P H Y S I O L O G Y ( O R A L BO I ROA LL OBGI O

Y L) O G Y

The Neural Mechanisms of Oral and

Facial Pain
SAMUEL W. CADDEN AND ROBERT ORCHARDSON

sufficient to provide a diagnosis. By

Abstract: Pain is a complex and variable phenomenon that can be influenced by many definition (see above), pain usually
factors. The neural pathways serving pain are not passive conduits, but are part of a signifies that something is wrong, such
dynamic system which can result in different levels of pain resulting from similar
as tissue damage or disease. However,
injuries under different circumstances. The passage of signals in these pathways may
be inhibited or enhanced at almost any level, from the peripheral sensory receptors to
although many pains have an obvious
the higher centres of the brain. This review will describe recent developments in our cause (e.g. dental caries) and can be
understanding of these mechanisms and how this knowledge may be used in alleviated by removal of that cause,
controlling pain. some pains arise where there is no
obvious tissue damage. Conversely,
Dent Update 2001; 28: 359-367 some quite severe injuries may cause
Clinical Relevance: An understanding of the neural processes responsible for pain little or no pain. A further problem from
and the factors that can modify them is important for the effective management of a clinical standpoint is that the source
orofacial pain. and site of a pain may be different – the
phenomenon of referred pain. Such
pains are usually referred between
structures of common embryological
origins. When this happens, they are
described as being segmental since

P ain may be defined as:

an unpleasant sensory or
changes in arousal, etc.) but the words
are not synonymous.
Much of our understanding of the
both the source and apparent location
of the sensation fall within the same
neural segment of the body. For
emotional experience associated mechanisms of pain comes from studies example, dental pains may be referred to
with actual or potential tissue not of pain itself, but of nociception in the ear or face – all three structures
damage, or described in terms of anaesthetized animals (which by being within the distribution of the
such damage definition do not feel pain). trigeminal nerve.
There are many types of orofacial
(International Association for the Study pain2 (see Table 1). Although the dentist
of Pain1). The term nociception, may view pain from the teeth and
Intracranial pain disorders
although more difficult to define, temporomandibular region as the most
Primary headache disorders (neurovascular
generally refers to the activation of common problems with which he or she disorders)
neural pathways by stimuli that damage has to deal, it is difficult to provide
Neurogenic pain disorders:
or threaten to damage the tissues precise information on the prevalence of
Paroxysmal neuralgias
(noxious stimuli). Pain is one result of these and other orofacial pains because
Continuous pain disorders
nociception (as are some reflexes, of procedural differences in different
Sympathetically mediated pain
epidemiological studies.3 These Intra-oral pain disorders
differences include the questions asked, Temporomandibular pain disorders
Samuel W. Cadden, BSc, BDS, PhD, FDS RCS the nature, severity and duration of the
(Edin.), Senior Lecturer in Oral Biology, Unit of Pain arising from disorders of associated
pain, and demographic factors. structures (e.g. eyes, ear, nose and throat)
Clinical Dental Sciences,The Dental School,
University of Dundee, and Robert Orchardson,
Pain is an important clinical symptom
Pain associated with mental disorders (e.g.
BSc, BDS, PhD, FDS RCPS (Glasg.), Senior and is one of the classical components psychogenic pains)
Lecturer in Physiology, Institute of Biomedical & of inflammation (dolor, calor, rubor,
Life Sciences, Laboratory of Human Anatomy, Table 1. Classifications of the origins of orofacial
tumor). Indeed, the pattern and pains. Based on a table published by the
University of Glasgow. presentation of pain can often be American Academy for Orofacial Pain.2

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 O R A L B I O L O G Y

Thus pain is clearly not a simple

sensation whereby a stimulus of
sufficient strength will always produce a
Damage
Damage
sensation that grows in intensity with
the strength of the stimulus. Seemingly
comparable injuries or disease states Skin or
can produce different levels of pain in mucosa
different people, and even in the same
person at different times. In this review
we will consider how these differences
occur. We will concentrate on the Phospholipids Kallikrein
mechanisms associated with simple
acute pain, i.e. pain resulting from a
noxious stimulus or tissue injury. In so * Platelet
Aggregation
H+
doing, we will bear in mind that most Kininogens
knowledge of these mechanisms derives
from studies of the limbs rather than the Arachidonic K+
Acid
orofacial region. However, there is
adequate evidence to make one believe
Mast Bradykinin
that mechanisms operating in the spinal
cord also apply to the trigeminal ** Serotonin
Cells

system.4 Peptides
Histamine
Prostaglandins
PERIPHERAL MECHANISMS Leucotriens
OF PAIN

