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Q: Nociceptors of the eye. Pain associated with bright light. ( No Answer,   7 Comments )
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Subject: Nociceptors of the eye. Pain associated with bright light.
Category: Science
Asked by: pittneuromonkey-ga
List Price: $100.00
Posted: 21 Dec 2002 20:02 PST
Expires: 15 Jan 2003 16:23 PST
Question ID: 132324
Are there pain receptors (nociceptors) in the eye that react to light?
To clarify: is there a Nociceptor in the eye somewhere around the
photoreceptors or the uvea that are responsible in situations, where
one would be exposed to high enough levels of light where it could
cause a "burn out/ bleaching" of the photoreceptors in the retina.

So my questions are: (1) are there nociceptors in the eye which are
responsive to high levels of light? and (2) where would these
nociceptors be located? (3)is there a reflex circuit that has been
found?

To get the money, you need to cite a research article that studies this phenomenon.

Request for Question Clarification by ragingacademic-ga on 22 Dec 2002 11:06 PST
pittneuromonkey -

Having searched a couple of well-regarded electronic medical
databases, it seems that if there are - we don't know about them yet.

I have, however, located several papers that examine nociceptor
response to chemical stimulation.  Would you be interested in the
relevant citations, and would you accept this information as an
answer?

thanks,
ragingacademic

Clarification of Question by pittneuromonkey-ga on 22 Dec 2002 11:11 PST
ragingacedemic-

Sorry, but I am only looking for light as the noxious stimulus. I have
tried thorough searches but haven't found any substantial research.
And as you said, it seems as if there are nociceptors present which
may do this, but I find it hard to believe that no one has done this
research. This would be a simple thesis for a college graduate student
in neuroscience or biology.

Well thanks for the try, but I am specifically looking for pain
reponses in reaction to light as a noxious stimulus.

PittNeuroMonkey

Request for Question Clarification by ragingacademic-ga on 22 Dec 2002 20:57 PST
pittneuromonkey -

I have searched several additonal databases including Dissertation
Abstracts International, Worldcat, Ebsco, and anything OCLC has under
its umbrella of holdings using the following strategies -

"nociceptor AND eye"
"nociceptor AND vision"
"nociceptor AND light"

I've even manually combed through the hundreds of titles I got from a
simple search on "nociceptor..." - nada, zilch, nothing...

Any other ideas?
I'd love to find something for you out there, but if it is out there,
it's super elusive...

thanks,
ragingacademic

Clarification of Question by pittneuromonkey-ga on 22 Dec 2002 21:09 PST
ragingacedemic-

I appreciate your dedication. On a previous struggle with this topic,
I contacted Dr. Simon Grant from London who specializes in the eye.
Although he could not provide any conclusive evidence, this is what he
had to say:
    "Yes, there are nociceptors in the eye. They are located mainly in
the
uveal layer (choroid, ciliary body & iris) with a few also extending
forward to innervate the inside of the cornea. The receptors are
attached to the ends of the long ciliary nerve, which exits the
eyeball
posteriorly and joins up with other peripheral nerve branches inside
the
orbit to form the nasociliary nerve. This, in turn, enters the
ophthalmic division of the trigeminal nerve &, via the trigeminal
ganglion. sends pain information to the spinal nucleus of V.
I suspect - although this is largely conjecture - that pain associated
with bright light is probably due to extreme contraction of ocular
tissues, especially the iris as the pupil constricts, and maybe other
mechanical deformations of the uveal layer."

But the problem is that I need a more specific answer which provides a
circuit and more importantly- research.

Once again, I appreciate your dedication ragingacademic. Happy
Searching.

PittNeuroMonkey

Clarification of Question by pittneuromonkey-ga on 22 Dec 2002 21:46 PST
Perhaps there may be somthing to be found under "noxiouos stimulus",
"light",, "light", "eye", "reflex".....hope these would help!

Clarification of Question by pittneuromonkey-ga on 23 Dec 2002 11:05 PST
OK since this looks to be an incredibly daunting task and most
researchers are leaning toward a mechanoreceptor reflex in response to
high levels of light I would like to redirect my question: So now I
would like to know: (1) where are these mechanoreceptors located
(probabally in the cillary body)? (2)how is this reflex proposed to
work? (3) what research articles cite this phenomenon?

I hope this helps! Thanks again everybody for your input up to this
point!

PittNeuroMonkey

Clarification of Question by pittneuromonkey-ga on 23 Dec 2002 13:58 PST
To be very specific, I am looking for research on what Dr. Grant is
reffering to:
 "that pain associated with bright light is probably due to extreme
contraction of ocular tissues, especially the iris as the pupil
constricts, and maybe other
mechanical deformations of the uveal layer."

Request for Question Clarification by hlabadie-ga on 29 Dec 2002 06:11 PST
It seems unlikely that the specific study to demonstrate conclusively
the statement by Dr. Grant has been made, due in part to the fact that
the size and placement of the neurons makes investigation difficult.
(See Journal of Physiology (2 1), 533.2, pp.493–5 1. "The mechanisms
that control the excitability of nociceptor terminals are largely a
matter of speculation because of their small size (< .5 Ám diameter)
and their inaccessibility in intact tissues like skin (see Belmonte,
1996)."

Note especially the articles co-authored by Belmonte. He is one record
as supporting the speculation that the nociceptors of the uvea are
polymodal, comparing them to those in the cornea. His findings
(Journal of Physiology (2 1), 533.2, pp.493–5 1) concerning the
division and identification of corneal neurons as polymodal,
mechano-sensory and cold-sensitive by direct measurement of impulses
supports the speculative analogy with the uveal neurons. Note the
findings (Invest Ophthalmol Vis Sci  1995 Jul;36(8):1615-24) showing
that 70% of the neurons in the uvea were C and compare this to the
statement by Bossut, Perl (J Neurophysiol 1995 Apr;73(4):1721-3) that
"induction of adrenergic responsiveness in nociceptors after partial
denervation in cutaneous MyHTMs appears to be less important for
mechanisms related to pathogenic pain than alterations in certain
C-fiber nociceptors."

You can also look up:



BELMONTE,  C.,  GARCIA-HIRSCHFELD,  J.  &  GALLAR,  J.  (1997).
Neurobiology of ocular pain. Progress in Retinal Eye Research 16,
117–156.


and the other publications cited in the comment, among them:


 Anat Embryol (Berl)  1998 Aug;198(2):123-32 

New indirect pathways subserving the pupillary light reflex:
projections of the accessory oculomotor nuclei and the periaqueductal
gray to the Edinger-Westphal nucleus and the thoracic spinal cord in
rats.

Klooster J, Vrensen GF.


 Neuroscience  1994 Sep;62(2):481-96 

The anatomical substrates subserving the pupillary light reflex in
rats: origin of the consensual pupillary response.

Young MJ, Lund RD.


 J Comp Neurol  1991 Apr 15;306(3):425-38 

The Edinger-Westphal nucleus: sources of input influencing
accommodation,
pupilloconstriction, and choroidal blood flow.

Gamlin PD, Reiner A.



