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Introduction
A thorough understanding of the mechanisms and
neurobiology of pain is important for both effective utilisation
of current drug regimes and for the future development of
new therapeutic targets. Pain is a net result of peripheral
and central neuronal sensitisation and a balance between
excitatory and inhibitory function at different levels within the
nervous system. Peripheral tissue damage and trauma release
neurotransmitters and result in increased local concentrations
of arachidonic acid metabolites, including prostaglandins
and leukotrienes. In addition to directly activating peripheral
sensory nerve fibres, these agents can trigger degranulation of
nearby mast cells and sensitise the peripheral nerve terminal
to subsequent stimuli. Activation of these nerves will result
in the generation of impulses that travel up sensory nerve
fibres and synapse in the dorsal horn of the spinal cord. e
transmitted impulses will then undergo further modulation
before transmission via the thalamus to the cortex where they
are perceived as pain (Fig. 1.01).
Persistent nociceptive stimuli and inflammation can lead to a
number of structural and functional changes along the nerve
pathway. Such plasticity of the nervous system may increase
the frequency and intensity of the action potentials propagated
proximally along a nerve fibre, thus amplifying the pain
signal to the central nervous system (CNS). Anatomical and
chemical changes such as increased substance P and glutamate
concentrations occur in the dorsal root ganglia (DRG), causing
proliferation and the sprouting of terminals into different
laminae of the DRG [25]. Glutamate activates spinal cord
amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)
and N-methyl-D-aspartate (NMDA) receptors [23]. Increased
sensitivity and responsiveness of central pain-signalling
neurons causes increased expression of cyclo-oxygenase-2
(COX-2) in the spinal cord [43,44]. is mechanism produces
INTRODUCTION
AT THE PERIPHERY
Nociceptors: types, location and
function
T
he inflammatory milieu
P
athway to the central nervous
system
SPINAL CORD
P
AIN AND
MEMORY
BRAIN
CONCLUSION
REFERENCES
Neurobiology and Mechanisms of Pain
1
Michael G. IRWIN, Gordon T.C. WONG
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2 Michael G. IRWIN, Gordon T.C. WONG
prostaglandins in the CNS influencing central pain
sensitisation. It is becoming apparent that poorly
controlled pain initiates changes in both peripheral
and CNSs through inflammation, neuronal
Figure 1.01 Diagram showing some of the important components of the pain pathway.
hyperexcitability and synaptic function alteration.
is can lead to persistence and amplification of
pain and possibly even the development of chronic
pain states.
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Neurobiology and Mechanisms of Pain 3
Nociceptors are ubiquitous throughout the body
and can be found in external tissues such as skin,
cornea and mucosa and certain internal organs such
as muscle, joint, bladder and gut. e cell bodies of
these neurons are located in either the dorsal root
ganglia or the trigeminal ganglia.
ere are several types of nociceptors and they
are classified according to the stimulus modalities
to which they respond, i.e. thermal, mechanical
or chemical. ey transduce a variety of stimuli
into receptor action potentials, which in turn
trigger action potentials along the afferent nerve
fibre. Some nociceptors respond to more than
one of these modalities and are, consequently,
designated polymodal. Others respond to none
of these modalities and are referred to as sleeping
or silent nociceptors. Estimates are that up to
40% of C and 30% of A-delta fibres are silent
nociceptors [27]. ese receptors may become
sensitised to certain physiological or chemospecific
stimuli under inflammatory conditions. ermal
nociceptors are activated by noxious heat or cold,
temperatures above 45°C and below 5°C [7].
Figure 1.02 The inflammatory milieu.
K
+
= potassium; AA = arachidonic acid; NorAd = noradrenaline; COX = cyclo-oxygenase; PGs = prostaglandins; LT =
leukotriene; ILs = interleukins; NGF = nerve growth factor; 5-HT = 5-hydroxytryptamine; SP = substance P; H
+
= protons.