Nociceptors
As pain is a perception, not a stimulus,
the term ‘pain receptor’ is not Nociceptive Nerve Ending
appropriate. Instead it is more proper to
refer to the receptors that respond to
harmful or potentially harmful (noxious)
stimuli as nociceptors. This is
particularly helpful as some stimuli can Figure 1. Tissue damage produces local chemical changes which can either directly or indirectly
excite nociceptors without producing affect nociceptive nerves. Some chemicals can activate or sensitize the endings, depending on whether
pain (e.g. temperatures around 41°C).5 they are in high or low concentrations respectively (purple arrows). Others can only activate (blue
arrows) or sensitize (green arrows). Note that the release of neuropeptides from the nerve ending itself
From a morphological point of view, (orange arrow) contributes to this process by what amounts to a positive feedback mechanism. The
most or all nociceptors are believed to diagram also shows the sites of action of steroidal (*) and non-steroidal (**) anti-inflammatory drugs.
be free nerve endings. However, they For clarity of presentation, not all the putative inflammatory agents are shown here (see text). Modified
differ with respect to whether their from Le Bars and Willer.9
axons are myelinated (A-fibres) or
unmyelinated (C-fibres) and in their
responsiveness to particular forms of Aδ-mechano-nociceptors.7–9 The next C-fibre Nociceptors
noxious stimuli. largest group of Aδ-fibre nociceptors Most of the unmyelinated nociceptors
responds to all types of noxious stimuli are also polymodal, responding to
A-fibre Nociceptors (mechanical, thermal, chemical) – or at strong mechanical stimuli, intense heat
With occasional exceptions (e.g. the Aβ least to all the types with which they or cold and various pain-producing
nerves supplying tooth-pulp 6), all have been tested7 – and are usually chemicals. C-fibre polymodal
myelinated nociceptors may be called Aδ polymodal nociceptors.7–9 nociceptors are the most numerous7 and
categorized as Aδ fibres, i.e. the thinnest Other Aδ nociceptors, which respond arguably the most important9
myelinated nerves. In humans, most Aδ- only to cold, or to hot and chemical but nociceptors in the human body.
fibre nociceptors respond only to not mechanical noxious stimuli, have In some parts of the body, a brief
noxious mechanical stimuli7 and are also been reported7,10 but their strong (e.g. electrical) stimulus can
known as A-mechanical nociceptors or importance is not yet clear. evoke two distinct painful sensations –

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prostaglandins, neuropeptides, not happen equally in all nociceptors

ARACHIDONIC ACID adenosine, noradrenaline and various (see above) and may apply only to some
cytokines.11 There is evidence that some of the types of stimuli that can excite a
COX-1 COX-2 of these agents are present in inflamed particular nociceptor (e.g. mechanical,
(constitutive) (inducible)
oral tissues, such as tooth extraction heat).
sockets,12 TMJ13 and the periodontium.14