 Vis Neurosci  1996 Jul-Aug;13(4):655-69 

Central neural circuits for the light-mediated reflexive control of
choroidal blood flow in the pigeon eye: a laser Doppler study.

Fitzgerald ME, Gamlin PD, Zagvazdin Y, Reiner A.



 Kaibogaku Zasshi  1999 Oct;74(5):577-86 

Lattice-like collagen fiber meshwork in the iris stroma of the cat: a
possible mechanism to generate the tension directed towards the iris
root which is required for pupillary dilatation in the
sympathectomized eye.

Sakuraba M, Yun S, Ichinohe N, Yonekura H, Shoumura K.



 J Neurosci  1999 Jun 15;19(12):5138-48 

Brain-derived neurotrophic factor modulates nociceptive sensory inputs
and NMDA-evoked responses in the rat spinal cord.

Kerr BJ, Bradbury EJ, Bennett DL, Trivedi PM, Dassan P, French J,
Shelton DB, McMahon SB, Thompson SW.


 Exp Eye Res  1991 Jul;53(1):3-11 

The 1990 Endre Balazs Lecture. Effects of some neuropeptides on the
uvea.

Anders B.

Department of Physiology and Medical Biophysics, Uppsala, Sweden.

"However, CCK (cholecystokinin) is a potent miotic in monkeys and
causes contraction of the human pupillary sphincter muscle. It has no
such effect in the lower species. The effect of CCK in primates seems
to derive from the presence of CCK receptors of the A-type on the
pupillary sphincter muscle, and can be blocked by lorglumide."




 Invest Ophthalmol Vis Sci  1995 Jul;36(8):1615-24

Sensory receptors in the anterior uvea of the cat's eye. An in vitro
study.

Mintenig GM, Sanchez-Vives MV, Martin C, Gual A, Belmonte C.

"Approximately 30% of the fibers conducted in the lowest range of the
A-delta group; the remaining 70% were C fibers. Sustained mechanical
stimulation
of the receptive area elicited a tonic response in approximately 60%
of the
units, and a phasic response in the remaining 40%. Exposure of the
receptive
field of mechanosensitive fibers to 600 mM NaCl evoked a long-lasting
discharge
in 50% of the units; application of 1 to 10 mM acetic acid elicited a
short
discharge in 30% of the fibers, often followed by inactivation.
Bradykinin (1 to
100 microMs) produced a long-lasting response in almost 50% of the
units.
Warming the receptive field recruited 20% of the explored units,
whereas 17%
were activated by low temperature. CONCLUSIONS. Two main functional
types of
sensory fibers innervating the iris and the ciliary body were
distinguished: (1)
mechanoreceptors, corresponding to afferent units sensitive only to
mechanical
stimuli were generally silent at rest, had relatively higher force
thresholds,
and discharged phasically in response to long-lasting mechanical
stimulation;
(2) polymodal nociceptors, which were activated by mechanical as well
as by
chemical and/or thermal stimuli, usually displayed spontaneous
activity, had
lower force thresholds, and fired tonically upon sustained mechanical
stimulation."



 J Neurophysiol  1995 Apr;73(4):1721-3 

Effects of nerve injury on sympathetic excitation of A delta
mechanical
nociceptors.

Bossut DF, Perl ER.

Department of Physiology, University of North Carolina at Chapel Hill
27599,
USA.

1. The effects of sympathetic stimulation and close arterial injection
of
norepinephrine were tested on cutaneous myelinated-fiber (A delta)
mechanical
nociceptors [high-threshold mechanoreceptors-(MyHTMs)] from normal and
from
partially transsected nerves. 2. Neither sympathetic stimulation nor
close
arterial injection of norepinephrine (200 ng) excited MyHTMs (18)
recorded from
the uninjured great auricular nerve of adult rabbits. 3. MyHTMs (58)
conducting
across the site of partial cut lesions, made 2 to 28 days previously,
had
threshold and responsiveness to mechanical stimuli, receptive field
organization, and absence of background discharge typical of such
elements in
normal nerve. 4. Four MyHTMs recorded from the injured nerves were
excited by
sympathetic stimulation and/or norepinephrine injection but only one
gave more
than two impulses within 60 s to either form of stimulation. 5. The
meagerness
of the sympathetic and adrenergic excitation of MyHTMs after nerve
injury
contrasts with that observed under similar conditions for C-fiber
polymodal
nociceptors. Therefore, induction of adrenergic responsiveness in
nociceptors
after partial denervation in cutaneous MyHTMs appears to be less
important for
mechanisms related to pathogenic pain than alterations in certain
C-fiber
nociceptors.



 Exp Neurol  1984 Apr;84(1):165-78

Responses of rabbit corneal nociceptors to mechanical and thermal
stimulation.

Tanelian DL, Beuerman RW.


 J Physiol  1981 Dec;321:355-68

Responses of cat corneal sensory receptors to mechanical and thermal
stimulation.

Belmonte C, Giraldez F.

"5. Damaging mechanical stimulation or the application of a strong
acid solution evoked a vigorous response followed by an earlier
discharge that persisted for hours. 6. The relation of these receptors
to other polymodal nociceptors and corneal sensation is considered."



 Fukushima J Med Sci 2001 Jun;47(1):13-20
                                                                      
                                           Accommodative
microfluctuation in asthenopia caused by accommodative spasm.

Kajita M, Ono M, Suzuki S, Kato K.

Department of Ophthalmology, Fukushima Medical University School of
Medicine, Fukushima City, Japan.

"BACKGROUND: Although many patients complain of eye fatigue caused by
accommodative spasm, there have been no reports of a good objective
examination method to diagnose it. PURPOSE: The spectral power of the
high frequency component of the accommodative microfluctuation
(spectral power of HFC) differs according to the constrictive degree
of the accommodation. In this paper, we expatiated upon our previously
reported analyzing processes of the spectral power of HFC, and we
investigated the relationship between normal subjects and subjects
with asthenopia. METHOD: The accommodative microfluctuation were
recorded when the subjects were looking at a stable target. The waves
of the accommodative microfluctuation were analyzed by FFT. RESULTS:
The spectral power of HFC for the distant target was 50-60 in the
subjects with normal vision, but it was higher in the subjects with
asthenopia. CONCLUSION: Our results suggested that the ciliary muscle
was also actively working in asthenopia caused by accommodative spasm
even if the patient was looking at a distant target."



Journal of Physiology (2 1), 533.2, pp.493–5 1
http://www.jphysiol.org/cgi/content/full/533/2/493
http://www.jphysiol.org/cgi/reprint/533/2/493.pdf

Differences between nerve terminal impulses of polymodal nociceptors
and cold sensory receptors of the guinea-pig cornea
James A. Brock, Svetlana Pianova and Carlos Belmonte

"Activation of the nociceptive nerve terminals in tissues such as skin
and joints generates action potentials that propagate both centrally
to cause painful sensations and locally, in the nerve terminal axons,
to trigger the release of neuropeptides producing neurogenic
inflammation. The mechanisms that control the excitability of
nociceptor terminals are largely a matter of speculation because of
their small size (< .5 Ám diameter) and their inaccessibility in
intact tissues like skin (see Belmonte, 1996). What is known has been
inferred indirectly from recordings from afferent axons when the
environment of the receptors is pharmacologically manipulated (e.g.
see Kress & Reeh, 1996). To investigate directly the mechanisms
controlling the excitability nociceptors, we recently developed an
extracellular recording technique that allows electrical activity to
be recorded from identified sensory nerve terminals in guinea-pig
cornea (Brock et al. 1998).