At the Periphery
Nociceptors: types, location and
function
Nociceptors are sensory receptors that generate
the signals that cause the perception of pain
(nociception). e receptors are usually activated
in response to tissue injury but these nerve endings
may also be responsible for persistent pain. One
type of such pain state termed neuropathic pain can
occur sometime after the resolution of peripheral
tissue damage or inflammation. Neuropathic pain
almost invariably involves lesions of a part of the
nociceptive pathway. Hyperalgesia relates to the
acquisition of transduction capacity for stimuli
that ordinarily do not activate nociceptors. ere
are two ways that nociceptors may be sensitised.
One is for the transduction channel to sensitise
(i.e. a bigger generator potential occurring from
a given natural stimulus). e other mechanism
is a decrease in threshold of the sodium channels
responsible for spike initiation [22].
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4 Michael G. IRWIN, Gordon T.C. WONG
Mechanical nociceptors respond to excess pressure
or mechanical deformation. Polymodal nociceptors
respond to damaging stimuli of a chemical, thermal
or mechanical nature. Primary afferent nerve fibres
transduce different forms of energy into generator
potentials. If of sufficient magnitude, these
generator potentials lead to action potentials. e
action potentials propagate along the axon to the
spinal cord.
The inammatory milieu
Intense pressure can cause cell damage and release
of arachidonic acid, potassium and hydrogen. is
will induce production of cyclo-oxygenase enzyme
in the peripheral tissue, which causes an increased
synthesis of prostaglandins from arachidonic
acid [37]. Arachidonic acid is also the precursor
for other prostanoids such as leukotrienes and
hydroxyacids. Besides triggering an inflammatory
cascade response, prostanoids also activate
nociceptors, increase their responsiveness to other
stimuli and start off the pain transmission [20].
During inflammation, noradrenaline is released
from the sympathetic efferent fibres, which will
also stimulate the nociceptors. Other inflammatory
mediators, such as interleukins, are known to have
a direct stimulating effect on nociceptors [12].
Kinins are structurally related polypeptides, such as
bradykinin and kallikrein. ey are members of the
autacoid family and have proinflammatory effects
such as release of cytokines and free radicals and
stimulate sympathetic neurons to contract vascular
endothelial cells [10]. ey also induce histamine
release from mast cells, serotonin (5-HT) from
platelets and mast cells and neuropeptides like
substance P from damaged tissue (axon reflex). ey
trigger significant vasodilatation and neurogenic
oedema. Following the release of these algogenic
chemical injury products, previously silent
receptors are activated by a wide range of thermal
and mechanical stimuli and may also develop a
background discharge [35].
e expression of nerve growth factor (NGF) is
high in injured and inflamed tissues, and activation
of the NGF receptor tyrosine kinase TrkA on
nociceptive neurons triggers and potentiates pain
signalling [1]. Sprouting of epidermal nerve fibres
is initiated by increased NGF and is found in
combination with localised pain and hyperalgesia
[36]. is also occurs in pruritic lesions, suggesting
that similar mechanisms of neuronal sprouting
and sensitisation exist for both pain and pruritus
on a peripheral level [32]. Consequently, anti-
NGF has the potential to be a novel class of
analgesic [14]. Nerve growth factor is known to
up-regulate neuropeptides, especially substance P
and calcitonin-gene-related peptide [39]. Although
substance P has been found to have an important
role in the induction of pain and hyperalgesia, there
is little evidence for the clinical analgesic efficacy of
antagonists of its receptor, the neurokinin 1 (NK1)
receptor [15].
Low pH also activates several ion channels to
transduce pain, i.e. acid-sensing ion channels,
vanilloid receptors, purinergic receptors and
potassium channels. is may be important in
ischaemia-induced pain [41]. Important ion
channels in pain include the following. Transient
receptor potential vanilloid (TRPV) channels are
phosphorylated and up-regulated by tissue injury
and inflammation [29]. Ankyrin-repeat TRP 1
(TRPA1) channels in peripheral nociceptors can be
opened with pungent chemicals (e.g. mustard, tear
gas) and high threshold mechanical stimuli [4].
P2X are purinergic receptors that are activated by
adenosine triphosphate, elevated levels of which are
found in inflamed tissues. P2X receptors are also
found in the dorsal root ganglion neurons and may
play a role in the development of neuropathic pain
after nerve injury [24].