Peripherally Acting Analgesics

“Protective” Activation of nociceptors
or “Inflammatory” The analgesic action of non-steroidal
“Physiological” Prostaglandins Nociceptors can be activated either anti-inflammatory drugs (NSAIDs) is
Prostaglandins
directly by the noxious stimulus itself or due to their ability to block synthesis of
Gastric protection Inflammation
Haemostasis Pain
indirectly by some of the chemicals in the prostaglandins, which sensitize
Vasodilation the damaged tissue. In addition, nociceptors. They do this by inhibiting
Renal Function
intradental nociceptors can be activated the enzyme cyclo-oxygenase (COX).
Figure 2. Arachidonic acid may be converted indirectly by hydrodynamic There are two forms of this enzyme
into prostaglandins by the enzymes COX-1 and mechanisms.6 The chemicals that can (Figure 2):
COX-2. The protective functions of prostaglandins activate nociceptors are known as
are produced by relatively low concentrations,
which are regulated mainly by COX-1, the algogenic (‘pain-producing’). Some
COX-1 the constitutive (constantly
constitutive form of the enzyme. COX-2 also has a algogenic substances are released by present) form, which is associated
limited constitutive role in some normal tissues, but the injury while others are the result of with the physiological ‘protective’
this isoenzyme is expressed mainly in damaged reactions triggered off in the damaged role of prostaglandins;
tissue. COX-2 produces the same prostaglandins tissue (Figure 1). Regardless of whether
COX-2 the inducible form, which is
as does COX-1, but in greater amounts. Thus,
the effects of prostaglandins in inflamed tissues a direct or indirect mechanism is associated mainly with inflammation
are due principally to their increased involved, one can assume that the and pain.15
concentrations rather than to the actual activation will involve an increase in the
prostaglandins present. membrane permeability of the nerve Selective COX-2 inhibitors are being
ending, resulting in a depolarization, developed which ideally will have
which, if large enough, will generate analgesic and anti-inflammatory actions
first (fast) and second (slow) pain – due action potentials in the nerve fibres. without the undesirable side-effects that
to the very different speeds of impulse are largely accountable to COX-1
propagation in Aδ- and C-fibres inhibition (notably gastrointestinal and
respectively. However, these two Sensitization of nociceptors haematological but also some renal and
components cannot easily be From personal experience we know that respiratory).15
distinguished in the orofacial region damaged or inflamed tissues display
because of the short conduction increased sensitivity, e.g. gentle
distances to the brain. Although mechanical stimulation of inflamed skin CNS PATHWAYS
probably a simplification, it is often said or a tooth with periapical inflammation The cell bodies of most orofacial
that first and second pains correspond can cause severe pain. This nociceptive neurons are in the trigeminal
to the sharp and burning pains that phenomenon, whereby pain is produced ganglion and the central axons of all
occur successively during and after an by stimuli which would not normally do three divisions project via the trigeminal
injury. so, is a type of hyperaesthesia called sensory root to synapse in trigeminal
allodynia. (Note: this condition used to nucleus caudalis (the hindmost part of
be known as primary hyperalgesia, but the so-called trigeminal spinal nucleus).
Chemical Changes in Damaged the term hyperalgesia is now reserved From here, second-order neurons project
Tissues for conditions where increased to the thalamus from where third-order
Damaged tissues release a cocktail of intensities of pain result from a stimulus neurons leave for the cortex (Figure 3).
chemicals – the inflammatory agents. that would usually produce a lesser Other cranial nerves, such as the
These have vascular and neural effects. level of pain.1) Allodynia is due largely glossopharyngeal and some cervical
The vascular effects are vasodilation to sensitization of peripheral spinal nerves, can also contribute to
(causing calor and rubor) and increased nociceptors (cf. hyperalgesia, see orofacial pain. There are at least two
vascular permeability (causing tumor). below) by inflammatory agents, types of second-order neurons in
The neural effects involve either including the algogenic substances nucleus caudalis that receive nociceptor
activating or sensitizing nociceptors when these are present in inputs:
(see below) and thus relate to pain concentrations that are too low to
(dolor). These agents include potassium produce a threshold depolarization
nociceptive-specific cells receive
ions, hydrogen ions, serotonin, (Figure 1). However, sensitization does inputs only from nociceptors

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 O R A L B I O L O G Y

A. Consciousness
Area X Area Y

Somatosensory
Cortex
Area X

Area Y

Thalamus

B. Consciousness
Area X Area Y

Noxious
Trigeminal Stimulus
Trigemino-thalamic Tract
nucleus
caudalis
CNS Area X

Area Y

Trigeminal PNS
Ganglion

C. Consciousness
Nociceptive
Area X Area Y
Nerves
Noxious
Stimulus

Area X
Nociceptors
Area Y
midline

Figure 3. Schematic representation of the pathway mediating signals Figure 4. (A) Divergence and convergence in nociceptive pathways.
that result in pain from the orofacial region. Note that the second- Peripheral nociceptive nerves, before synapsing in the CNS, branch and
order neurons in the trigemino-thalamic tract cross the midline and diverge to make contact with more than one second-order neuron. In this
project to the contralateral thalamus; thus the sensation of pain is way, information may ‘converge’ onto these second-order neurons. In this
generated on the opposite side of the brain to the injury that causes it. theoretical model, the ‘straight-through’ pathways from the peripheral
Abbreviations: CNS, central nervous system; PNS, peripheral nervous nociceptors map on to corresponding areas within the ‘conscious’ parts of the
system. brain. (B) Radiating pain. If one of these nociceptive nerves is activated, it
may result in activation not only of its ‘own’ second-order neuron but also of
neighbouring ones (activated neurons shown in red). This can result in a
conscious perception that the pain is originating from a larger area (X+Y)
than it actually is (X). (C) Referred pain. Under certain circumstances, the
signal in the ‘straight-through’ pathway may not reach, or not be recognized
by, the conscious centres – the pain is then ascribed to the uninjured area (Y)
rather than the injured area (X). Again activated neurons are shown in red.