The cornea is very densely supplied by small-diameter sensory nerve
endings, which terminate in the most superficial layer of the corneal
epithelium (Belmonte et al. 1997). Three types of sensory receptor
(polymodal, mechano-sensory and cold-sensitive) are found in the
cornea (Gallar et al. 1993). Using a small-diameter suction electrode
(~5 Ám) applied to the surface of the cornea, nerve impulses can be
recorded and identified as originating in single sensory nerve
terminals (Brock et al. 1998). Activation of these terminals by local
stimuli enables them to be classified as belonging to one of the three
functional classes."

[...]

"DISCUSSION Differences between NTIs in polymodal and cold-sensitive
receptors

All the NTIs recorded from corneal polymodal nociceptors and
cold-sensitive receptor nerve terminals had a diphasic
(positive–negative) shape, with a prominent positive component.
Comparison between the NTIs recorded from polymodal nociceptors and
cold-sensitive receptors did, however, reveal two major differences.
Firstly, the average positive-peak amplitude of NTIs recorded from
polymodal nociceptors was smaller than that recorded from
cold-sensitive receptors. This difference in amplitude could reflect
the spatial relationship between the nerve terminals and the sites of
recording, with polymodal nociceptors terminating farther from the
epithelial surface than the cold-sensitive receptors. Alternatively,
the membrane currents generated at polymodal nociceptor terminals may
be smaller than those at cold-sensitive receptor nerve terminals. This
possibility may reflect structural and/or functional differences
between the two types of nerve ending. Secondly, the NTIs recorded
from polymodal nociceptors had faster maximum rates of change of
voltage during the downstroke of the NTI than during the initial
upstroke, while in cold-sensitive receptors the maximum rates of
change of voltage during the initial upstroke and the downstroke of
the NTI were very similar. This difference in time course suggests
that the currents underlying the NTIs may differ between polymodal
nociceptors and cold-sensitive receptor nerve endings. To appreciate
the possible reasons for this difference in time course it is
necessary to consider the factors that determine the configuration of
the NTIs. Diphasic NTIs similar in shape to those recorded in the
present study have been recorded extracellularly from motor nerve
terminals (Dudel, 1963; Katz & Miledi, 1965) and synaptic terminations
in the CNS (Brooks & Eccles, 1947), where their configuration can be
explained by either active or passive invasion of the nerve terminal
(see Smith, 1988). In both cases the recorded signal is proportional
to the membrane current at the site of recording, positive and
negative signals being produced by net outward and inward current,
respectively (see Fig. 4). The membrane current consists of both
capacitive and ionic components. If the nerve terminal is passively
invaded, the NTI is produced by the electrotonic spread of potential
from a point more proximal in the axon where the action potential
fails. In this case, where it is assumed there is no excitable ionic
current, the membrane current will be composed of a capacitive and a
resistive ionic component and the NTI will be positive during
depolarization of the nerve terminal and negative during
repolarization (Fig. 4A). If the nerve terminal is actively invaded
there is an additional excitable ionic current and this will be
reflected primarily in a speeding of the rate of the downstroke of the
NTI, which reflects the inward Na+ current at the site of recording
(Fig. 4B, t2). The later currents (i.e. K+ and Ca2+ currents) in the
action potential are poorly reflected in the NTI because they are
slower in activation and because, for much of the decaying phase of
the action potential, the magnitudes of the inward and outward ionic
currents are closely matched, leading to little net current across the
membrane (Fig. 4B, t3). The findings with bath-applied TTX and
lignocaine confirm that action potentials propagating in the
re-terminal axons are supported by Na+ influx and that TTX-resistant
Na+ channels alone are able to support action potential generation in
the sensory nerve terminals (see also Brock et al. 1998). However,
when bath applied, the Na+ channel-blocking agents will affect the
entire nerve axon, so it is not possible to discern whether the
observed effects on NTI configuration are due to local blockade of Na+
influx at nerve endings or to blockade at a point more proximal in the
axon. The possibility that NTIs in polymodal nociceptors and
cold-sensitive receptors are generated by voltage-dependent Ca2+
influx can be excluded as, in the presence of TTX, blockade of Ca2+
entry with Cd2+ did not prevent their occurrence (Brock et al. 1998).
Perfusing the recording electrode with lignocaine is expected to
restrict the effects of the local anaesthetic to the area of the
membrane where the signals recorded are being generated. Local
application of lignocaine to polymodal nociceptors produced a marked
slowing of the normalized maximum rate of change of voltage during the
downstroke of the NTI. This change is consistent with a blockade of
Na+ influx at the site of recording and provides clear evidence that
the terminals of polymodal nocice tors are able to support
regenerative, Na+ -dependent action potentials. In contrast, local
application of lignocaine to cold-sensitive receptors did not
significantly change the normalized maximum rates of change of voltage
during either the initial upstroke or the downstroke of the NTI. The
simplest explanation for this finding is that the nerve terminals of
the cold-sensitive receptors are passively invaded and that lignocaine
applied through the recording electrode did not reach the point of
action potential failure. Locally applied lignocaine did reduce both
the positive- and negative- peak amplitudes of the cold-sensitive
receptor NTIs. This finding demonstrates that locally applied
lignocaine did reach the cold-sensitive receptor nerve terminals and
can be explained if this agent reduces the leak conductance of the
nerve terminal membrane, as has been reported for crayfish stretch
receptor neurones (Lin & Rydqvist, 1999). These observations have
important implications for the functioning of the sensory nerve
terminals. The present findings do not resolve the site of action
potential initiation in the polymodal nociceptors, which may be
located proximal to the nerve terminal where generator potentials
spreading from a number of sensory endings are integrated and where
there is a high safety factor for triggering action potentials.
However, once initiated, action potentials can propagate both
orthodromically to provide information to the CNS and antidromically
to trigger the secretion of neuropeptides from the nerve terminals."


Journal of Physiology (2001), 534.2, pp.511–525 12243 511
http://www.jphysiol.org/cgi/reprint/534/2/511.pdf

Sensory experiences in humans and single-unit activity in cats evoked
by polymodal stimulation of the cornea

M. Carmen Acosta, Carlos Belmonte and Juana Gallar

"Peripheral nociceptive neurones are primarily characterised by their
response to one or several forms of energy at intensities near or
within the range of tissue injury (Sherring on, 1906 Bessou & Perl,
1969). In the skin and deep tissues of mammals including man, various
functional subclasses of nociceptive neurone have been categorised,
based upon the form of noxious energy (mechanical, chemical, thermal)
by which they are preferentially activated (see Campbell & Meyer,
1996). Microneurography and microstimulation in humans have provided
convincing evidence that excitation by noxious stimuli of the
peripheral axons of some types of primary nociceptive neurones
innervating he skin is accompanied by pain sensations (Torebj÷rk et
al. 1984  Ochoa & Torebj÷rk, 1989 Handwerker & Kobal, 1993). However,
it is unclear whether a qualitatively different experience is evoked
by selective excitation of each one of the various subpopulations of
primary nociceptive neurones.

