Paper of the Month: Separating out the desirable from the undesirable in opioid use

About the School of Medicine Paper of the Month

The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Senior Associate Dean for Research Mary Stenzel-Poore, Ph.D., Associate Dean for Clinical Science Eric Orwoll, M.D., and Assistant Dean for Basic Research Mary Heinricher, Ph.D.

This month's featured paper is from the lab of Susan Ingram, Ph.D., associate professor of neurological surgery, and is titled, "Contribution of Adenylyl Cyclase Modulation of Pre- and Postsynaptic GABA Neurotransmission to Morphine Antinociception and Tolerance." It was published in Neuropsychopharmacology.

Ingram lab

April 28, 2014

Opioids are powerful analgesics with the ability to relieve severe and chronic pain. But the body's rapid development of tolerance to the pain-relieving effects, termed antinociception, of opioids leads to increasingly larger doses in order to achieve effective treatment. Currently, each year over $8.6 billion dollars are spent in the United States for health, work and legal issues associated with the use and abuse of prescription opioids. 

Pain involves complex neurobiological mechanisms that are being researched by many here at OHSU. Susan Ingram, Ph.D., associate professor of neurological surgery, has recently made major strides in understanding both the cellular and molecular facets of the complex opioid pain problem.

Previous work in this area of research demonstrated that mu opioid receptors (MOPrs) in the brain are involved in opioid-induced antinociception. However, scientists have yet to develop a molecular understanding of why opioid-induced pain relief decreases with repeated or continuous administration. 

A significant advancement in this field was accomplished when a MOPr knockout mouse model was developed by Dr. Brigitte Kieffer at the Universite Louis Pasteur. Administration of morphine had no analgesic effects in this mouse model.  Physiological adaptations normally induced by chronic morphine administration in a specific area of the brain called the ventrolateral periaqueductal gray (vlPAG) were also abolished. These results indicated that MOPrs are critical for opioid analgesia, tolerance and dependence. 

Subsequently, much research has focused on physiological adaptations induced during the development of morphine tolerance, with attention focused on MOPrs desensitization. Dr. Ingram's previous work demonstrated that desensitization was, in fact, not an important cellular adaptation involved in antinociceptive tolerance. With desensitization off the table as a molecular mechanism, Dr. Ingram's focus moved towards a different, well characterized morphine-induced molecular adaptation: increased regulatory enzyme activity. 

Repeated morphine administration that leads to development of tolerance and dependence results in the upregulation of an enzyme known as adenylyl cyclase. Inhibition of this enzyme's action during morphine pretreatment blocks the development of morphine tolerance and dependence. However, it was not known how modulation of adenylyl cyclase leads to changes in antinociception.

Dr. Ingram's lab has recently published new findings in the journal Neuropsychopharmacology illuminating the role of adenylyl cyclase in opioid pain pathways.  "We demonstrate in this paper that activation of adenylyl cyclase promotes antinociceptive tolerance," said Dr. Ingram. "Conversely, inhibition of adenylyl cyclase activity blocked the development of tolerance. This indicates that blocking adenylyl cyclase activity is sufficient to reverse morphine tolerance." 

Electrophysiological studies demonstrated that activation of adenylyl cyclase increased the frequency of presynaptic release of GABA, an inhibitory neurotransmitter in the central nervous system. GABAA receptor function in the vlPAG was also found to be altered after repeated morphine injections.

"The upregulation of adenylyl cyclase activity caused by repeated morphine administration produces antinociceptive tolerance by modulating both pre- and postsynaptic GABA neurotransmission," said Dr. Ingram. This is the first time that opioid regulation of GABAA receptors has been demonstrated in the vlPAG.

"This important paper provides new insights into the plasticity of the nervous system's response to opioid analgesic drugs," said Mary Heinricher, Ph.D., assistant dean for basic science. "I chose this article as the Paper of the Month because this team used a combination of approaches to elegantly tease out molecular effects. This is really interesting because separation of the different actions of opioids will allow us to potentially separate out the desirable analgesic effects from the undesirable tolerance and dependency effects of these drugs." 

The finding that both pre- and postsynaptic GABA neurotransmission is modulated in morphine tolerance will help unravel the myriad of molecular compensatory changes that have been associated with morphine tolerance. 

"It is possible that adenylyl cyclase inhibitors and allosteric GABAA agonists may be targets for rational drug design," said Dr. Ingram. "This could potentially improve opioid antinociception and decrease tolerance issues." 

Future studies planned by Dr. Ingram and colleagues include determining if the regulation of GABAA receptors is due to altered expression or trafficking of the proteins.

Contribution of Adenylyl Cyclase Modulation of Pre- and Postsynaptic GABA Neurotransmission to Morphine Antinociception and Tolerance.
Bobeck EN, Chen Q, Morgan MM, Ingram SL.
Neuropsychopharmacology. 2014 Mar 13. doi: 10.1038/npp.2014.62. [Epub ahead of print]

Bobeck, E.N.aChen, Q.bMorgan, M.M.aIngram, S.L.b 

Department of Psychology, Washington State University, Vancouver, WA, USA
Department of Neurological Surgery, Oregon Health and Science University, Portland, OR, USA


Left to right: Katherine Suchland, Dr. Ingram, Karen Tonsfeldt and Minghua Li