Pathway to the Central nervous
system
Nociceptors may have either A-delta fibre axons
(transmit signals at 20 m/s) or more slowly
conducting C fibre axons (2 m/s). us, pain
often comes in two phases. e first is mediated
by the fast-conducting A-delta fibres responding
either to dangerously intense mechanical or to
mechanothermal stimuli, which have receptive
fields that consist of clusters of sensitive spots.
e unmyelinated C fibres conduct to thermal,
mechanical and chemical stimuli, which is why
their nociceptors are referred to as polymodal.
Together these nociceptors allow the person to feel
pain in response to damaging pressure, excessive
heat, excessive cold and a range of chemicals,
the majority of which are damaging to the tissue
surrounding the nociceptor. Afferent nociceptive
fibres travel back to the spinal cord where they
form synapses in its dorsal horn.
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Neurobiology and Mechanisms of Pain 5
Spinal Cord
e dorsal horn of the spinal cord is the pivotal
gateway for pain transmission to the CNS. When
the action potentials from A-delta or C fibres reach
the central terminals of sensory neurons in the
spinal cord, calcium influx through presynaptic
voltage-gated calcium channels triggers the
release of pronociceptive neurotransmitters
and neuromodulators, which excite or sensitise
secondary neurons in the superficial lamina of
the dorsal horn. e cells in the dorsal horn are
divided into physiologically but not anatomically
distinct layers called laminae and the various types
of fibre form synapses in different layers. ere is
a degree of overlap between these laminae, with
each lamina containing more than one type of
neuron. A-delta fibres form synapses in laminae
I, II and V; C fibres connect with neurons in
lamina I and II; and A-beta fibres connect with
lamina IV. Postsynaptic fibres converge in lamina
V where wide dynamic range neurons are present.
Wide dynamic range neurons are those that
receive input from both noxious and non-noxious
stimuli. ey can increase their firing rate in
response to increasing levels of stimulation (graded
response); the high threshold neurons are those
that are activated only by noxious stimulation,
and low threshold neurons are only activated by
non-noxious stimulation. Central terminals of
primary afferents release excitatory amino acids
such as aspartate, glutamate and neurokinins
(e.g. substance P), which activate receptors on
the postsynaptic cells. Activation of AMPA and
NK1 receptors leads to priming of the NMDA
receptor complex. Glutamate release results in
further activation with removal of a magnesium
“plug” from the NMDA receptor and subsequent
calcium influx. e interaction of these three
receptors is thought to play an important role
in the pathophysiology of persistent pain states
[28]. Calcitonin-gene-related peptide is released
from high threshold fibres along with substance P
and can expand the spinal cord area from which
substance P is released, thereby further increasing
excitability. Substance P itself can also increase
the release of excitatory amino acids enhancing
the responses of dorsal horn neurons to glutamate
or NMDA. As a result, neuropeptide antagonists
may have therapeutic potential in preventing
central sensitisation [2].
Intracellular calcium influx to the NMDA receptor
acts on a calmodulin sensitive site and activates the
enzymes nitric oxide synthase and cyclo-oxygenase-
2 (COX-2). Excessive production of nitric oxide and
prostaglandin plays major roles in neural and glial
excitation and central sensitisation. Neurochemical
changes result in several plasticity responses
including apoptosis (glial and neuronal cell death),
axonal sprouting and new afferent connections.
Normally, A-beta fibre stimulation by innocuous
stimuli is unable to activate dorsal horn cells. As a
result of central sensitisation, however, A-beta fibre
input becomes sufficient and low-threshold stimuli
now produce painful responses. ese anatomical
changes underlie the development of long term
potentiation and chronic pain [17].