The contribution to pain of primary sensory neurones activated by
innocuous mechanical and thermal stimulation is also still a matter of
controversy. It is generally accepted that in the skin mechanical
stimulation of neurones preferentially responding to low intensity
mechanical forces does not elicit pain except when there is abnormal
processing of peripheral information by the central nervous system
(CNS) (Torebj÷rk et al. 1992). Likewise, warming of the skin becomes
painful only when the population of polymodal nociceptive neurones is
recruited (Van Hees & Gybels, 1981 Campbell & LaMotte, 1983 Adriaensen
et al. 1984)."




The apparent absence of any light sensitive nociceptors and the
positive identification of mechanoreceptors and temperature and
chemical sensitive nociceptors tends to exclude the hypothetical
direct pain reaction to intense light and to confirm the speculations
of Grant and Belmonte as the best explanation currently possible for
the pain response to illumination.

Does this constitute an answer?

hlabadie-ga
Answer  
There is no answer at this time.

Comments  
Subject: Re: Nociceptors of the eye. Pain associated with bright light.
From: sublime1-ga on 22 Dec 2002 08:22 PST
 
pittneuromonkey...

I couldn't find any study that addresses your query,
however, if anyone is likely to know, it's this man:
C Belmonte, Past Secretary-General of the International
Brain Research Organization. His contact information
is on this page, along with a link to his mini-cv,
which cites innumerable references to research he
has done relating to ocular nociceptors:
http://www.ibro.org/docs/exec_comm.htm

If you obtain a satisfactory answer by contacting
him, let me know if you want me to post this as
an answer.

sublime1-ga
Subject: Re: Nociceptors of the eye. Pain associated with bright light.
From: pittneuromonkey-ga on 22 Dec 2002 09:44 PST
 
Thanks Sublime... if you find any other paths to try, please leave a
note. I e-mailed Dr. Belmonte, so I will keep you informed if I get a
good response. Well thanks again!

pittneuromonkey
Subject: Re: Nociceptors of the eye. Pain associated with bright light.
From: jcg-ga on 23 Dec 2002 02:35 PST
 
Dear Pittneuromonkey,

As a scientist, I appreciate your desire to get to the bottom of this.
 Suggest you contact Dr. Klaus Lucke in Bremen (Germany) at
k.lucke@retina-to.  Tell him Jessie sent you.  This may interest him
enough that he will take the time to provide you with an answer.  See
his website at www.retina-to.  Good luck.

JCG
Subject: Re: Nociceptors of the eye. Pain associated with bright light.
From: pittneuromonkey-ga on 23 Dec 2002 11:07 PST
 
JCG-

Thanks! Already E-mailed him. I hope dropping you name helps! Just out
of curiosity what kind of scientist are you and where are you located?

Thanks Again for your help!

PittNeuroMonkey
Subject: Re: Nociceptors of the eye. Pain associated with bright light.
From: pittneuromonkey-ga on 23 Dec 2002 19:23 PST
 
sublime1-

I got in contact with C belmonte and this is what he had to say:
*************
"...[previous research] showed that inside the eye, particularly in
the iris and anterior uvea there exist polymodal nociceptors,
mechano-nociceptors and some cold receptors (similar to those found in
the outer coats of the eye). We noticed that some of the nociceptors
in the iris respond to movements of the iris caused by light, but not
directly to light. Thus, it is unlikely a direct effect of light
stimulus on the nociceptor endings... My personal view is that
photofobia (pain caused by strong illumination) is due to mechanical
stimulation of nociceptors in the ciliary body due to the strong
contraction of the ciliary and iridal muscles. I wish you good luck in
your work..."
*************

So he also supports the 'mechanoreceptor theory'. I believe someone
should have done this research. I hope I have not stumpped the Google
Experts with this one. I know alot of them are trying. Dont give up!

Happy Hunting!

PittNeuroMonkey
Subject: Re: Nociceptors of the eye. Pain associated with bright light.
From: jcg-ga on 23 Dec 2002 23:43 PST
 
Dear PittNeuroMonkey,

Hey, you've got us all going!  Hope the combined effort turns up the
answer.  I am in SF Bay Area.  My Ph.D. is in Physiology and
Biophysics (1979).  After an early academic career (where I met
Lucke), I have been in the pharmaceutical and biotech sector, with a
great deal of satisfaction.  Keep the faith.

JCG
Subject: Re: Nociceptors of the eye. Pain associated with bright light.
From: hlabadie-ga on 25 Dec 2002 13:41 PST
 
I am reluctant to cliam that this is an answer, given that so many
people have been working on the question. If one breaks the problem
into sub-units, it becomes more manageable.

Based on the refined criteria of the question, I put this out for what
it is worth. One ought to be able to formulate a model of the system
from the original light stimulus through the complex reflex to the
eventual pain stimulus using the neuro-ophthalmic, chemical, and
mechanical aspects detailed in the research articles.

There are more related articles available. At least this should give a
foundation for more searches.


Ciliary reflex pathway:


 J Am Optom Assoc  1995 Jul;66(7):415-8 

The pupillary light reflex pathway of the primate.

Gamlin PD, Clarke RJ.

School of Optometry, University of Alabama at Birmingham 35294, USA.

BACKGROUND: Many studies of the pupillary light reflex pathway in
mammals have indicated that the pretectum is important for this
reflex. However, no single retinorecipient pretectal nucleus has been
unequivocally identified as being involved in the light reflex
pathway. In this study, anatomical studies in the rhesus monkey were
carried out to identify the relevant retinorecipient pretectal nucleus
and to better define the central pathway of this reflex. METHODS: An
injection of Wheatgerm Agglutinin/Horseradish peroxidase, a
neuroanatomical tracer, was placed under physiological guidance into
the Edinger-Westphal nucleus. Intravitreal injection of the same
tracer in another animal was used to define the pretectal retinal
terminal fields. RESULTS: Following injection of tracer in the
Edinger-Westphal nucleus, retrogradely labeled cells were found in
only one retinorecipient nucleus, the pretectal olivary nucleus. Most
labeled cells were located contralateral to the injection site. A few
labeled cells were located ipsilaterally. Intravitreal injection of
tracer resulted in anterograde labeling of all the retinorecipient
pretectal nuclei, including the pretectal olivary nucleus. The retinal
terminal field in the pretectal olivary nucleus coincided with the
location of the cells that were retrogradely labeled by the injection
of tracer into the Edinger-Westphal nucleus. CONCLUSIONS: These
results demonstrate that there is a direct projection from the
pretectum to the Edinger-Westphal nucleus, that it arises from only
one retinorecipient pretectal nucleus, the pretectal olivary nucleus,
and that cells in the pretectal olivary nucleus almost all appear to
project to the contralateral Edinger-Westphal nucleus.


