Developmental neuroanatomy and neurophysiology of pain

1. Article Lead Author: Fitzgerald, Maria Date: ?
Article: Developmental Neuroanatomy and Neurophysiology of Pain
1. Pain felt at:
a. If the article specifically asserts unborn children feel pain, at what post­
fertilization age?
b. Page: 12, Left Column, First Paragraph. " ...there is little doubt that pain
responses exist even in the youngest preterm infant."
2. Nociceptors:
a. Ifthe article states nociceptors are present, at what post-fertilization age?
b. Page: 12, Left Column, Second Paragraph. "The properties of the peripheral
nociceptors, at birth, are analogous to those of mature nociceptors."
3. Thalamus link:
a. If the article states nerves link nociceptors to the thalamus, at what post­
fertilization age?
b. Page:
4. Subcortical plate link:
a. If the article states nerves link to the subcortical plate, at what post-fertilization
age?
b. Page:
5. Noxious stimuli reaction:
a. Does the article refer to reaction to noxious stimuli? At what post-fertilization
age?
b. Page :
6. Stress hormones:
a. Does the article refer to increase in stress hormones with noxious stimuli? At
what post-fertilization age?
b. Page:
7. Long-term effects:
a. Does the article describe long term harmful effects from exposure to noxious
sti muli?
b. Page:
8. Fetal anesthesia:
a. Does the articl e refer to use of fetal anesthesia and its effect? At what post­
fertilization age?
b. Page: 15, Left Column, Second Paragraph. "This response is a permanent one,
whereby the injury results in a structural and functional reorganization of the
nervous system and alters the final adult pattern of connections."

2. Page: 15, Left Column, Third Paragraph, "However, in many cases, developing
neural processes require particular conditions at critical times in order to
develop normally."
9. Cortex:
a. Does the article relate to the asserted need for cortical involvement to
experience pain? How?
b. Page:
10. OTHER
a. Page: 12, Right Column, Last Paragraph. "Recent evidence has shown that the
cingulated gyrus is especially important in the emotional and attentional
aspect of pain and it would be interesting to know something of the
development of this region."

3. 2
Developmental Neuroanatomy
and Neurophysiology of Pain
Maria Fitzgerald
K.J.S Anand
Although the study of the developmental TIME COURSE OF PAIN
neurobiology of pain pathways is stili very RESPONSES
new, we are beginning to gain some insights
into how pain responses become organized In the mid-1980s an important change took
in infancy. In this chapter our present place in the study of pain. Patrick Wall pu-:---_ _ _ _~
knowledge of the structural and functional lished a paper entitled "Future Trends in
development of pain pathways will be re­ Pain Research" (2) in which he pointed out
viewed . To do this effectively we have that the scientific study of pain had been re­
drawn on principles established in two other stricted to the instant events that follow a
areas of neurobiology. The first of these is noxious stimulus, and that while these
the general developmental processes that events were important, clinical pain often in ­
underlie the growth and maturation of the volved much longer-term events. Pain, it
nervous system. These are important be­ was argued, falls into different time ep ­
cause they provide the context within which ochs-the immediate pain lasting seconds or
immature pain mechanisms are operating. minutes, the medium-term pain lasting
The second is the study of adult pain path­ hours or days, and the longer-term pain last ­
ways, which are important because they ing weeks or years. Although all three ep ­
provide an end point toward which devel ­ ochs are important, they are not equal in
oping pain pathways are heading. Research­ terms of human anguish. The mechanisms
ers interested in pediatric pain need to keep involved may be the same for each epoch,
abreast of ad vances in both these areas to differing only in time course, but it is becom ­
fully comprehend how infants and children ing increasingly evident that different mech ­
respond to pain and to noxious stimuli. anisms are involved in longer-term acute
Much of our knowledge of the basic bi ­ and chronic pain. Now, in the early 1990s
ology of pain development has been ob ­ we are becoming more aware of the ability of
tained fro m studies on laboratory rats. Rats the nervous system to switch on long­
~nd h umans hav e different developmental lasting changes in response to certain stimuli
~l me ta bles, bu t the basic sequence of events and we are increasing our research into
In the ma tura tion of sensory systems are the such longterm responses to noxous s timuli .
