168
SECTION III
Central & Peripheral Neurophysiology
Mapping experiments show that the skin has discrete cold-
sensitive and heat-sensitive spots. There are 4 to 10 times as
many cold-sensitive as heat-sensitive spots. The threshold for
activation of
warmth receptors
is 30 °C, and they increase their
firing rate up to 46 °C.
Cold receptors
are inactive at tempera-
tures of 40 °C, but then steadily increase their firing rate as skin
temperature falls to about 24 °C. As skin temperature further
decreases, the firing rate of cold receptors decreases until the
temperature reaches 10 °C. Below that temperature, they are
inactive and the cold becomes an effective local anesthetic.
Because the sense organs are located subepithelially, it is the
temperature of the subcutaneous tissues that determines the
responses. Cool metal objects feel colder than wooden objects
of the same temperature because the metal conducts heat
away from the skin more rapidly, cooling the subcutaneous
tissues to a greater degree.
A major advance in this field has been the cloning of three
thermoreceptors and nociceptors. The receptor for moderate
cold is the
cold-
and
menthol-sensitive receptor 1 (CMR 1).
Two types of
vanilloid receptors
respond to noxious heat (
VR1
and
VRL-1
). Vanillins are a group of compounds, including
capsaicin, that cause pain. The VR1 receptors respond not only
to capsaicin but also to protons and to potentially harmful tem-
peratures above 43 °C.
VRL-1,
which responds to temperatures
above 50 °C but not to capsaicin, has been isolated from C
fibers. There may be many types of receptors on single periph-
eral C fiber endings, so single fibers can respond to many dif-
ferent noxious stimuli. However, the different properties of the
VR1 and the VRL-1 receptors make it likely that there are many
different nociceptor C fibers systems as well.
CMR1, VR1, and VRL1 are members of the
transient
receptor potential (TRP)
family of excitatory ion channels.
VR1 has a PIP
2
binding site, and when the amount of PIP
2
bound is decreased, the sensitivity of the receptors is
increased. Aside from the fact that activation of the cool
receptor causes an influx of Ca
2+
, little is known about the
ionic basis of the initial depolarization they produce. In the
cutaneous receptors in general, depolarization could be due to
inhibition of K
- channels, activation of Na
channels, or inhi-
bition of the Na
–K
pump, but the distinction between these
possibilities has not been made.
CLASSIFICATION OF PAIN
For scientific and clinical purposes,
pain
is defined by the In-
ternational Association for the Study of Pain (IASP) as, “an
unpleasant sensory and emotional experience associated with
actual or potential tissue damage, or described in terms of
such damage.” This is to be distinguished from the term
noci-
ception
which the IASP defines as the unconscious activity in-
duced by a harmful stimulus applied to sense receptors.
Pain is sometimes classified as fast and slow pain. A painful
stimulus causes a “bright,” sharp, localized sensation
(fast pain)
followed by a dull, intense, diffuse, and unpleasant feeling
(slow
pain).
Evidence suggests that fast pain is due to activity in the
A
δ
pain fibers, whereas slow pain is due to activity in the C pain
fibers.
Itch
and
tickle
are related to pain sensation (see Clinical
Box 10–1).
Pain is frequently classified as
physiologic
or
acute pain
and
pathologic
or
chronic pain,
which includes
inflamma-
tory pain
and
neuropathic pain.
Acute pain typically has a
sudden onset and recedes during the healing process. Acute
pain can be considered as “good pain” as it serves an impor-
tant protective mechanism. The withdrawal reflex is an exam-
ple of this protective role of pain.
Chronic pain can be considered “bad pain” because it persists
long after recovery from an injury and is often refractory to
common analgesic agents, including nonsteroidal anti-inflam-
matory drugs (NSAIDs) and opiates. Chronic pain can result
from nerve injury
(neuropathic pain)
including diabetic neu-
ropathy, toxin-induced nerve damage, and ischemia.
Causalgia
is a type of neuropathic pain (see Clinical Box 10–2).
Pain is often accompanied by
hyperalgesia
and
allodynia.
Hyperalgesia is an exaggerated response to a noxious stimulus,
whereas allodynia is a sensation of pain in response to an innoc-
uous stimulus. An example of the latter is the painful sensation
from a warm shower when the skin is damaged by sunburn.CLINICAL BOX 10–1
Itch & Tickle
Itching
(pruritus)
is not much of a problem for normal indi-
viduals, but severe itching that is difficult to treat occurs in
diseases such as chronic renal failure, some forms of liver dis-
ease, atopic dermatitis, and HIV infection. Especially in areas
where many naked endings of unmyelinated nerve fibers oc-
cur, itch spots can be identified on the skin by careful map-
ping. In addition, itch-specific fibers have been demon-
strated in the ventrolateral spinothalamic tract. This and
other evidence implicate the existence of an itch-specific
path. Relatively mild stimulation, especially if produced by
something that moves across the skin, produces itch and
tickle. Scratching relieves itching because it activates large,
fast-conducting afferents that gate transmission in the dorsal
horn in a manner analogous to the inhibition of pain by stim-
ulation of similar afferents. It is interesting that a tickling sen-
sation is usually regarded as pleasurable, whereas itching is
annoying and pain is unpleasant. Itching can be produced
not only by repeated local mechanical stimulation of the skin
but also by a variety of chemical agents.
Histamine
pro-
duces intense itching, and injuries cause its liberation in the
skin. However, in most instances of itching, endogenous his-
tamine does not appear to be the responsible agent; doses
of histamine that are too small to produce itching still pro-
duce redness and swelling on injection into the skin, and se-
vere itching frequently occurs without any visible change in
the skin. The
kinins
cause severe itching.