 Brain Res  1993 Dec 31;632(1-2):260-73 

The peripheral and central projections of the Edinger-Westphal nucleus
in the
rat. A light and electron microscopic tracing study.

Klooster J, Beckers HJ, Vrensen GF, van der Want JJ.

The Netherlands Ophthalmic Research Institute, Department of
Morphology, Amsterdam.

The peripheral and central efferent projections of the rostral part of
the Edinger-Westphal nucleus in the rat were investigated at the light
and electron microscopic level by means of iontophoretic injections of
the anterograde tracer Phaseolus vulgaris-leucoagglutinin and
retrograde tracer injections of Fast blue and Nuclear yellow into the
facial nucleus and into the principal olive. Two pathways leaving the
rostral part of the Edinger-Westphal nucleus were studied, a
peripheral and a central descending pathway. Fluorescent experiments
demonstrated that the central pathway fibers originated from distinct
individual Edinger-Westphal neurons. These neurons were mainly
distributed throughout the rostral part of the Edinger-Westphal
nucleus and had fusiform cell bodies. The neurons rarely form
collateral projections. The central descending pathway left the
Edinger-Westphal nucleus medially and terminated bilaterally in the
principal olive, in the subnuclei A, B and C of the inferior olive and
ipsilaterally in the medial accessory olive. The central pathway also
terminated contralaterally in the lateral parabrachial nucleus, the
facial nucleus, the trigeminal brainstem nuclear complex, the lateral
reticular nucleus and the rostroventral reticular nucleus. The
projection to the facial nucleus provides evidence for the existence
of a polysynaptic loop forming the central part of the corneal blink
reflex. Projections from the Edinger-Westphal nucleus to the
cerebellar cortex or the deep nuclei, as described in cat and primate,
could not be confirmed. The peripheral pathway left the
Edinger-Westphal nucleus ventrally and terminated on dendrites of
ciliary ganglion cells, along smooth muscle cells of ciliary ganglion
associated arterioles and in the proximity of ciliary ganglion
associated venules. The central and peripheral terminals that
originate in the Edinger-Westphal nucleus all had similar
ultrastructural features: clear, round vesicles and electron dense
mitochondria. The terminals originating from the central descending
pathway were often found to be arranged in glomerular-like structures.
The central and peripheral terminals made asymmetric synaptic membrane
specializations (Gray type one), except terminals innervating the
ciliary ganglion associated vessels, which showed no synaptic
contacts.



 Brain Res  1995 Aug 7;688(1-2):34-46 

Efferent projections of the olivary pretectal nucleus in the albino
rat
subserving the pupillary light reflex and related reflexes. A light
microscopic
tracing study.

Klooster J, Vrensen GF, Muller LJ, van der Want JJ.

The Netherlands Ophthalmic Research Institute, Department of
Morphology, Amsterdam, The Netherlands.

The olivary pretectal nucleus is a primary visual centre sensitive to
luminance changes. It is involved in the pupillary light reflex, the
consensual pupillary light reflex and related reflexes, such as the
lid closure reflex whereby pupillary constriction takes place. Since
the olivary pretectal nucleus is a small nucleus, previous studies
using degeneration, horseradish peroxidase and radioactive amino acid
tracing were limited regarding to the exclusiveness of the projections
from the olivary pretectal nucleus. In the present study the position
of the olivary pretectal nucleus in the rat was first localized by
physiological recording of the neurons upon luminance stimulation.
Subsequently, an anterograde tracer Phaseolus vulgaris leucoagglutinin
was injected iontophoretically. This allows a much more precise
localization of the olivary pretectal nucleus projections. Ascending
and descending pathways originating from the olivary pretectal nucleus
were observed. Ascending fibres project bilaterally to the
intergeniculate leaflet, the ventral part of the lateral geniculate
nucleus and ipsilaterally to the anterior pretectal nucleus. In
addition, contralateral projections were observed to the zona incerta
and the fields of Forel. Descending fibres project bilaterally to the
periaqueductal gray, the nucleus of Darkschewitsch, the interstitial
nucleus of Cajal, the Edinger-Westphal nucleus and the intermediate
gray layer of the superior colliculus. Also a contralateral projection
to the oculomotor nucleus and an ipsilateral projection to the pontine
nucleus and the nucleus of the optic tract were found. Furthermore,
the contralateral olivary pretectal nucleus received a small
projection. Retrograde tracing experiments using two fluorescent dyes
revealed that the fibres projecting to the contralateral olivary
pretectal nucleus and to the contralateral interstitial nucleus of
Cajal are collaterals. The projection from the olivary pretectal
nucleus to the facial nucleus which has been described to receive an
input in cats could not be confirmed for the rat. The fact that the
Edinger-Westphal nucleus, the interstitial nucleus of Cajal and the
superior colliculus receive an input from the olivary pretectal
nucleus suggests that this primary visual centre is not only involved
in the pupillary light reflex, but also in controlling eye and head
position and saccadic eye movements. Although visual acuity largely
depends on receptive field sizes of retinal ganglion cells and their
central connections, the stronger sympathetic influence during the
pupillary light reflex in animals with frontally placed eyes compared
to animals with laterally placed eyes may also contribute to the
higher visual acuity in animals with frontally placed eyes.



 Arch Ital Biol  1984 Dec;122(4):311-9 

Projections from the Edinger-Westphal complex of monkeys as studied by
means of retrograde axonal transport of horseradish peroxidase.

Sekiya H, Kawamura K, Ishikawa S.

By means of retrograde axonal transport of horseradish peroxidase, an
experimental study was made in the Japanese monkey of the projection
from the anteromedian nucleus (AM) and Edinger-Westphal nucleus (EW)
to the ciliary ganglon, cerebellar nuclei and spinal cord. Special
attention was paid on the labeled cell forms. Neurons projecting to
the cerebellar nuclei or the spinal cord were small (8-11 microns in
diameter) and spindle-shaped, and they were located in almost the
entire parts of both AM and EW. On the other hand, cells which gave
off their axons to the ciliary ganglion were large (25-40 microns in
diameter) and oval/round in shape. Their locations were confined to
the medial parts of both AM and EW, except for the most caudal part of
EW. In addition, a few cells in the "nucleus of Perlia" were found to
project to the ciliary ganglion.



 Neuroscience  1994 Sep;62(2):481-96 

The anatomical substrates subserving the pupillary light reflex in
rats: origin of the consensual pupillary response.

Young MJ, Lund RD.

Department of Anatomy, University of Cambridge, U.K.