s am in both species. Comparative studies of (3, 4) .
somatos nsory and motor development
show th at a lthough rats are relatively im ­
ma ture at birth, at ap p roximately the same IMMEDIATE PAIN RESPONSE
sta.ge as a hu man infan t is at 24 weeks ges­ A n oxious stimulus results in an immediate
ta tIOnal age, rats' d velopment is h igh ly ac­ response in both the somatic and autonomic
celerated (1). For th purpose of this chap ter, nervous sys tems (Fig. 2.1A) . In ma ny cases
therefore, data o bt ained from newborn rats the response is a p ro tective one, su h s the
relate to prematu r human infants and data withdrawa l flexion refl x. That uch pail re­
from 2- to 3- week -old rats to infants d uring ponses exi t in neonates has been a subject
their first year . of considerab le study (5-9). Despite some
11

4. 12 / 1 Theoretical Background
variability and a certain lack of spedfidty in- - very slow synaptic-ttansmission;-with-pro--­
the responses resulting in difficulties in mea­ longed synaptic delays, rapid adaption, and
surement, there is little doubt that pain re­ habituation for some considerable time (12,
sponses exist even in the youngest pretenn 18). Furthermore, lack of local inhibitory l!:!I!:rul!
infant. control produces large receptive fields and ~
activati
Examination of the anatomical and phys­ prolonged responses during the postnatal immature n,
iological development of the pathways in­ period (18). Thus, the after-discharge of a path'.l
-- - ---_ -YQI-yeg tn the~~E~e..o~~es reveals that neural dorsal nom cell is often greater than its initial
elements are in place frama-neaTly Stageof··­ -Tesponse--t~ti-m-ulus-.-.Jn..£act,jhepr:o-<iuJ::: __ ___._. _ _ _ _.
_
development and continue to mature well tion of large receptive fields and prolonged
into postnatal life. In the rat, peripheral no­ responses might increase the chance of
ciceptors, both those with Ao and C fibers, transmission in a weakly connected system,
develop soon after cutaneous axons reach because it greatly reduces precision and in­
the skin, early in fetal life (10). The proper­ creases preservation of stimulus timing and
ties of the peripheral nociceptors, at birth, intensity. Local spinal intemeurones in sub­
are analogous to those of mature nociceptors stantia gelatinosa are the last spinal neuron
(11). Large diameter dorsal root fibers grow system to mature, only beginning postna­
into the cord first and small diameter C fibers tally (15). Levels of enkephalin, a neuropep­
later, just before birth. The response of fetal tide in many of these neurons and known to
. - - - - - - --- dors-al -horn-neurons--to-botM'm~ing-and inhibU C-flber transmitter releas~, are very
pinching the skin must therefore be trans­ low in the neonatal cord(IO}l"aann(idntrrhife·jpi1io[)!s;;tt::-~----'--"--'--'-'---~
, - ·
mitted by large A fibers (12). When A fibers natal opiate receptor changes in sensitivity
grow into the spinal cord they rapidly pro­ and distribution are considerable (19, 20).
duce synaptically evoked activity in dorsal It is not clear whether central postsynap­
hom cells; however, this is not true of C fi­ tic excitation by C fibers is equally immature
bers which do not produce spikes in dorsal in the human neonate; however, immaturity
hom neurones until the end of the first post­ may be one explanation for the somewhat
natal week (13). The reason for the long unreliable nature of the immediate newbom
delay between the arrival of C fibers in the pain response and the difficulty in measur­
spinal cord and their ability to excite dorsal ing a consistent change to noxious stimuli.
hom ceUs is not clear. It may reflect slow Immediate pain responses at higher levels
maturation of presynaptic (14) or postsyn­ of the nervous system will, of course, de­
aptic (15) elements in the neonatal spinal pend on the output of the spinal cord (or
cord, in adequate transmitter levels (16), or equivalent levels of the trigeminal system) .
