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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." 1

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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.” 2

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.

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.

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An illustration showing a nociceptor and an A-beta mechanoreceptor moving toward the feelings of pain and touch in the normal brain.An illustration showing sustained nociceptive input over a long period leading to excitotoxicity in the brain.
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.

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