While the olivary pretectal nucleus has been shown to be central to
the pupillary constriction response in rats, it is not at all clear at
which level the consensual response is generated. To examine this we
have investigated the efferent projections of this nucleus, as well as
the effect of unilateral lesions of the olivary pretectal nucleus, on
the direct and consensual pupillary light reflexes. The results
demonstrate that the olivary pretectal nucleus projects bilaterally to
the Edinger-Westphal nucleus, as well as to the nucleus of the
posterior commissure, which itself projects bilaterally to the
Edinger-Westphal nucleus. The olivary pretectal nucleus also projects
to the ipsilateral ventral lateral geniculate nucleus. Unilateral
lesions of the olivary pretectal nucleus decrease, but do not abolish,
the direct and consensual pupillary light reflexes by as much as 66%.
Since some degree of consensual response remains, this is likely to be
due to the bilateral projection from the olivary pretectal nucleus,
either directly or indirectly through the nucleus of the posterior
commissure, to the Edinger-Westphal nucleus. These results show that
while the bilateral projection from the olivary pretectal nucleus to
the Edinger-Westphal nucleus contributes to the consensual pupillary
light reflex, the bilateral retinal projection to the olivary
pretectal nucleus is the more determinant component of the pathway. In
addition to providing insights into the anatomical substrates of the
pupillary response, this work also provides a background to ongoing
studies of the retinal graft-mediated pupillary light reflex, as well
as serving as a model of a relatively simple reflex system.



 J Neurophysiol  1983 Mar;49(3):582-94 

Connections of midbrain periaqueductal gray in the monkey. II.
Descending efferent projections.

Mantyh PW.

1. We have defined the descending efferent projections of the midbrain
periaqueductal gray (PAG) by injecting small amounts of [3H]leucine
into the various regions of the squirrel monkey PAG. 2. Despite the
fact that different regions of the PAG were injected in separate
animals, the majority of the brain stem areas labeled remained
constant. 3. The PAG exhibited a dense projection to the superior
colliculus, the nucleus cuneiformis, and the locus ceruleus. Parts of
the reticular formation (nucleus reticularis: pontis oralis, pontis
caudalis, gigantocellularis, magnocellularis, and ventralis) received
a projection from the PAG, as did the nucleus parabrachial pars
lateralis, ambiguous, the nucleus raphe magnus, and raphe pallidus. 4.
In contrast to the brain stem, the deep laminae of the nucleus
caudalis and the deep laminae of the cervical spinal cord were labeled
only after injections of the lateral aspect of the PAG. 5. The main
route for the PAG leads to brain stem projections is through the
lateral edge of the paramedian reticular formation. The great majority
of the anterograde labeling was ipsilateral to the injection although
a small contralateral projection was present. 6. These results
indicate that the PAG projects to the brain stem and spinal cord in
the monkey. Many of the brain stem areas that the PAG projects to are
known to project to the spinal cord. These secondary spinal
projections coupled with the direct PAG leads to spinal projection
provide a wide variety of routes through which the PAG may influence
spinal cord activity.



 J Comp Neurol  1991 Apr 15;306(3):425-38 

The Edinger-Westphal nucleus: sources of input influencing
accommodation,
pupilloconstriction, and choroidal blood flow.

Gamlin PD, Reiner A.

Department of Physiological Optics, School of Optometry, University of
Alabama, Birmingham 35294.

This study used neuroanatomical techniques to investigate sources of
afferents to the Edinger-Westphal nucleus (EW) of the pigeon. The EW
contains the parasympathetic preganglionic neurons that, by way of the
oculomotor nerve, project to the ciliary ganglion (Narayanan and
Narayanan, '76; Lyman and Mugnaini, '80). The ciliary ganglion, in
turn, innervates the internal musculature of the eye; the ciliary
body, the iris sphincter muscle, and the smooth muscle of choroidal
blood vessels (Marwitt et al., '71; Pilar and Tuttle, '82). In the
bird, the neurons in the ciliary ganglion that innervate the iris
sphincter muscle and the ciliary body receive input specifically from
cells in the lateral EW (EWl), whereas those that innervate choroidal
blood vessels receive input from cells in the medial EW (EWm) (Reiner
et al., '83). Thus neurons in the EWl mediate pupilloconstriction and
accommodation, whereas neurons in the EWm modulate choroidal blood
flow. To study the afferents to EW, injections of horseradish
peroxidase (HRP) were placed in this nucleus. These injections
resulted in labeled cells in the area pretectalis, a retinorecipient
pretectal nucleus and the suprachiasmatic nucleus, a retinorecipient
hypothalamic nucleus. We have previously identified both these areas
as being sources of afferents to EW (Gamlin et al., '82, '84). In
addition, these HRP injections into EW resulted in labeled cells in
the medial mesencephalic reticular formation (MRF) lateral and ventral
to the oculomotor nucleus and in a localized area of the rostral
lateral mesencephalic reticular formation (LRF) dorsolateral to
nucleus subpretectalis. Injections of tritiated amino acids into the
MRF labeled the entire EW, while such injections into the LRF labeled
only the lateral EW. Both of these projections were predominantly
contralateral. This study has identified the sources of two previously
undocumented inputs to the avian EW. Both sources of input, the MRF
and rostral LRF, receive afferents from visuomotor areas of the
telencephalon and visual structures in the midbrain. The MRF input to
EW could have either direct or modulatory influences on pupil
diameter, accommodation, and choroidal blood flow. The LRF input to EW
could play a role in controlling accommodation and possibly the
pupillary near response.




 J Comp Neurol  2000 Aug 14;424(1):111-41 

Periaqueductal gray matter projections to midline and intralaminar
thalamic nuclei of the rat.

Krout KE, Loewy AD.

Department of Anatomy and Neurobiology, Washington University School
of Medicine, St. Louis, Missouri 63110, USA.

The periaqueductal gray matter (PAG) projections to the intralaminar
and midline thalamic nuclei were examined in rats. Phaseolus
vulgaris-leucoagglutinin (PHA-L) was injected in discrete regions of
the PAG, and axonal labeling was examined in the thalamus. PHA-L was
also placed into the dorsal raphe nuclei or nucleus of Darkschewitsch
and interstitial nucleus of Cajal as controls. In a separate group of
rats, the retrograde tracer cholera toxin beta-subunit (CTb) was
injected into one of the intralaminar thalamic nuclei-lateral
parafascicular, medial parafascicular, central lateral (CL),
paracentral (PC), or central medial nucleus-or one of the midline
thalamic nuclei-paraventricular (PVT), intermediodorsal (IMD),
mediodorsal, paratenial, rhomboid (Rh), reuniens (Re), or caudal
ventral medial (VMc) nucleus. The distribution of CTb labeled neurons
in the PAG was then mapped. All PAG regions (the four columns of the
caudal two-thirds of the PAG plus rostral PAG) and the precommissural
nucleus projected to the rostral PVT, IMD, and CL. The ventrolateral,
lateral, and rostral PAG provided additional inputs to most of the
other intralaminar and midline thalamic nuclei. PAG inputs to the VMc
originated from the rostral and ventrolateral PAG areas. In addition,
the lateral and rostral PAG projected to the zona incerta. No evidence
was found for a PAG input to the ventroposterior lateral
parvicellular, ventroposterior medial parvicellular, caudal PC, oval
paracentral, and reticular thalamic nuclei. PAG --> thalamic circuits
may modulate autonomic-, nociceptive-, and behavior-related forebrain
circuits associated with defense and emotional responses. Copyright
2000 Wiley-Liss, Inc.


 Anat Embryol (Berl)  1998 Aug;198(2):123-32 

New indirect pathways subserving the pupillary light reflex:
projections of the accessory oculomotor nuclei and the periaqueductal
gray to the Edinger-Westphal nucleus and the thoracic spinal cord in
rats.