imma ture pharmacological receptor proper­ Little is known of the maturation of projec­
ties (17). tion pathways and of thalamic and cortical
The functional importance of this long connections in relation to pain processing. In
delay in C fiber functional maturation lies in the rat spinal cord, projection cells develop
the fact that C fibers are the main group of prenatally and their axons reach the thala­
nociceptors responsible for transmitting mus around birth (15); in the human spinal
chemical and thermal as well as mechanical cord, lamina I (some of which project ros­
noxious inputs to the central nervous sys­ trally) cells are mature by 25 weeks (21).
tem. Thus, the peripheral nociceptors are Evoked potentials in the rat somatosensory
un able to produce a rapid postsynaptic spike cort x from the forepaw develop the adult
response in the CNS that will be propagated form by P12 (22). Evoked potentials in hu- Figure 2.1.
to rugher levels even though the peripheral mans suggest that thalamic inputs reach the to the foot a
receptors can " recognize" pain . When C fi ­ cortex at 29 weeks (23) and this is supported spinal cord.
b r do begin to evoke rapid spike responses by anatomical studies (24) . Unfortunately, velopmen t .
centrally, they still require a consid rable pe­ this tells us little about the analysis of nox­ tablished pi
termin a ls. I
n od of time to mature. Indeed, levels of neu­ ious inputs in the infant cortex. Recent evi­ peralgesia i'
ropeptides such as su bs tance P ( P) in small de nce has shown tha t the cingula te gyrus is sidered . C.
diameter sensory afferents reach adul llevels especiall y importan t in th e em otiona l and al - dam ge of I
at about P (postnatal day) 2 1 ( 16), whereas tentional aspect of pain (25,2 6) and it wou ld tionaI reorg
SP receptor d istri ution is not dense and be int resting to know something of the de- to p rman c
widesprea d until P60 (17). This results in ve lopm n t of this regi n.

5. 2 / Neuroanatomy a/ld Neuropllysiology of Pain / 13
Sensation Sensation
-Established Pain
Immediate Established Pain
Response Response
activation 01 activation 01
immature nociceptive long term processes
pathways in immature nociceptive
pathways
~
. .'. 'Sensitization'
. - --;~~: ':... - ­ ._-_. _ ... . -.­
--_
J ,-<'
trvo o Altered
excitability
Reflexes
Sensation
Long Term
Effects
permanent structural
changes in
sensory pathways
Cell I
d~
~ ISp,"oliog
A,,,,,,, U
Figure 2.1 . A, A schematic diagram of the immediate pain response in the neonate. A noxious stimulus
to the foot acti vates nOciceptor primary afferents which in turn produce rapid postsynaptic events in th e
spina l cord . These can evoke reflexes and excite projection pathways to higher brain centers . The de­
velo pment and maturation of all these steps need to be considered . B, A schematic diagram o f the es­
ta blished pain response in the neonate. An injury in the peripheral tissue will sensitize local nociceptor
t ~rmi n a l s . It will also Tesult in altered levels of excitability in central cells leading to tenderness and hy­
peralgesia in the affected area. The development and maturation of these mechanisms needs to be con­
Sid ered . C. A schematic dia gram of the longterm effects of peripheral injury in the newborn. Axonal
d amage of local n rves w ill lead to permanent cell death in the dorsa l root ga n glia . Stru ctural and fun c­
tilln al reurgani zation occurs in th e eNS as a res ult f sproutin g and alte red con necti vit y wh ich m ay lea d
t I l perma nent ly altered sens a tion.

6. .L J fIt:Ult:llLUI vacKground
ESTABUSHED PAIN RESPONSE important to study the maturation of long­ ', . function.