wide dynamic range (or neurons – the phenomenon of structure other than the injured one
nociceptive-non-specific) cells divergence. Furthermore, each second- (Figure 4C). It is not clear why pains
receive inputs from nociceptors, order neuron receives inputs from many should be misinterpreted in this way.
mechanoreceptors and primary afferents – the phenomenon of However, it seems possible that when
thermoreceptors. convergence (Figure 4A). Convergence the consciousness receives signals
and divergence of inputs may explain why emanating from second-order neurons
It seems that these neurons serve pains often ‘radiate’ and appear to arise that receive inputs from superficial and
different but complementary functions: from a larger area than that which has deep structures, it interprets them as
nociceptive-specific neurons may signal been injured or is diseased (Figure 4B). In originating from the more superficial
the presence and location of a noxious addition, neuronal convergence may structure since such inputs normally
stimulus while the wide dynamic range cause hyperalgesia (see above) in the predominate.17 Thus, pain may be
cells may grade its overall severity.16 area surrounding an injury. referred from jaw muscles to the teeth or
Within nucleus caudalis the primary Neuronal convergence is also the from the teeth to the face18 but rarely if
afferent neuron terminals branch and most likely explanation for referred pain, ever in the opposite direction.
synapse with several second-order whereby pain appears to come from a Second-order nociceptive cells in

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have roles in the emotional and motor

responses to pain.9 Some of these
A. projections are direct while others
involve an intermediate synapse in the
Primary Afferent 2nd Order Afferent reticular formation.
neurons neurons
Third-order neurons from the
"Gate"
ventrobasal thalamus project to the
primary somatosensory cortex. Other
nociceptive neurons project to other
B. Inhibitory
Interneurons
parts of the cerebral cortex, including
the secondary somatosensory cortex,
b
a the insula and anterior cingulate gyrus.
Recent studies using positron emission
+
tomography have shown that the
Primary Afferent 2nd Order Afferent anterior cingulate gyrus is the only
neurons neurons cortical area to be activated uniquely by
noxious thermal stimuli.19 Despite these
findings, the role of the cortex in pain is
poorly understood and complicated by
the facts that pain is still felt after
C. Aβ fibre ablation of large areas of cortex and that
mechanoreceptors it is difficult to produce pain by focal
+
+ electrical stimulation of cortical
structures.9
+
Aδ and C fibre
nociceptors DISCREPANCIES BETWEEN
INJURIES AND PAIN
Although pain often arises from obvious
causes (e.g. injury or disease), there may
Higher Centres be no clear relationship between the
D. degree of damage and the amount of
pain perceived:

Injuries causing severe tissue

damage do not always cause pain;
or the pain is not as intense as one
+ might expect. The classical examples
+ involve people wounded in battle or
injured on the sports field.
Aδ and C fibre
+
Pain sometimes occurs without any
nociceptors obvious tissue injury – e.g.
trigeminal neuralgia; thermal grill
Figure 5. The Gate Control Theory of Pain. (A) The concept. Signals carried by primary afferent illusions.19
nociceptive nerves must pass through a ‘gate’ before being passed on by second-order afferents in the
CNS. (B) The same scheme using the conventional shorthand for nerves. The primary afferent nerves Also, pain can be modified by many
excite (+) the second-order afferent neurons. The ‘gate’ is made up of small inhibitory interneurons (a,
factors in many circumstances. For
b), which can either reduce the amount of excitatory transmitter released by the primary afferents (a)
or directly inhibit the second-order neurons (b). The inhibitory interneurons themselves may be excited: example:
(C) by activity in adjacent large diameter mechanoreceptive nerves (‘segmental inhibition’), or (D) by
activity originating in higher centres in the CNS (‘descending inhibition’).
Procedures such as acupuncture20,
hypnosis21 and the placebo effect.22

