head
was until recently disputed and some aspects
remain uncertain. It is hardly possible for the
minute geniculate ganglion to provide the
proprioceptive and nociceptive innervation of
the mimic musculature, and it is probably
affected by trigeminofacial anastomoses (77).
The proprioception of the extrinsic muscles of
the tongue is still unclear while that of the
intrinsic muscles of the tongue is probably
relayed by a microganglion, interstitial to the
hypoglossus nerve fibers, and by the first
cervical nerve (6).
Another
question
of
considerable
functional significance is whether descending
fibers from MTN neurons supply the tooth
pulp and the temporomandibular joint. From a
classical point of view, the peripheral
terminations of MTN neurons reach the
temporomandibular joint (15). Conversely, as
ponted out by Sessle (73) in his review, these
neurons do not supply the tooth pulp so it
receives innervation by thin myelinated A
and unmyelinated C nociceptive fibers
originating exclusively from TG neurons.
Nowadays, it is well documented that, like the
dual innervation of the periodontal ligament,
neuronal cell bodies with peripheral receptive
fields in the tooth pulp, in addition to their
usual location in the TG, are also present in
the MTN (2, 94).
On the other hand, the MTN innervation of
the temporomandibular joint is denied at
present (8) and it has become apparent that it
is supplied by both myelinated and
unmyelinated primary afferents arising from
the TG cells located in its mandibular division
(11). Similar arguments have been put
forward against the claim that Golgi tendon
organ afferents have their cell bodies in the
MTN (13, 82).
Trakia Journal of Sciences, Vol.1, No 1, 2003
N. LAZAROV and K. USUNOFF
The fiber system descending from the
MTN, particularly from its pontine portion, is
known as Probst’s tract (16, 65). Branches
from it join the descending tract of the
trigeminal nerve and run caudally. The results
of the systematic studies on these descending
pathways in the cat clearly indicate that the
MTN neurons project directly to the spinal
cord (55, 57). Furthermore, it was found that
they send their axons exclusively ipsilaterally
as far as caudally to C3. Similarly, MTN
maintains a spinal projection, which does not
reach beyond C3 in the adult rat (43).
Collaterals of this tract terminate in the
supratrigeminal nucleus, the motor nucleus of
trigeminal, facial and hypoglossal nerves, the
solitary nucleus and the reticular formation
(54, 70).
In spite of these hodological findings in
trigeminal primary afferent neurons, detailed
knowledge of their chemical neuroanatomy
under normal and abnormal conditions is far
from complete. So, during the last decade
most studies on peripheral MTN connectivity
have been focused on their neurochemistry. In
recent years, numerous transmitters and other
neuroactive substances have been examined.
At present, out of all neurochemicals tested
in rats and cats, only GLU (and perhaps
aspartate) is undoubtedly associated with
MTN neurons located throughout the nucleus
(14, 47, 48), as in the pseudounipolar cells in
the TG (80, 90, 92). Besides, this excitatory
amino acid is responsible for monosynaptic
transmission between MTN afferents and
trigeminal jaw-closing motoneurons acting on
both N-methyl-D-asparate (NMDA) and nonNMDA receptors (12). On the other hand, the
inhibitory transmitter amino acid GABA is
also present in certain smaller neurons in the
mammalian MTN (47, 48). Moreover,
GABAergic interneurons have been found in
regions that innervate the jaw-closing muscles
of adult rats (28). In addition, our
observations provide evidence that nitric
oxide
(NO)
may
participate
in
mediating/modulating
proprioceptive
information and, thus, it is important for both
these aspects of intercellular signal processing
in the trigeminal sensory system (47, 48). On
the contrary, dopaminergic and serotonergic
inputs to the MTN have repeatedly been
pointed out (14, 47, 48). Remarkably, under
normal circumstances no immunoreactivity to
any of the neuropeptides examined has been
observed in the cell bodies of MTN neurons
and only fibers and their terminals show
peptide-immunolabeling (47, 49). Taken
together, the above-mentioned findings
strongly suggest that monoamines and
peptides might play an important modulatory
role as pure modulators in the integration and
transmission of trigeminal proprioceptive
information.
It should be kept in mind that the peptide
involvement in proprioceptive function
develops mainly under abnormal conditions
since masseteric nerve transection induces a
remarkable increase in the expression of
certain neuropeptides such as NPY, CGRP
and GAL (for a review see 47 and references
therein). Therefore, we believe that the newly
synthesized neuropeptides may play a
supportive role in the adaptive processes as
neurotrophic factors involved in reply to
injury,
thus
protecting
peripherally
axotomized MTN neurons.
CONCLUSIONS
A further characteristic feature of the
trigeminal sensory system is that its efferent
connectivity is far more complicated that
hitherto assumed. At the same time, certain
aspects of the trigeminal central organization
seem to be dictated by functional demands in
the periphery.
On the other hand, studies of its
neurochemistry contribute to an increased
knowledge of exploring the neurotransmitter
labyrinth and establishing the communication
in a well-characterized experimental system.
Contrary to the prevalent view, it seems quite
alluring to conclude that GLU is unlikely to
be the sole common neurotransmitter in
trigeminal primary afferent neurons (79).
Rather, other transmitters such as GABA and
NO are possibly involved in the processing of
orofacial somatosensory information under
normal conditions as well.
The occurrence of catecholaminergic,
serotonergic, peptidergic and nitrergic
arborizations around the perikarya in the TG
and MTN is remarkable as this probably
means they receive a sympathetic,
parasympathetic and sensory innervation,
each of them specifically organized with
respect to its neurochemical phenotype.
Furthermore, the levels of transmitter
substances in TG and MTN neurons may vary
in case of marked changes in the
environmental
cues,
thus
implying
neurochemical plasticity as a major attribute
of trigeminal primary afferent neurons.
In conclusion, each population of
trigeminal primary afferent neurons acting on
a specific target is presumably chemically
coded and appears, in most instances, to
release more than one neuroactive substance.
Trakia Journal of Sciences, Vol.1, No 1, 2003
9
N. LAZAROV and K. USUNOFF
Differential expression of classical and
peptide transmitters in central versus
peripheral trigeminal primary afferent cell
groups is of developmental interest as it may
be related to differences in the milieu of the
neural crest and ectodermal placodes from
which these structures originate. Obviously,
more definite information is needed regarding
the
peripheral
distribution
and
the
neurochemical content of efferent projections
arising from the TG and MTN neurons under
normal and experimental conditions. So far, a
few initial steps have been taken along this
complex path. Studies are currently in
progress in our laboratory to ascertain whether
efferent connections are indeed multifaceted
in their chemical coding.
ACKNOWLEDGEMENTS
This study is supported by a grant from the
Faculty of Medicine at the Thracian
University Stara Zagora (project no. 3/2002).
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