An unexplained clinical paradox is that opioids can produce unexpected abnormal pain (i.e., hyperesthesias including hyperalgesia and allodynia) during their use for pain relief. Opioid-induced hyperalgesia (i.e., increased sensitivity to noxious or non-noxious sensory stimuli) is also reliably demonstrated in animals while opioids are continuously delivered suggesting that this phenomenon is not the result of opioid withdrawal. In our previous funding period, we demonstrated that continuous opioid administration to animals over a period of several days elicits remarkable, pronociceptive neuroplastic adaptations in both the peripheral and central nervous systems, which are likely to underlie the observed hyperalgesia. In spite of the potential clinical significance of such opiate-induced changes in the nervous system (i.e., the possibility that these may produce deleterious effects in patients), the mechanisms of opiate-induced hyperalgesia remain unknown. Hyperalgesia resulting from injury are characterized by a state of """"""""central sensitization"""""""" which results from repetitive inputs to the central nervous system from injury-induced enhanced discharge of afferent fibers. Opioid-induced hyperalgesic states also might be characterized by a state of """"""""central sensitization"""""""" or an analogous state of """"""""sensitization"""""""" in the spinal dorsal horn. The hyperalgesia associated with opiates, however, develops in the absence of an injury with no known basis for sustained afferent discharge to the spinal cord. Opioid-induced hyperalgesia may well share some common mechanisms with injury-induced hyperalgesic states but could equally have other unique sustaining mechanisms. This proposal is designed to explore the hypothesis that opioids induce a state of """"""""spinal sensitization"""""""" which may occur as consequence of (1) activation of descending pain facilitation mechanisms arising in the rostral ventromedial medulla (RVM) through enhanced release of RVM CCK;(2)upregulation of spinal dynorphin as a consequence of descending facilitation;and (3) the dynorphin-dependent increase in basal and/or evoked spinal PGE2 release which acts to sensitize primary afferent fibers to peripheral stimuli. This hypothesis will be tested, using behavioral, neurochemical and electrophysiological approaches. Given the prevalent reliance of our society on opiates for treatment of pain, understanding of the fundamental biological mechanisms associated with exposure to these drugs is essential in developing approaches that prevent the neurobiological changes which may promote pain.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IFCN-K (02))
Program Officer
Rapaka, Rao
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Arizona
Schools of Medicine
United States
Zip Code
Bannister, Kirsty; Qu, Chaoling; Navratilova, Edita et al. (2017) Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain. Pain 158:2386-2395
Lee, Yeon Sun; Muthu, Dhanasekaran; Hall, Sara M et al. (2014) Discovery of amphipathic dynorphin A analogues to inhibit the neuroexcitatory effects of dynorphin A through bradykinin receptors in the spinal cord. J Am Chem Soc 136:6608-16
De Felice, Milena; Melchiorri, Pietro; Ossipov, Michael H et al. (2012) Mechanisms of Bv8-induced biphasic hyperalgesia: increased excitatory transmitter release and expression. Neurosci Lett 521:40-5
Bannister, Kirsty; Sikandar, Shafaq; Bauer, Claudia S et al. (2011) Pregabalin suppresses spinal neuronal hyperexcitability and visceral hypersensitivity in the absence of peripheral pathophysiology. Anesthesiology 115:144-52
De Felice, Milena; Ossipov, Michael H; Wang, Ruizhong et al. (2010) Triptan-induced latent sensitization: a possible basis for medication overuse headache. Ann Neurol 67:325-37
Chen, Qingmin; Vera-Portocarrero, Louis P; Ossipov, Michael H et al. (2010) Attenuation of persistent experimental pancreatitis pain by a bradykinin b2 receptor antagonist. Pancreas 39:1220-5
Ossipov, Michael H; Dussor, Gregory O; Porreca, Frank (2010) Central modulation of pain. J Clin Invest 120:3779-87
De Felice, Milena; Ossipov, Michael H; Wang, Ruizhong et al. (2010) Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal ganglion dural afferents underlies increased responsiveness to potential migraine triggers. Brain 133:2475-88
Rahman, Wahida; Bauer, Claudia S; Bannister, Kirsty et al. (2009) Descending serotonergic facilitation and the antinociceptive effects of pregabalin in a rat model of osteoarthritic pain. Mol Pain 5:45
Lai, Josephine; Luo, Miaw-chyi; Chen, Qingmin et al. (2008) Pronociceptive actions of dynorphin via bradykinin receptors. Neurosci Lett 437:175-9

Showing the most recent 10 out of 19 publications