Klooster J, Vrensen GF.

The Netherlands Ophthalmic Research Institute, Department of
Morphology, Amsterdam.

The pupillary light reflex (PLR) is under the control of retinal
ganglion cells projecting to the olivary pretectal nucleus (OPN). The
OPN has a major projection to the Edinger-Westphal (EW) nucleus, which
exerts its parasympathetic action on the iris musculature via the
ciliary ganglion. The accessory oculomotor nuclei (AON) and the
periaqueductal gray (PAG) receive input from the OPN and influence the
PLR. The present study in rats aimed to elucidate the possible
projections from the AON and PAG to the EW nucleus. The anterograde
tracer Phaseolus vulgaris leucoagglutinin (PHA-L) was
iontophoretically injected into the interstitial nucleus of Cajal
(INC), the nucleus of the posterior commissure (NPC), the nucleus of
Darkschewitsch (ND) and the rostral part of the PAG. The projections
were studied at the light and electron microscopic level. The INC, NPC
and ND have small projections to the EW nucleus, whereas the rostral
part of the PAG densely projects to the EW nucleus. Without exception
INC, NPC, ND and PAG varicosities are presynaptic to dendritic
profiles in the EW nucleus and contain electron dense mitochondria,
round vesicles and make asymmetric synaptic contacts. In addition the
ND and PAG project to the thoracic level of the spinal cord. The
fibres are presynaptic to dendritic profiles and contain electron
dense mitochondria, round vesicles and make asymmetric synaptic
contacts. The present observations allow the conclusion that the
parasympathetic preganglionic neurons in the EW nucleus are not only
controlled by the OPN-EW pathway but also by indirect pathways running
via the AON and PAG. Moreover light-sensitive information is also
transferred via an OPN-PAG-spinal cord pathway to the sympathetic
superior cervical ganglion (SCG) that innervates the iris, suggesting
that the PAG may have an integrative function in the sympathetic and
parasympathetic control of the PLR.



 Vis Neurosci  1996 Jul-Aug;13(4):655-69 

Central neural circuits for the light-mediated reflexive control of
choroidal blood flow in the pigeon eye: a laser Doppler study.

Fitzgerald ME, Gamlin PD, Zagvazdin Y, Reiner A.

Department of Anatomy and Neurobiology, University of
Tennessee-Memphis 38163,
USA. malinda@nb.utmem.edu

Electrical stimulation in pigeons of the input from the medial
subdivision of the nucleus of Edinger-Westphal (EWM) to the choroidal
neurons of the ipsilateral ciliary ganglion, which themselves have
input to the choroidal blood vessels of the ipsilateral eye, increases
choroidal blood flow (ChBF). Since the EWM receives input from the
contralateral suprachiasmatic nucleus (SCN), which in turn receives
contralateral retinal input, the present study sought to determine if
activation of the SCN by microstimulation or by retinal illumination
of the contralateral eye would also yield increases in ChBF in that
same eye. Using laser Doppler flowmetry (LDF) to measure ChBF, we
found that electrical activation of the contralateral SCN by 100-Hz
anodal pulse trains yielded increases in ChBF that were stimulus
related and proportional to the stimulating current. These increases
in ChBF elicited by the SCN stimulation were accompanied by increases
in choroidal volume (vasodilation), but not by increases in systemic
blood pressure. Furthermore, the increases could be blocked reversibly
by lidocaine injection into the EWM. These results suggest that the
increases in ChBF in the eye contralateral to the SCN stimulation were
specifically mediated by the SCN-EWM pathway. Retinal illumination
with a fiber optic light source was also found to increase ChBF in the
illuminated eye, and these effects too could be blocked reversibly
with lidocaine injection into the EWM or permanently by the EWM
lesion. Control studies confirmed that the light-elicited increases
were mediated by increases in choroidal volume (i.e. vasodilation),
were not accompanied by systemic blood pressure increases, and were
not artifactually generated by transocular illumination of the LDF
probe. Thus, the SCN-EWM circuit may be involved in regulating ChBF in
response to the level of retinal illumination and/or the visual
patterns falling on the retina.




Contractile Mechanisms:

 Kaibogaku Zasshi  1999 Oct;74(5):577-86 

Lattice-like collagen fiber meshwork in the iris stroma of the cat: a
possible mechanism to generate the tension directed towards the iris
root which is required for pupillary dilatation in the
sympathectomized eye.

Sakuraba M, Yun S, Ichinohe N, Yonekura H, Shoumura K.

Department of Anatomy, Hirosaki University School of Medicine, Japan.

NaOH digestion technique for collagen fiber dissection and scanning
electron microscopy demonstrated a lattice-like meshwork in the
anterior surface of the iris stroma of the cat. The mesh threads were
made of collagen fibril bundles. In the constricted pupil, the meshes
were square to rhomboid with the diagonals in the direction of the
radius or circumference of the iris. In the dilated pupil, however,
the meshes were strongly flattened rhomboid or ellipse with a longer
diagnoal or axis in the circumferential direction. At the mesh corners
facing the pupillary margin or the iris root, the collagen fibril
bundles were strongly bent in the iris of the constricted pupil, while
they were almost straight or slightly wavy in the iris of the dilated
pupil. Accumulation of elasticity tension generated by this small
distortion of the iris-mesh threads in the constricted pupil was
considered to generate a tension directed towards the iris root, which
is required for pupillary dilatation in the sympathectomized eye. On
the posterior surface of the iris stroma, numerous thin pleats tightly
woven with collagen fibrils traversed straightway through the radial
length of the ciliary zone of the iris in both constricted and dilated
pupils. The structural changes of these pleats in miosis and mydriasis
were very small compared with the meshwork of the anterior aspect of
the iris. Therefore, they were considered to work mainly as an iris
skeleton.


Brain-derived neurotrophic factor:


 J Neurosci  1999 Jun 15;19(12):5138-48 

Brain-derived neurotrophic factor modulates nociceptive sensory inputs
and NMDA-evoked responses in the rat spinal cord.

Kerr BJ, Bradbury EJ, Bennett DL, Trivedi PM, Dassan P, French J,
Shelton DB, McMahon SB, Thompson SW.

Neuroscience Research Centre, Guy's, King's, and St. Thomas' School of
Biomedical Sciences, Kings College London, London SE1 7EH, United
Kingdom.

Central sensitization, the hyperexcitability of spinal processing that
often accompanies peripheral injury, is a major component of many
persistent pain states. Here we report that the neurotrophin,
brain-derived neurotrophic factor (BDNF), is a modulator of
excitability within the spinal cord and contributes to the mechanism
of central sensitization. BDNF, localized in primary sensory neuron
cell bodies and central terminals, potentiates nociceptive spinal
reflex responses in an in vitro spinal cord preparation and induces
c-fos expression in dorsal horn neurons. NMDA receptor-mediated
responses, known as a major contributor to central sensitization, were
significantly enhanced by exogenous BDNF. Systemic NGF treatment, a
procedure that mimics peripheral inflammatory states, raises BDNF
levels in sensory neurons and increases nociceptive spinal reflex
excitability. This increased central excitability is reduced by
trkB-IgG, a BDNF "antagonist." We also show directly that inflammatory
pain-related behavior depends on BDNF release in vivo. Thus behavioral
nociceptive responses induced by intraplantar formalin and by
intraplantar carageenan are significantly attenuated by trkB-IgG.
Hence BDNF is appropriately localized and regulated in inflammatory
states and is sufficient and necessary for the expression of central
sensitization in the spinal cord. We propose that BDNF may function as
a modulator of central sensitization in pathological states, and our
results suggest that pharmacological antagonism of BDNF may prove an
effective and novel analgesic strategy for the treatment of persistent
inflammatory pain states.