Psychological considerations, such
nucleus caudalis project to the tract to synapse in the ventrobasal as individual and cultural factors, the
contralateral thalamus (Figure 3). Those nuclei. In addition, there are projections situation, its emotional impact, etc.23
concerned with the sensation of pain to the posterior and medial groups of
travel directly via the trigemino-thalamic thalamic nuclei, which are believed to It should also be borne in mind that

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surgical interruption of the presumed order cells (in the spinal cord or the
A
nociceptive pathways does not always trigeminal system) have to pass through
permanently remove pain.24 a ‘gate’, which may be wide open (in
These factors, amongst others, point which case the resulting pain may be Increased transmitter release from
pre-synaptic neuron*
to the fact that pain is not the inevitable severe), closed (in which case no pain
consequence of action potentials will be felt) or, most commonly, partly Increased expression of receptors on
post-synaptic neuron
travelling to the central nervous system open. In practice it seems that the ‘gate’
along nociceptive nerves. However, it is consists of interneurons which can Enhanced post-synaptic depolarization*

also clear that the discrepancies inhibit activity beyond the first synapse, Metabolic changes in post-
synaptic neuron
between injury and pain do not result either by decreasing the release of the
B
simply from the conscious parts of the excitatory transmitters (presynaptic
Figure 6. Central sensitization. The effects of
brain ‘ignoring’ or ‘misinterpreting’ the inhibition) or by inhibiting the second-
afferent nerve input (A) on a post-synaptic
incoming signals. Rather it is because order cells (postsynaptic inhibition) neuron (B) can be enhanced in several ways.
nociceptive pathways are part of a (Figure 5B). These inhibitory effects are These mechanisms may be triggered by
dynamic system in which neural activity mediated by a variety of agents, persistent nociceptive inputs or by damage to
can be modified to suppress or enhance including γ-amino butyric acid (GABA), peripheral nerves. The facilitatory mechanisms
marked * may also be produced by the removal
the amount of pain that is experienced in glycine and endogenous opioid
of inhibitory influences.34
different circumstances. It is as if there peptides such as enkephalins and
is some sort of ‘volume control’ in the dynorphins. The interneurons
pathway linking the periphery with the themselves may be activated either by
consciousness. signals in other afferent nerves or by Knowledge of these segmental
signals descending from the brain. controls gave rise to the principle of
These mechanisms are outlined below transcutaneous electrical nerve
TRANSMISSION IN but readers may wish to refer to more stimulation – TENS26 – whereby
NOCICEPTIVE PATHWAYS detailed reviews.8 selective activation of Aβ nerves with
Transmission at the first synapse in electrical stimuli has been used to
nociceptive pathways is mediated by a Activation of Gate Control Interneurons by relieve pain. This concept has also been
number of chemicals, including Other Primary Afferent Neurons exploited in various forms of so-called
glutamate, Substance P and calcitonin There is ample evidence that activity in electronic dental analgesia, although
gene-related peptide. These substances large diameter (Aβ) afferent nerves from these are not always successful.27
are ‘excitatory’ in that they tend to the same neural segment of the body It should be noted that not all forms
depolarize (and thus produce activity in) can inhibit activity in second-order of TENS work via Aβ fibres acting
the post-synaptic neurons. However, nociceptive neurons (Figure 5C). Since segmentally. In particular, when TENS is
these excitatory effects can be the vast majority of Aβ nerves are used at relatively high intensities it may
decreased (‘inhibited’) by physiological mechanosensitive, these segmental exert its effects via descending
control mechanisms or enhanced inhibitory controls can be activated pathways (see below).
(‘facilitated’) under certain – often naturally by rubbing close to an injury
pathological – circumstances. (or a diseased tooth). From a clinical Activation of Gate Control Interneurons by
standpoint it is worth considering that, Pathways Descending from Areas in the
under normal circumstances, these Brain
Inhibitory Controls controls will almost always be active to a Electrical stimulation of sites in the
The inhibitory controls that modulate limited extent (given that mechano- brain (Figure 5D), and particularly the
activity in nociceptive pathways (Figure receptors are constantly being excited by brainstem, (e.g. the periaqueductal or
5) are often referred to as gate controls. our movements). Thus anything that periventricular grey matter, the raphe
The Gate Control Theory of Pain was reduces mechanoreceptive activity from nuclei) can produce analgesia, and
first proposed in 1965 by Melzack and part of the body is likely to increase the inhibit the responses of second-order
Wall.25 Although many of the details of sensitivity of that area for pain by nociceptive neurons. It is generally
the original model have been modified ‘opening the gate’. For example, this assumed that the underlying
as knowledge has increased, the might occur after pressure damage to a mechanisms again involve activation of
concept has endured because it is nerve (Aβ fibres are amongst the most interneurons mediating the gate
consistent with both clinical easily damaged by physical insult) or controls – on this occasion by nerve
observations of pain and laboratory when a patient reduces movement of a fibres descending from the brain
findings regarding nociceptive chronically painful region. This may (Figure 5D). In addition, some of the
mechanisms. The principle (Figure 5A) explain why re-establishing normal descending pathways may directly
is that the signals passing from primary mobility can contribute to the successful inhibit the nociceptive pathways (i.e.
afferent nociceptive nerves to second- treatment of some chronic pains. without the intermediary interneurons).