IN NEONATES lasting painful events in the spinal cord and "'>'~ mechani:
brain. Several transmitter receptor systems, ~ which d,
An established pain response is one that out ­ e.g., for peptides and the glutamate NMDA newborn
lasts the initial noxious stimulus (Fig. 2.18). receptor, have been implicated in prolonged .f cating fa
The response lasts for hours and days, not postsynaptic responses to noxious stimuli (3, apses an.
seconds and minutes. It is this response that 4). Despite low levels of neuropeptides in af ­ sion dUll
is most important clinically, and as yet its de ­ ferent terminals in the newborn, stimulation might bE
velopment has not been well studied. Pre­ of C fibers does produce substance P release recepton
mature infants clearly mount a metabolic in the neonatal spinal cord (33). Further­ onstrate(
stress response postoperatively that can be more, stimulation· of C fibers produces a appearar
blunted or blocked by the intravenous ad­ long-lasting depolarization of motoneurons tions ne'i
ministration of opioids. (27). Crying is in­ that far outlasts the stim!:!.I.l!~'(31),S1Jch_a_de: .. it may nc
_ - - - - _ " _ .creased.JOl:.sevemltiays-ft>Hmving-circumdc pOliii'iZanon-lslifocked by SP antagonists findings .
sion (28). In our own study, the sensitivity of (33) and might be expected to result in long­ knowled
the skin of the heel following repeated lanc­ lasting changes in excitability of those mo­
ing over days and weeks was shown to be el­ toneurons. In the dorsal hom, where, as dis­
evated, indicating a lasting hyperalgesic re ­ cussed above, C-fiber stimulation in the ne ­ LONG'
sponse to the injury (29,30). onate does not produce a spike response that TISSUl
To understand the mechanisms underly ­ can be propagated to higher levels (13), such
ing the established pain response and find long-lasting changes in excitability have A third I
ways of measuring it, we must search for been demonstrated. Mustard oil, a specific beyond I
CNS processes that are initially triggered by C-fiber stimulus, has no direct effect on neo ­
a noxious stimulus or in but that last for na@l dOI:!ial horn cells. but doesincre.ase ·their­ - - .. - - .. -_
._-,.,...." '"
a
nv("v.·" in es­ noxious stimuli (1). an increase In cen ­
tablishing a prolonged response to injury in­ tral excitability is analogous to that proposed nervouS :
volves sensitization of peripheral sensory re ­ in the adult to underlie hypersensitivity or tern of CI
ceptors. In the adult rat, monkey, and allodynia in the site of an injury (3, 4). It is (
human, the threshold of cutaneous nodcep ­ A search for molecular and chemical nervous
tors to a noxious stimulus and the magnitude changes underlying persistent neuronal ery than
of the response produced by peripheral sen­ changes in the CNS has led to considerable cases, d,
sory receptors can be increased for hours fol­ interest in the role of proto-oncogenes, such particula
lowing injury. This occurs whether the in ­ as c-fos, as "third messengers" in longterm to devel(
jury occurs directly to the receptor or within responses. In the adult, c-fos is rapidly ex­ is the del
its receptive field (see reference 31 for re ­ pressed in the spinal cord, brainstem nuclei, sory neu
view). As yet, the ability of immature pe­ thalamus, and cortex following noxious tissues d
ripheral n Ociceptors to become sensitized stimulation or injury (for review see refer ­ sensory
following noxious stimulation is unknown. ence 35). A similar expression is seen in new ­ stage of '
However, on e related property of peripheral born rats (36) following peripheral injury will be CI
nociceptors, namely, the production of neu ­ but not with pure C-fiber stimuli. of the de
rogenic edema, is not functional in the new ­ In adults, established pain responses are trophic S
born. Neurogenic edema is an inflammatory thought to also involve activation of a num ­ by nervE
response resulting in plasma extravasation ber of endogenous pain control systems. duced in
which is produced by antidromic activation One of these is the descending inhibitory to the c(
of polymodal nociceptors by way of an axon fiber tracts from the brainstem, which act to from ax,
reflex mechanism. Newborn rats, while per ­ reduce the activity of spinal -cord cells nous N(
fectly capable of producing a nonspecific in ­ evoked by noxious inputs (37). This system only tru
flamma tory response, do not develop neu­ is not functional in the newborn and only cells; m(
rogenic edema until PI 0 (32) . The reason for begins its actions on postnatal day 10 (38) . spinal c(
this is not know n, but may be caused by in ­ The reason for this is unclear because the de­ cut off I
adequ a te levels of the appropriate media ­ scending axon tracts are apparently present men. Ft:
tors . from before birth (39) . The delayed postna­ onal da:
E ta blished pain responses are likely to tal fu nction likely reflects low transmitter nerve dt:
involve centra l m echanisms; th erefore, it is le vels (40) or low pharmacological receptor going be

7. 2 / Neuroanatomy alld Nellrophysiology of Pain / 15
function. A further endogenous control ies. The death of these peripheral neurons
mechanism is the release of endorphins leaves an area of deafferentation in the spi­
which does appear to be established in the nal cord . This causes severe retardation of
newborn (see reference 7). Further compli­ postsynaptic growth, and the somadendritic
cating factors are the role of transient syn­development of second order spinal-cord
apses and receptor and transmitter expres­ cells is virtually arrested (45). Furthermore,
sion during development. Examples of this nearby intact sensory neurons send collat­
might be high-density or poorly organized eral sprouts considerable distances into the
receptors (17) or, as has recently been dem ­deafferented area of the cord and form syn­
onstrated in the developing spinal cord, the aptic connections within the region (46, 47).