Ciliary nociceptors:


 Eur J Neurosci  1999 Mar;11(3):899-906

c-Jun expression after axotomy of corneal trigeminal ganglion neurons
is dependent on the site of injury.

De Felipe C, Belmonte C.

Instituto de Neurociencias, Universidad Miguel Hernandez, Ap. Correos
18, 03050 San Juan, Alicante, Spain. cdf@umh.es

The proto-oncogene c-Jun has been implicated in the control of
neuronal responses to injury and in axonal growth during regenerative
processes. We have investigated the expression of c-Jun during normal
terminal remodelling in trigeminal ganglion neurons innervating the
cornea and after acute injury of epithelial nerve terminals or parent
axons. Remodelling and rearrangement, or damage limited to corneal
epithelium endings, was not a trigger for activation of c-Jun
expression. However, injury of parent axons in the stroma or in the
orbital ciliary nerves induced c-Jun expression in 50% of the
population of corneal neurons, which included all of the large
myelinated and 20% of the small neuropeptide-containing corneal
neurons. This suggests that c-Jun expression in trigeminal ganglion
neurons is not associated with normal remodelling or regeneration of
peripheral nerve terminals, and that it takes place only when parent
axons are injured. A substantial number of damaged neurons do not
express c-Jun, indicating that in primary sensory neurons, injury and
regeneration may not always be coupled to the expression of this
proto-oncogene.



 Invest Ophthalmol Vis Sci  1995 Jul;36(8):1615-24

Sensory receptors in the anterior uvea of the cat's eye. An in vitro
study.

Mintenig GM, Sanchez-Vives MV, Martin C, Gual A, Belmonte C.

Departmento de Ciencies Fisiologiques Humanes i de la Nutricio,
Universitat de Barcelona, Spain.

PURPOSE. To identify electrophysiologically the functional types of
sensory fibers innervating the iris and the ciliary body of the cat's
eye. METHODS. The uveal tract tract of cat's eye was excised and
placed in a superfusion chamber. Recordings were made from single
afferent units of ciliary nerve branches responding to mechanical
stimulation of the iridal surface, the ciliary body, and the choroid
with a nylon filament or a glass rod. Chemical sensitivity was
explored by applying acetic acid, hypertonic NaCl, and bradykinin.
Warm (60 degrees C) and cold (4 degrees C) saline and a
servocontrolled thermode were used for thermal stimulation. RESULTS.
Thirty per cent of the studied population of sensory units (n = 95)
were spontaneously active when the recording was started.
Approximately 30% of the fibers conducted in the lowest range of the
A-delta group; the remaining 70% were C fibers. Sustained mechanical
stimulation of the receptive area elicited a tonic response in
approximately 60% of the units, and a phasic response in the remaining
40%. Exposure of the receptive field of mechanosensitive fibers to 600
mM NaCl evoked a long-lasting discharge in 50% of the units;
application of 1 to 10 mM acetic acid elicited a short discharge in
30% of the fibers, often followed by inactivation. Bradykinin (1 to
100 microMs) produced a long-lasting response in almost 50% of the
units. Warming the receptive field recruited 20% of the explored
units, whereas 17% were activated by low temperature. CONCLUSIONS. Two
main functional types of sensory fibers innervating the iris and the
ciliary body were distinguished: (1) mechanoreceptors, corresponding
to afferent units sensitive only to mechanical stimuli were generally
silent at rest, had relatively higher force thresholds, and discharged
phasically in response to long-lasting mechanical stimulation; (2)
polymodal nociceptors, which were activated by mechanical as well as
by chemical and/or thermal stimuli, usually displayed spontaneous
activity, had lower force thresholds, and fired tonically upon
sustained mechanical stimulation.



 Exp Neurol  1984 Apr;84(1):165-78

Responses of rabbit corneal nociceptors to mechanical and thermal
stimulation.

Tanelian DL, Beuerman RW.

We recorded 116 units from dissected strands of the long ciliary nerve
of rabbit and tested them with punctate mechanical, cool, or warm
stimulation. Seventy-two percent of the units responded only to
mechanical stimulation, 17% responded only to cooling, and 11% were
bimodal, responding to both warming and mechanical stimulation.
Mechanical responses were rapidly adapting and decreased on successive
stimulation at the same locus. Conduction velocities determined for 43
mechanical units were in the same low range of the A-delta group (mean
= 2.71 m/s). Receptive fields for all classes of units found here
overlapped and did not extend beyond the center of the cornea. Precise
determination of field size for 20 mechanical units showed that most
included 5 to 20% of the corneal surface and a few extended to about
40%. Activation of units responding to stimulation below the adapting
temperature (33 degrees C) showed them to be sensitive to cooling
steps of 0.5 degrees C. The average conduction velocity of five cold
units was 0.94 m/s. Bimodal units were not active at 33 degrees C and
responded to warming above 39 degrees C with an increased discharge
frequency; however, the response did not include an initial
high-frequency discharge as did that of the cool units.



 J Physiol  1981 Dec;321:355-68

Responses of cat corneal sensory receptors to mechanical and thermal
stimulation.

Belmonte C, Giraldez F.

1. The afferent responses evoked by mechanical and thermal stimulation
of the cat cornea were recorded extracellularly from strands of long
and mixed ciliary nerves under deep anaesthesia. 94% of the units
studied (n = 53) responded consistently to both stimuli. 2. Conduction
velocities, measured by electrical stimulation of the receptive field,
corresponded to the lower range of the A-delta fibre group (average =
5.4 m/sec). Receptive fields covered approximately a quadrant of the
corneal surface and showed continuous sensitivity and overlapping.
Units were silent in the absence of stimulation but an ongoing
activity was commonly present after repeated mechanical and thermal
stimulation. 3. Mechanical responses were evoked at low thresholds and
consisted of a dynamic and static response that paralleled the
amplitude of the stimulus. The pattern of the discharge was irregular
and fatigue was easily developed by repeated stimulation. 4.
Thresholds to heating were above 38 degrees C and the response
increased monotonically with the temperature over the range from
threshold to 50 degrees C. The heat response could be sensitized by
repeated long suprathreshold stimulation while variable changes in the
response were induced by briefer stimuli. Also depression was observed
in some circumstances. A weak response to cooling was present in 50%
of the units tested. 5. Damaging mechanical stimulation or the
application of a strong acid solution evoked a vigorous response
followed by an earlier discharge that persisted for hours. 6. The
relation of these receptors to other polymodal nociceptors and corneal
sensation is considered.


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