Synaptic transmission between the primary afferent
nociceptors and the dorsal horn neurons can be
modified by a number of mechanisms, e.g. repetitive
stimulation from the periphery can amplify or
prolong the response to noxious input. is use-
dependent synaptic plasticity has been described as
“wind up” [26]. Wind up is dependent on NMDA
and neurokinin receptor activation [38] and is
a separate phenomenon to central sensitisation,
which is an increased excitability of neurons within
the spinal cord with an expansion in receptive
field, reduction in threshold and the recruitment of
novel inputs. Clinically, central sensitisation results
in secondary hyperalgesia, allodynia and pain
generation by activating A-beta mechanoreceptors
and signal transduction pathways. It has been
suggested that wind up initiates and maintains
central sensitisation [38].
Central sensitisation results in hyperalgesia and
two types of mechanical hyperalgesia can be
differentiated. In allodynia, touch that is normally
painless can trigger painful sensations (touch- or
brush-evoked hyperalgesia). Although this sensation
is mediated by myelinated mechanoreceptor units,
it requires the ongoing activity of primary afferent
C-nociceptors. e second type of mechanical
hyperalgesia results in slightly painful pin prick
stimulation being perceived as more painful. is
type has been called punctate hyperalgesia and does
not require ongoing activity of primary nociceptors
for its maintenance. Administration of cyclo-
oxygenase inhibitors reduces the development of
hyperalgesia and allodynia [18].
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6 Michael G. IRWIN, Gordon T.C. WONG
Types of hyperalgesia
Touch- or brush-evoked hyperalgesia
Punctate hyperalgesia
Other receptors that are present in the dorsal horn
and are known to have moderating effects on
neurotransmission include alpha-2-adrenoceptors
(subtype A) and opioid receptors. Descending
noradrenergic inhibitory pathways modulate
nociceptive transmission and spinal sensitisation
after tissue injury. Spinal alpha-2-adrenoceptor
agonists as well as noradrenaline transporter
inhibitors relieve mechanical hyperalgesia [30] and
alpha-2-activation also depresses nerve fibre action
potentials, especially in the small unmyelinated
C fibres [13]. Calcium channel auxiliary subunit
alpha-2-delta-1 also plays an important role in
neuropathic pain processing as it is up-regulated
in the DRG after spinal nerve injury. Intrathecal
alpha-2-delta-1 antisense oligonucleotides block
injury-induced dorsal horn alpha-2-delta-1 subunit
up-regulation and diminish tactile allodynia in
rats [21]. Pregabalin, used in the treatment of
neuropathic pain and anxiety disorders, binds
specifically to the alpha-2-delta-1subunit of voltage-
dependent Ca
2+
channels with a high affinity and
reduces calcium current [5]. Activation of opioid
receptors reduces neuronal excitability through
the inhibition of voltage-dependent Ca
2+
channels
and adenylyl cyclase, and opening of K
+
channels,
and this opioid induced reduction in excitability
will lead to an inhibition of pain [34]. Adenosine
triphosphate sensitive potassium (K
ATP
) channels
are opened and modulated by both opioid and
non-opioid G-protein coupled receptors to also
produce antinociception [42].
ere is evidence that activation of central
sensitisation and pain is also mediated via humoral
messengers. Although it was thought that peripheral
cytokines could not cross the blood-brain barrier, it
has now been demonstrated that cerebral vascular
cells that form the blood-brain barrier express
components that enable a blood-borne cytokine to
stimulate the production of prostaglandin E2, an
inflammatory mediator and powerful modulator
of nociception [11]. ese cells have, on their
surface, receptors that specifically recognise
interleukin (IL)-1-beta indicating that the activated
immune system controls central reactions to
peripheral inflammation through a prostaglandin-
dependent, blood-borne cytokine-mediated
pathway. Interestingly, it is mainly the increase
in cerebrospinal levels of IL-1-beta that mediates
local inflammation in the brain and not the sensory
inflow from nerve fibres, which is thought to be
mainly important for the widespread induction
of COX-2 expression in the CNS leading to the
release of prostanoids and resulting in pain [33].
It has also been shown that high concentrations
of proinflammatory cytokines (IL-1-beta, IL-2,
IL-6, IFN-gamma, tumour necrosis factor [TNF]-
alpha) in the plasma correlate with increasing
pain intensity. Chronic pain patients also show a
significant increase in plasma levels of nitric oxide
in comparison to healthy controls [16].
