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  Future Directions

Ruda and Iadarola have continued their laboratory investigations of pain, but have worked to integrate their studies vertically with clinical observations and research. Their studies have established that the plasticity observed in the behavioral responses to pain, and implied in the theory of chronic pain disorders as a toxic excitability of nociceptive neurons, can also be understood as a phenomenon of altered gene expression which underlies the neurochemical activity of the synaptic pathways.

“It makes no sense to assume that male and female processing of pain are the same.” 15
- M. A. Ruda on gender and pain

Working with colleagues, including Ke Ren, Marino DeLeon, and Richard Nahin, in recent work, Ruda has concentrated on problems of gender differences in pain, and the effects of pain on neonatal development. She has examined the responses of newborn rats to painful stimuli and later retested the same rats as adults. Her observations suggest that the experience of pain during neonatal development has longterm sensory and behavioral consequences. She has also demonstrated crucial differences in pain responses between male and female animals and in different phases of the females' reproductive cycles.

A graph showinghyperalgesic responses to heat stimuli in estrous female rats v. non-estrousfemale and male rats. The first graph shows Paw Withdrawal Latancy and The second of twographs showing hyperalgesic responses to heat stimuli. This graph depicts Thermal Hyperalgesia.

Hyperalgesic responses to heat stimuli in estrous female rats v. non-estrous female and male rats. From Heather Bradshaw, Julie Miller, Qingdong Ling, Kirsten Malsnee, and M.A. Ruda, Sex differences and phases of the estrous cycle alter the response of spinal cord dynorphin neurons to peripheral inflammation and hyperalgesia. Pain v. 88 (2000): 97.

The 1998 NIH Symposium, " Gender and Pain ", organized by Ruda, brought together researchers from all over the country to discuss male/female differences in the epidemiology, physiology, pharmacology, and psychology of pain. Ladarola, working with such collaborators as Dr. H-Y. T. Yang, Jun Gu, and Donna Messersmith, has worked on describing the multi-step genetic expression of the precursor proteins for dynorphin and enkephalin under painful and stressful stimuli. His lab has helped to develop the new methods required for these experiments, including transient transfection (infection of a cell with nucleic acid to induce replication) and injections of drugs such as cocaine, morphine, and clonidine. Most recently, he and his co-workers have employed subtraction cloning to identify new pain-relevant genes in the dorsal horn.

In the mid-1990s, Iadarola, with Gracely, Dionne, and colleague Robert Coghill, began a series of studies of the brain, using PET [Positron Emission Tomography] imaging. In these images, researchers are for the first time able to observe the activity of brain cells responding to, and integrating, the pain information sent by the nervous system. They can compare the differential responses of normal volunteers and pain patients to heat, cold, and inflammation, and can correlate these with the subject's verbal assessment of the pain sensation.

A particularly exciting project began in 1998, when Iadarola and his co-workers decided to investigate a genetic therapy for chronic pain. They developed an innovative gene-transfer model that triggers meningeal cells to secrete beta-endorphin into the cerebrospinal fluid. The new therapy will soon be tested in clinical trials. For more information please view the NIH Catalyst article and NIH Catalyst commentary.

Back To Top | Photography Credits


15 Oral history interview with M. A. Ruda, 1999. Tapes and transcript to be deposited in the NIH History Office and the John C. Liebeskind History of Pain Collection, UCLA.

Photograph of M.A. Ruda, mid-1990s. Photograph courtesy of NIDCR Public Information Office.
M.A. Ruda, 1990s
Photograph of Michael Iadarola with young visitors to the laboratory, mid-1990s.
Michael Iadarola with visitors his laboratory, 1990s


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