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A Laboratory Model For Clinical Pain
Mitchell Max's clinical trials with diabetic neuropathy and postherpetic
neuralgia patients addressed the major enigma of the pain field: the mechanism
involved in chronic neuropathic pain. The classic neuropathic pain disorders
are the agonizing conditions known as causalgia -- "the most terrible
of all tortures", in the words of S. Weir Mitchell , the Civil War
physician who first described it -- and reflex sympathetic dystrophy (RSD)
(more recently termed chronic regional pain syndrome).
Usually occurring after nerve injury to a hand, foot, arm or leg, causalgia
and RSD may be triggered by any minor injury, by a surgical procedure,
or a serious trauma. They are characterized by pain which persists after
the original injury has healed; by hyperalgesia , intensified perception
of a mild painful stimulus, and allodynia , perception of pain in response
to the lightest of touches; even by spontaneous pain, where the patient
reports pain although no stimulus is present! The pain often proves
resistant to all treatment, including medication, counter- stimulation,
anesthetic blocks, psychotherapy, and even neurosurgery. The unhappy
victim of such a syndrome becomes withdrawn and depressed, resists all
physical contact, and guards the affected limb constantly.
Researchers had tried to reproduce the symptoms of neuropathic pain in
animals, but without success. At NIDR, they injected the hind paws of
rats with solutions causing brief inflammation, such as Freund's adjuvant
or capsaicin , then tested them for hyperalgesia and allodynia by placing
them on warmed surfaces and timing the "withdrawal latency"
- the time before the rat lifted the affected paw. An improved method,
developed by Kenneth Hargreaves of the NAB, was to place the rat in a
glass box and direct a pinpoint radiant heat stimulus at the inflamed
paw. An attached photoelectric cell measured the withdrawal latency in
fractions of seconds. The rats showed increased withdrawal times, moving
the affected paws more quickly when exposed to warm and mild heat stimuli.
But the symptoms were short lived and there was no evidence of spontaneous
pain.
In 1988, Gary Bennett , a physiological psychologist working in the NAB,
and Yi -Kuan Xie, a visiting scientist from Beijing, decided to try tying
loose ligatures around the sciatic nerve of the rat's left hind leg, to
observe any changes in the firing rates of the affected nerves. (These
changes would reverse as soon as the sutures were absorbed.) They left
the rat overnight and came back the next day to find it guarding the affected
paw in a very unusual way, refusing to let it touch the ground. This was
the first observation of the chronic constriction injury model: the rat
with symptoms similar to causalgia or RSD.
Bennett and Xie recognized the characteristic guarding action of a causalgia
or RSD patient. Excitedly, they tested various non-painful and mildly
painful stimuli on the rat's paw and found hyperalgesia and allodynia
responses similar to those observed in patients. And, although the rat
continued to eat, sleep and groom normally, the continued guarding behavior
was evidence of some spontaneous pain.
Looking for human subjects to compare observations, Bennett consulted
with Max and his colleagues at the Clinical Center , who were interested,
but were not working with these disorders. He found the patients he needed
at a clinic in Philadelphia, and, with their cooperation, began a series
of comparison tests. As Bennett describes these studies, "It got
to the point where we were doing so many things so rapidly to these patients
that we started videotaping it, because things were happening very quickly....And
some of these wonderful patients would come back two, three, four times
for us; these people demonstrated courage, real courage." 12
This was the beginning of a close and exciting collaboration between Bennett
in the lab and Max and Gracely in the clinic, comparing and discussing
their observations.
Mitchell Max on the CCI model collaboration:
“Prior to this, the clinical work had been kind of isolated….now
every month, the basic scientists had a new animal observation [to be verified
in patients]; it was a very exciting time.” 13
Through careful comparison studies, Bennett and his colleagues established
that the rat's behavioral responses to pain were very similar to those of
the RSD patients. (One difference was that, after a period of time, the
rat's abnormal behavior disappeared as the sutures were absorbed and the
constriction relieved.) Bennett and his colleagues began recording the nerve
activity patterns in the area of the rat's injury; these were characterized
by persistent, spontaneous firing. Even in the absence of any direct stimulus,
the rat's sensory system behaved exactly as it would in response to pain.
In an important 1988 paper, Bennett, Gracely, and Susan Lynch hypothesized
that when certain injuries or inflammatory conditions triggered persistent
firing over a long period of time, the ongoing nociceptive, or noxious,
input created a toxic excitation of the brain and spinal cord cells - such
that the entire system was chronically primed to signal pain in response
to the mildest stimulus, or even to none at all.
Development of " excitotoxicity " in response to
ongoing pain signals from an injured nerve. Illustration by Donald Bliss,
adapted from: Richard Gracely, Susan Lynch, and Gary Bennett, Painful neuropathy:
altered central processing maintained dynamically by peripheral input. Pain
v. 51 (1992): 188.
The chronic constriction injury model helped open new avenues of research
into the mechanisms of all forms of neuropathic pain and the search for
effective treatments.
Back To Top | Photography Credits
References
12 Oral history interview
with Gary Bennett, 1999. Tapes and transcript to be deposited in the NIH
History Office and the John C. Liebeskind History of Pain Collection,
UCLA.
13 Oral history interview
with Mitchell Max, 1999.
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A World War II causalgia patient.
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A rat guarding its paw. |
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Gary Bennett. |
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