Pain and Memory
e prolonged changes in sensitivity observed
during central sensitisation are similar to the
synaptic changes required for learning and memory.
e NMDA-dependent long term potentiation
(LTP) within the hippocampus appears to be
integral in the cellular mechanisms of memory as
this is the principal cellular mechanism thought
to underlie neuronal plasticity [31]. A recent
report has provided data in humans that pain and
memory have very similar mechanisms and that
LTP in nociceptive pathways enhances human pain
sensitivity via interaction of two afferent pathways
[19]. It has been suggested that, consequently, it
may be difficult to develop treatments that only
affect pain without influencing memory [8].
Brain
Information is sent from the spinal cord to the
thalamus and the cerebral cortex in the brain. e
receptive fields of all pain-sensitive neurons are
relatively large, particularly at the level of the thalamus
and cortex, presumably because the detection of pain
is more important than its precise localisation.
Pain is a complex experience consisting of sensory
discriminative, affective, cognitive and motivational
components. Brain imaging studies have significantly
widened our knowledge and understanding of the
complexity of pain presentation by attempting to
correlate different aspects of the pain sensation
to particular brain areas. It is generally accepted
that spatial, temporal and intensity aspects of
pain perception are processed in the primary
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Neurobiology and Mechanisms of Pain 7
and secondary somatosensory cortex (S1 and S2
respectively), whereas the anterior cingulate cortex
and insular cortex are involved in the affective-
motivational component [40]. Somatotropic
representation of pain is reported for the S1, but
might be much clearer in the dorsal posterior
insula [3]. is would confirm a different central
projection pathway for pain primary projections to
the dorsal posterior insula. is part of the brain
may function as a basic interoceptive cortex with
homeostatic functions [6].
Conclusion
e body of knowledge regarding nociception
continues to grow as techniques in characterising
receptors and neurotransmitters continue to
improve. e transmission of a pain signal from
the periphery to the brain involves complex
interactions between different types of neurons,
through release of various neurotransmitters
and receptor and ion channel activation. e
perception of pain is also affected by descending
influences from the brain. e components of the
“pain pathway” have potential for modification
both in terms of structure and function. Changes
in the neuronal makeup are largely influenced
by the biochemical makeup of their immediate
environment. Such plasticity in the system is
responsible for the development of abnormal and
chronic pain states, well beyond the duration of the
inciting injury. Understanding of the neurobiology
behind pain transmission is pivotal in the effective
use of available analgesics and for the development
of future therapy.
Key points
• Pain perception is the net result of ascending
and descending excitatory and inhibitory
influences
• Anatomical and biochemical changes can
alter nociception anywhere along the pain
pathway
• Nociceptors are ubiquitous throughout the
body and may be mono- or polymodal
• Peripheral tissue damage and/or inflammation
increases the local concentration of mediators
that activate and up-regulate nociceptors and
ion channels
• e dorsal horn of the spinal cord is an
important target for pain modulation as
primary afferent fibres from peripheral
nociceptors synapse here
• Central sensitisation can result in mechanical
hyperalgesia.
References
Allen SJ, Dawbarn D. Clinical relevance of the neurotrophins and their receptors. Clin Sci 2006;110:175–91.
Ambalavanar R, Moritani M, Moutanni A, et al. Deep tissue inflammation up-regulates neuropeptides and evokes
nociceptive behaviors which are modulated by a neuropeptide antagonist. Pain 2006;120:53–68.
Apkarian AV, Bushnell MC, Treede RD, et al. Human brain mechanisms of pain perception and regulation in health
and disease. Eur J Pain 2005;9:463–84.
Bautista DM, Jordt SE, Nikai T, et al. TRPA1 mediates the inflammatory actions of environmental irritants and
proalgesic agents. Cell 2006;124:1269–82.
Bian F, Li Z, Offord J, et al. Calcium channel alpha2-delta type 1 subunit is the major binding protein for pregabalin
in neocortex, hippocampus, amygdala, and spinal cord: An ex vivo autoradiographic study in alpha2-delta type 1
genetically modified mice. Brain Res 2006;1075:68–80.
