Under the leadership of Allan I. Basbaum, Ph.D., neuroscientists at the University of California at San Francisco (UCSF) and the University of Minnesota have found that mice with a mutation in a gene that encodes for two chemicals, peptides called substance P and neurokinin A, have a reduced response to increased pain stimuli.
The experiment suggests that these peptides play a role in the body's pain responses and are essential components in the production of moderate-to-severe pain.
"After seeing this change, we now believe that substance P and neurokinin A must work in combination to account for pain responses in the body," said Dr. Basbaum, Chair of the Department of Anatomy and Physiology and the Division of Neuroscience at UCSF.
The scientists interrupted the gene encoding for preprotachykinin, whose peptide products include substance P, long believed to play an important role in pain response, and neurokinin A. They observed that the colony of mutant animals maintained the same response to mild pain as their non-mutant mouse counterparts. The mutant mice, however, exhibited a reduced response when subjected to stimuli producing moderate-to-intense pain. Scientists believe that neurokinin A, along with substance P, is released directly in response to intensified pain stimuli.
The study authors received funding from several institutes at the National Institutes of Health, including the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Dental Research, and the National Institute on Drug Abuse. Additional support came from the Howard Hughes Medical Institute.
"Although pain can in most cases be effectively treated, it is still a major health problem. More than 50 million Americans are partially or totally disabled by pain, from the occasional migraine headache to chronic back pain to the pain that accompanies diseases such as cancer," says NINDS Acting Director Audrey S. Penn, M.D. "There is a pressing need for more compounds in the arsenal of pain medications available to physicians and patients. This study puts us one step closer to correcting this very serious problem."
Certain chemicals, glutamate, for example, act in the transmission of pain messages by stimulating pain receptors. It has been previously demonstrated that when glutamate receptors are blocked, experimental mice exhibit a reduction in their responses to pain, providing scientists with compelling evidence of the chemical's role in transmission of pain messages.
Together with glutamate, substance P is known to stimulate pain receptors, but its precise action is less clear and its function complex. In the current study, release of substance P and neurokinin A causes inflammation and a pain response that is markedly reduced in the mutant mouse colony. Release of neurokinin A, the scientists believe, is required to produce moderate-to-intense pain.
Neurokinin A is a tachykinin, a type of peptide belonging to a family of chemicals known as kinins. Kinins play a role in inflammation and, in the case of pain, are thought to stimulate pain receptors in the body.
The study authors believe that drugs involved with the release of neurokinin A, called neurokinin antagonists, might one day be used in combination with morphine as a treatment for moderate-to-severe pain.
"There are many factors present in pain perception," says Cheryl Kitt, Ph.D., a health scientist administrator at the NINDS. "This research is a first step in looking at the role of tachykinins in moderate-to-intense pain. Although the findings have great potential for the development of new drugs for treating pain, we still need to investigate the roles of other factors, such as additional kinin genes."
"These results, if demonstrated in clinical studies, might result in a combination of neurokinin A antagonists and morphine for the treatment of moderate to intense pain. Such a treatment would have fewer side effects and would enable lower doses of morphine to be used," said Dr. Basbaum.
The NINDS, one of the National Institutes of Health located in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system and a lead agency for the Congressionally designated Decade of the Brain. The Institute is also one of 21 NIH components participating in the recently-established NIH Pain Research Consortium.
1Cao, Y.Q., Mantyh, P.W., Carlson, E.J., Gillespie, A.M., Epstein, C.J., Basbaum, A.I. Primary Afferent Tachykinins are Required to Experience Moderate to Intense Pain. Nature, Vol. 392, March 26, 1998, P. 390-394.