Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 10

Pain & Temperature 169

Hyperalgesia and allodynia signify increased sensitivity of
nociceptive afferent fibers. Figure 10–1 shows how chemicals
released at the site of injury can further activate nociceptors lead-
ing to inflammatory pain. Injured cells release chemicals such as
K

• that depolarize nerve terminals, making nociceptors more
  responsive. Injured cells also release bradykinin and Substance P,
  which can further sensitize nociceptive terminals. Histamine is

released from mast cells, serotonin (5-HT) from platelets, and

prostaglandins from cell membranes, all contributing to the

inflammatory process and they activate or sensitize the nocicep-

tors. Some released substances act by releasing another one (eg,

bradykinin activates both A

δ

and C fibers and increases synthesis

and release of prostaglandins). Prostaglandin E

2

(a cyclooxygen-

ase metabolite of arachidonic acid) is released from damaged

cells and produces hyperalgesia. This is why aspirin and other

NSAIDs (inhibitors of cyclooxygenase) alleviate pain.

DEEP PAIN

The main difference between superficial and deep sensibility is

the different nature of the pain evoked by noxious stimuli.

This is probably due to a relative deficiency of A

δ

nerve fibers

in deep structures, so there is little rapid, bright pain. In addi-

tion, deep pain and visceral pain are poorly localized, nauseat-

ing, and frequently associated with sweating and changes in

blood pressure. Pain can be elicited experimentally from the

periosteum and ligaments by injecting hypertonic saline into

them. The pain produced in this fashion initiates reflex con-

traction of nearby skeletal muscles. This reflex contraction is

similar to the muscle spasm associated with injuries to bones,

tendons, and joints. The steadily contracting muscles become

ischemic, and ischemia stimulates the pain receptors in the

muscles (see Clinical Box 10–3). The pain in turn initiates

more spasm, setting up a vicious cycle.

VISCERAL PAIN

In addition to being poorly localized, unpleasant, and associ-

ated with nausea and autonomic symptoms, visceral pain of-

ten radiates or is referred to other areas.

CLINICAL BOX 10–2

Neuropathic Pain

Neuropathic pain

may occur when nerve fibers are injured.

Commonly, it is excruciating and a difficult condition to treat.

It occurs in various forms in humans. For example, in

causal-

gia,

spontaneous burning pain occurs long after seemingly

trivial injuries. The pain is often accompanied by

hyperalge-

sia

and

allodynia. Reflex sympathetic dystrophy

is often

present as well. In this condition, the skin in the affected area

is thin and shiny, and there is increased hair growth. Research

in animals indicates that nerve injury leads to sprouting and

eventual overgrowth of noradrenergic sympathetic nerve fi-

bers into the dorsal root ganglia of the sensory nerves from

the injured area. Sympathetic discharge then brings on pain.

Thus, it appears that the periphery has been short-circuited

and that the relevant altered fibers are being stimulated by

norepinephrine at the dorsal root ganglion level. Alpha-adre-

nergic blockade produces relief of causalgia-type pain in hu-

mans, though for unknown reasons

α

1

-adrenergic blockers

are more effective than

α

2

-adrenergic blocking agents. Treat-

ment of painful sensory neuropathy is a major challenge

and

current therapies are often inadequate.

FIGURE 10–1
In response to tissue injury, chemical mediators can sensitize and activate nociceptors.
These factors contribute to hy-
peralgesia and allodynia. Tissue injury releases bradykinin and prostaglandins that sensitize or activate nociceptors, which in turn releases sub-
stance P and calcitonin gene-related peptide (CGRP). Substance P acts on mast cells to cause degranulation and release histamine, which activates
nociceptors. Substance P causes plasma extravasation and CGRP dilates blood vessels; the resulting edema causes additional release of bradykinin.
Serotonin (5-HT) is released from platelets and activates nociceptors.
(From Kandel ER, Schwartz JH, Jessell TM [editors]:
Principles of Neural Science.
McGraw-Hill, 2000.)

Lesion 5-HT

Bradykinin

Prostaglandin

K+

Mast cell

Spinal cord

Histamine

CGRP

CGRP

Blood

vessel

Substance P

Dorsal root

ganglion neuron

Substance P