Brooks J, Tracey I. From nociception to pain perception: Imaging the spinal and supraspinal pathways. J Anat
2005;207:19–33.
Caterina MJ, Rosen TA, Tominaga M, et al. A capsaicin-receptor homologue with a high threshold for noxious heat.
Nature 1999;398:436–41.
Coyle DE. Spinal mechanisms of pain. Int Anesthesiol Clin 2007;45:83–94.
Craig AD. A new view of pain as a homeostatic emotion. Trends Neurosci 2003;26:303–7.
Dray A. Inflammatory mediators of pain. Br J Anaesth 1995;75:125–31.
Ek M, Engblom D, Saha S, et al. Inflammatory response: Pathway across the blood-brain barrier. Nature
2001;410:430–1.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
https://t.me/medicina_free
8 Michael G. IRWIN, Gordon T.C. WONG
Ferreira SH. e role of interleukins and nitric oxide in the mediation of inflammatory pain and its control by peripheral
analgesics. Drugs 1993;46(Suppl 1):1–9.
Gaumann DM, Brunet PC, Jirounek P. Clonidine enhances the effects of lidocaine on C-fiber action potential. Anesth
Analg 1992;74:719–25.
Hefti FF, Rosenthal A, Walicke PA, et al. Novel class of pain drugs based on antagonism of NGF. Trends Pharmacol Sci
2006;27:85–91.
Hill R. NK1 (substance P) receptor antagonists — why are they not analgesic in humans? Trends Pharmacol Sci
2000;21:244–6.
Koch A, Zacharowski K, Boehm O, et al. Nitric oxide and proinflammatory cytokines correlate with pain intensity in
chronic pain patients. Inflamm Res 2007;56:32–7.
Koltzenburg M. Neural mechanisms of cutaneous nociceptive pain. Clin J Pain 2000;16:S131–8.
Koppert W, Wehrfritz A, Korber N, et al. e cyclo-oxygenase isozyme inhibitors parecoxib and paracetamol reduce
central hyperalgesia in humans. Pain 2004;108:148–53.
Lang S, Klein T, Magerl W, et al. Modality-specific sensory changes in humans after the induction of long-term
potentiation (LTP) in cutaneous nociceptive pathways. Pain 2007;128:254–63.
Levine JD, Fields HL, Basbaum AI. Peptides and the primary afferent nociceptor. J Neurosci 1993;13:2273–86.
Li CY, Song YH, Higuera ES, et al. Spinal dorsal horn calcium channel 2delta-1 subunit up-regulation contributes to
peripheral nerve injury-induced tactile allodynia. J Neurosci 2004;24:8494–9.
Magerl W, Fuchs PN, Meyer RA, et al. Roles of capsaicin-insensitive nociceptors in cutaneous pain and secondary
hyperalgesia. Brain 2001;124:1754–64.
Malmberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclo-
oxygenase inhibition. Science 1992;257:1276–9.
McGaraughty S, Chu KL, Namovic MT, et al. P2X(7)-related modulation of pathological nociception in rats.
Neuroscience 2007;146:1817–28.
McMahon SB, Cafferty WB, Marchand F. Immune and glial cell factors as pain mediators and modulators. Exp Neurol
2005;192:444–62.
Mendell LM, Wall PD. Responses of single dorsal cord cells to peripheral cutaneous unmyelinated fibres. Nature
1965;206:97–9.
Michaelis M, Habler HJ, Jaenig W. Silent afferents: A separate class of primary afferents? Clin Exp Pharmacol Physiol
1996;23:99–105.
Nishiyama T, Yaksh TL, Weber E. Effects of intrathecal NMDA and non-NMDA antagonists on acute thermal
nociception and their interaction with morphine. Anesthesiology 1998;89:715–22.
Numazaki M, Tominaga M. Nociception and TRP channels. Curr Drug Targets CNS Neurol Disord 2004;3:479–85.
Obata H, Conklin D, Eisenach JC. Spinal noradrenaline transporter inhibition by reboxetine and Xen2174 reduces
tactile hypersensitivity after surgery in rats. Pain 2005;113:271–6.