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Facilitation
In contrast to the inhibitory controls
described in the previous section, the
Somatosensory transmission of signals at the first
Cortex synapse in nociceptive pathways may
also be increased (‘facilitated’). When
general anaesthetics, such a ‘gain’ occurs in the nociceptive
hypnotic analgesia system, the effect is to increase the
strength and/or duration of the resulting
Thalamus pain. The most studied example of this is
the phenomenon of wind-up, whereby
narcotic analgesics, repetitive activation of nociceptive C-
electrical stimulation systems fibres brings about an enhanced
(TENS, EDA), response to subsequent activity in
counterirritation
these fibres.29 Wind-up may be brought
about by a number of factors, including
Trigeminal Trigemino-thalamic Tract
increased release by presynaptic
nucleus neurons of transmitters such as
caudalis
CNS Substance P, and increased
responsiveness of post-synaptic
receptors for Substance P (NK1
Surgical
receptors) and glutamate (NMDA
Trigeminal interruption PNS
Ganglion
receptors).30 The mechanisms of wind-
up may be similar but not identical31 to
those responsible for ‘long-term
potentiation’ that is believed to underlie
Nociceptive
some forms of learning and which also
Nerves results from repeated activation of
local anaesthetics NMDA receptors, notably in the
hippocampus.32 Indeed, it has been
suggested that wind-up may contribute
to the development of a ‘pain memory’
Nociceptors
at lower centres of the nervous
midline system.30
e.g. simple analgesics Perhaps more immediately relevant
(e.g. NSAIDs), than wind-up from a clinical perspective,
topical anaesthetics are the central sensitization
phenomena33,34 that occur in response to
Figure 7. Sites of action of pain control procedures. The most common means of controlling pain (blue
arrows) act primarily (but not exclusively) at the indicated points in the nociceptive pathways. Other persistent nociceptive inputs and to
classes of drug used in the control of orofacial pain – including antidepressants and membrane- peripheral nerve injuries. These can
stabilizing drugs (e.g. carbamazepine) – may have several sites of action, and for clarity of involve one or all of the processes
presentation these are not shown here. In addition, some forms of intractable pain are sometimes shown in Figure 6. Central sensitization
treated by surgically interrupting these pathways – most often at the points indicated by the green may contribute to hyperalgesia and
arrows.
some forms of allodynia (see above).
There is one other – recently
The descending fibres involved usually stimulus in another part of the body. discovered – mechanism that may
release the monoamine transmitters, enhance activity in central nociceptive
serotonin (5-HT) and noradrenaline. The first of these may explain the pathways with potentially enormous
It is not entirely clear how these reduced levels of pain felt in battle or on consequences for our understanding of
pathways are activated naturally but the sports field (see above) while the pain. Studies in vitro have shown that
there is evidence that this may occur latter is almost certainly the basis for some mammalian neurons, which may be
under at least two different counter-irritation phenomena28 whereby second-order nociceptive cells, have
circumstances: ‘one pain masks another’. It is possible intrinsic properties that allow them to
that some traditional methods for pain behave in a fashion which electrical

conditions of stress or anxiety; control, such as acupuncture, may be engineers would describe as bistable,

when there is a noxious/painful forms of counter-irritation. i.e. once these cells are depolarized by a

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transient excitatory influence they 6. Orchardson R, Cadden SW. The physiology of Pain 1975; 1: 213–231.
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