appearance of functional receptor popula- This means that, now, totally inappropriate
.. t!QI1.snever seen in the adult (41). As a result
cord regions, normally devoted to inputs
it may not alwciysbeappropriiite fo iriterpn'lfrom the damaged area, are processing in­
findings in the immature CNS in the light of formation from nearby undamaged skin. In
knowledge of adult mechanisms. other words, the nearby skin areas have a
greater than normal representation in the
CNS . This reorganization is also observed in
LONGTERM RESPONSES TO the trigeminal regions following facial inju­
TISSUE INJURY ries (48). The effects are not restricted to the
first synapse either, but continue on up
A third type of response to injury goes far through the CNS. Peripheral nerve injury in
beyond the immediate and established pain the neonate alters connections in the thala­
responses discussed in the pr.!?y:i9u~ secti9ns mus and the somatosensory cortex (49, SO),
---------~~.-kJ~)~~~~~~s~m~~~s~a-~~tinaI~nL--f~~~~~ll~~~orgrr~0n~p~~·~~~ti~·b~n~o~f-- ----~
· · · · ·· ·
one, whereby the in results a struc- the bOdy surface, or map,
tural and functional reorganization of the brain. Secondary transneuronal degenera­
nervous system and alters the final adult pat- tion even of the corticospinal tract (CST) has
tern of connections. been induced after nerve section in newborn
It is commonly thought that the infant rats (51) .
nervous system has greater powers of recov - These longterm consequences of injury in
ery than that of the adult. However, in many laboratory rats are not simply early embry­
cases, developing neural processes require ological events of interest to developmental
particular conditions at critical times in order biologists, but have important implications
to develop normally (42). An example of this in human premature and full-term infants
is the dependence on trophic support of sen- who undergo painful experiences. For ex­
sory neurons provided by peripheral target ample, traumatic interventions of the kind
tissues during development. If a cutaneous that are necessarily undertaken in neonatal
sensory a xon is damaged during a critical intensive-care wards may well cause a simi­
stage of d evelopment, this essential support lar reorganization in the somatosensory and
will be cut off and result in irreversible dea th motor svstems as are seen in the rat model.
of the dorsal root ganglion cells (43, 44). The While ~e are discovering the nature of the
trophic support is provided, at least in part, new functional connections that can be
by nerve growth factor (NGF) which is pro- formed in the rat we still remain ignorant of
duced in target tissues and transported back what, if any, sensory disturbances such re-
to the cell bodies. The cell death resultin g organization may cause in human infants .
from axotomy can be prevented by exoge- Obvious Iv more research both in the labo­
nous N GF administration (43). This is not ratary and clinical setting is needed to fur-
only true of p eripheral sensory ganglion th er expa nd Our knowledge in this area.