Pastalkova E, Serrano P, Pinkhasova D, et al. Storage of spatial information by the maintenance mechanism of LTP.
Science 2006;313:1141–4.
Roosterman D, Goerge T, Schneider SW, et al. Neuronal control of skin function: e skin as a neuroimmunoendocrine
organ. Physiol Rev 2006;86:1309–79.
Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to
inflammatory pain hypersensitivity. Nature 2001;410:471–5.
Satoh M, Minami M. Molecular pharmacology of the opioid receptors. Pharmacol er 1995;68:343–64.
Schmidt R, Schmelz M, Torebjork HE, et al. Mechano-insensitive nociceptors encode pain evoked by tonic pressure to
human skin. Neuroscience 2000;98:793–800.
Sivilia S, Paradisi M, D’Intino G, et al. Skin homeostasis during inflammation: A role for nerve growth factor. Histol
Histopathol 2008;23:1–10.
Smith WL, DeWitt DL, Garavito RM. Cyclo-oxygenases: Structural, cellular, and molecular biology. Annu Rev Biochem
2000;69:145–82.
Urban L, ompson SW, Dray A. Modulation of spinal excitability: Co-operation between neurokinin and excitatory
amino acid neurotransmitters. Trends Neurosci 1994;17:432–8.
Verge VM, Richardson PM, Wiesenfeld-Hallin Z, et al. Differential influence of nerve growth factor on neuropeptide
expression in vivo: A novel role in peptide suppression in adult sensory neurons. J Neurosci 1995;15:2081–96.
Vogt BA. Pain and emotion interactions in subregions of the cingulate gyrus. Nat Rev Neurosci 2005;6:533–44.
Woo YC, Park SS, Subieta AR, et al. Changes in tissue pH and temperature after incision indicate acidosis may
contribute to postoperative pain. Anesthesiology 2004;101:468–75.
Wood JN. Ion channels in analgesia research. Handb Exp Pharmacol 2007;177:329–58.
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:1765–9.
Yaksh TL, Dirig DM, Malmberg AB. Mechanism of action of nonsteroidal anti-inflammatory drugs. Cancer Invest
1998;16:509–27.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
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Introduction
e conceptualisation of pain has clear significance for its
explanation, assessment and treatment. roughout recorded
history ideas about the nature of pain have fluctuated and
even today multiple views are held. is chapter attempts to
critically review the different concepts of pain that exist today
and their implications for assessment and treatment. is
understanding should provide the reader with a perspective
from which to make sense of the different assessment and
treatment modalities, whether they are physical, psychological
and/or social.
Denitions of Pain
While most people would agree with Kleinman’s [38] observation
that pain is a ubiquitous human experience, agreement on
definitions of pain has proved more elusive. At the lay level,
pain might be defined as that which hurts. Unfortunately, this
has a circular aspect: what hurts is pain. Not surprisingly, the
definition of pain (as well as its explanation and treatment) has
always depended on the perspective or framework from which
it is viewed [25]. Although a comprehensive review of the
history of pain is beyond the scope of this chapter (see Bonica
and Loeser [12]), some coverage of the major concepts of pain
through history should help to provide a useful perspective for
understanding the current debates on the nature of pain.
A key debate over definitions of pain has centred around
questions of whether it is a sensation, like smell, or something
more complex, like a need state [66] or an emotional experience,
or even a type of response. Wall [66], for example, wrote:
Pain is better defined as an awareness of a need state
rather than a sensation. It serves more to promote healing
INTRODUCTION
DEFINITIONS OF PAIN
HISTORICAL PERSPECTIVES
PAIN AS A SENSATION OR
EMOTION?
MODERN PERSPECTIVES
BIOPSYCHOSOCIAL MODELS OF
PAIN
PAIN AS A RESPONSE RATHER
THAN A SENSATION?
CLINICAL IMPLICATIONS
Psychological Concepts of Pain
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Michael K. NICHOLAS
https://t.me/medicina_free
Соседние файлы в папке Библиотека им академика М.И. Перельмана