There is an urgent need for effective, non-opioid treatments for pain. Although the brain possesses pain- relieving (analgesic) circuits that are independent of endogenous opioids, little is known about substances capable of activating these systems. Dr. Lindsay Hough and colleagues at Albany Medical College discovered a novel class of non-opioid analgesic drugs derived from histamine antagonists. The prototype compound was named improgan. Improgan is highly effective in attenuating thermal and mechanical pain behaviors in rats and mice, but does not impair motor coordination or locomotor activity, and at least in limited testing, does not produce tolerance with daily dosing. Improgan's analgesic effects are not mediated by known opioid or histamine receptors. Nevertheless, improgan's actions appear to intersect with those of opioids in that focal application of improgan in the midbrain periaqueductal gray or in the rostral ventromedial medulla (RVM) produces effective antinociception. Moreover, the analgesic actions of intracerebroventricularly administered improgan are attenuated or blocked by inactivation of the RVM. Thus, improgan, like opioids, appears to activate an output from the RVM to produce its antinociceptive effect. Previous work from my laboratory has provided a number of insights into the actions of opioids in the RVM, and how these are translated into behaviorally measurable antinociception. The goal of the present experiments is to use our knowledge of opioid actions in the RVM as a framework for understanding the actions of improgan at the level of neuronal circuitry. We will use a combination of single cell recording and behavioral pharmacology to characterize the neural substrate of improgan analgesia within the RVM at the level of individual neurons and of the RVM circuit as a whole. These data will therefore provide mechanistic understanding of the link between improgan pharmacology and behavior. By comparing the neural mechanisms of this novel, non-opioid analgesic with the well-documented actions of opioids, these studies should provide new knowledge that may lead to development of clinically useful, non-opioid analgesic drugs.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Aigner, Thomas G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oregon Health and Science University
Schools of Medicine
United States
Zip Code
Cleary, Daniel R; Phillips, Ryan S; Wallisch, Michael et al. (2012) A novel, non-invasive method of respiratory monitoring for use with stereotactic procedures. J Neurosci Methods 209:337-43
Phillips, Ryan S; Cleary, Daniel R; Nalwalk, Julia W et al. (2012) Pain-facilitating medullary neurons contribute to opioid-induced respiratory depression. J Neurophysiol 108:2393-404
Heinricher, M M; Martenson, M E; Nalwalk, J W et al. (2010) Neural basis for improgan antinociception. Neuroscience 169:1414-20
Heinricher, Mary M; Maire, Jennifer J; Lee, Delaina et al. (2010) Physiological basis for inhibition of morphine and improgan antinociception by CC12, a P450 epoxygenase inhibitor. J Neurophysiol 104:3222-30