cells; m toneurons and central cells in th e
spin al cord and brain die if their axons are
cut o ff from their targe ts during develop ­
APPLIED PHYSIOLOGY OF PAIN
men t. Furthermore, the con sequences of ax­ The previous sections describe experimental
on al damage t even a small p riphera l stu dies of the developmen tal neuroanatomy
nerve during de velopm e nt are fa r-reach in g, a nd neuro physiology of the pain system, de ­
going beyond the d eath of its own cell bo d - ta ilin g the effe cts of noci ceptive stimuli in

8. -
. 2 I Neuroanatomy and Nellrophysiology of Pain I 15
function. ~. further endogenous control ies. The death of these peripheral neurons
". mechanism is the release of endorphins leaves an area of deafferentation in the spi­
.;.which does ~ppe~r to be established in the nal cord. This causes severe retardation of
~bom (see reference 7). Further compli­ postsynaptic growth, and the somadendritic
cating factors are the role of transient syn­ development of second order spinal-cord
apses and receptor and transmitter expres­ cells is virtually arrested (45). Furthermore,
sion during development. Examples of this nearby intact sensory neurons send collat­
might be high-density or poorly organized eral sprouts considerable distances into the
receptors (1 7) or, as has recently been dem­ deafferented area of the cord and form syn­
onstrated in the developing spinal cord, the aptic connections within the region (46,47).
appearance of functional receptor popula­ This means that, now, totally inappropriate
tions never seen in the adult (41). As a result cord regions, normally devoted to inputs
it may not always be appropriate to interpret from the damaged area, are processing in­
findings in the immature CNS in the light of formation from nearby undamaged skin. In
knowledge of adult mechanisms. other words, the nearby skin areas have a
greater than normal representation in the
CNS. This reorganization is also observed in
LONGTERM RESPONSES TO the trigeminal regions following facial inju­
TISSUE INJURY ries (48). The effects are not restricted to the
first synapse either, but continue on up
A third type of response to injury goes far through the CNS. Peripheral nerve injury in
beyond the immediate and established pain the neonate alters connections in the thala­
responses discussed in the previous sections mus and the somatosensQry <;Qrtex (49, .'20), . .
one, whereby the the body surface, or somatotopic map, in the
tural and fu reorganization of the brain. Secondary transneuronal degenera­
nervous system and alters the final adult pat­ tion even of the corticospinal tract (CST) has
tern of connections. been induced after nerve section in newborn
It is commonly thought that the infant rats (51).
nervous system has greater powers of recov ­ These longterm consequences of injury in
ery than that of the adult. However, in many laboratory rats are not simply eady embry­
cases, developing neural processes require ological events of interest to developmental
particular conditions at critical times in order biologists, but have important implications
to develop normally (42). An example of this in human premature and full-term infants
is the dependence on trophic support of sen­ who undergo painful experiences. For ex­
sory neurons provided by peripheral target ample, traumatic interventions of the kind
tissues during development. If a cutaneous that are necessarily undertaken in neonatal
sensory axon is damaged during a critical intensive-care wards may well cause a simi­
stage of development, this essential support lar reorganization in the somatosensory and
will be cut off and result in irreversible death motor systems as are seen in the rat model.
of the dorsal root ganglion cells (43, 44) . The While ~e are discovering the nature of the
trophic support is provided, at least in part, new functional connections that can be
by nerve growth factor (NGF) which is pro­ formed in the rat we still remain ignorant of
duced in target tissues and transported back what , if any, sensory disturbances such re­
to the cell bodies. The cell death resulting organization may cause in human infants.
from axotomy can be prevented by exoge­ Obviously more research both in the labo­
nous NGF administration (43) . This is not ratory and clinical setting is needed to fur­
only true of peripheral sensory ganglion ther expand our knowledge in this area.
cells; m otoneurons and central cells in the
spinal cord and brain die if their axons are
cu t off from their targets during d evelop ­
APPLIED PHYSIOLOGY OF PAIN
ment. Furthermore, the consequences of ax­ Th e previous sections describe experimental
onal damage to even a sm all perip h ra I stu d ies of the developm ental neuroanatomy
nerve during developmen t are far-reaching, and n eur ophysiology of th e pain system, de­
go ing beyond th death of its own cell bod - tailing the effects of n ociceptive stimuli in