The use of opiates to treat pain is a significant cause of addiction, but there are no adequate alternatives. Neurokinins and opioids are two neuropeptides important in acute and chronic pain; hence mechanisms that control their release in the spinal cord could be targets for the development of new analgesics. Neurokinin release from primary afferent terminals appears to be inhibited by muopioid, cannabinoid, alpha2 adrenergic and GABAB receptors, but their mechanisms of action, relative efficacy and physiological relevance have not been established. Receptors that modulate spinal opioid release are virtually unknown. Long term objectives: A) to create a model integrating the actions of receptors that control neurokinin release from primary afferents; B) to understand how different physiological states determine the release of opioids in the spinal cord, identifying the neural pathways and neurotransmitter systems involved.
Specific Aims : 1) to determine whether opioid, cannabinoid, adrenergic and GABAB receptors inhibit neurokinin release from primary afferent terminals using a common signalling pathway; 2) to identify neurotransmitter systems that inhibit opioid release in the dorsal horn; 3) to identify neuronal pathways that evoke opioid release in the dorsal horn. Research Design: Rat spinal cord slices will be electrically stimulated at the dorsal root to evoke neurokinin release, or at the dorsal horn or the dorsolateral funiculus to evoke opioid release. Internalization of neurokinin 1 receptors and mu-opioid receptors will be used to measure neurokinin and opioid release, respectively. This will be validated using immunoassays and transgenic mice. In vivo experiments will compare the effect of drugs on behavioral pain responses and receptor internalization in the dorsal horn. They will also determine whether noxious stimuli or stimulation of the periaqueductal gray or the nucleus raphe magnus produce mu-opioid receptor internalization in the spinal cord. The neural pathways involved will be studied using selective spinal cord lesions.

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
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Zhang, Guohua; Chen, Wenling; Lao, Lijun et al. (2010) Cannabinoid CB1 receptor facilitation of substance P release in the rat spinal cord, measured as neurokinin 1 receptor internalization. Eur J Neurosci 31:225-37
Chen, W; Zhang, G; Marvizón, J C G (2010) NMDA receptors in primary afferents require phosphorylation by Src family kinases to induce substance P release in the rat spinal cord. Neuroscience 166:924-34
Zhang, Guohua; Chen, Wenling; Marvizón, Juan Carlos G (2010) Src family kinases mediate the inhibition of substance P release in the rat spinal cord by ?-opioid receptors and GABA(B) receptors, but not ?2 adrenergic receptors. Eur J Neurosci 32:963-73
Adelson, D; Lao, L; Zhang, G et al. (2009) Substance P release and neurokinin 1 receptor activation in the rat spinal cord increase with the firing frequency of C-fibers. Neuroscience 161:538-53
Marvizón, Juan Carlos G; Chen, Wenling; Murphy, Niall (2009) Enkephalins, dynorphins, and beta-endorphin in the rat dorsal horn: an immunofluorescence colocalization study. J Comp Neurol 517:51-68
Chen, W; Marvizón, J C G (2009) Acute inflammation induces segmental, bilateral, supraspinally mediated opioid release in the rat spinal cord, as measured by mu-opioid receptor internalization. Neuroscience 161:157-72
Chen, Wenling; Song, Bingbing; Zhang, Guohua et al. (2008) Effects of veratridine and high potassium on micro-opioid receptor internalization in the rat spinal cord: stimulation of opioid release versus inhibition of internalization. J Neurosci Methods 170:285-93
Lao, Lijun; Song, Bingbing; Chen, Wenling et al. (2008) Noxious mechanical stimulation evokes the segmental release of opioid peptides that induce mu-opioid receptor internalization in the presence of peptidase inhibitors. Brain Res 1197:85-93
Chen, Wenling; Song, Bingbing; Marvizon, Juan Carlos G (2008) Inhibition of opioid release in the rat spinal cord by alpha2C adrenergic receptors. Neuropharmacology 54:944-53
Marvizon, J C G; Perez, O A; Song, B et al. (2007) Calcitonin receptor-like receptor and receptor activity modifying protein 1 in the rat dorsal horn: localization in glutamatergic presynaptic terminals containing opioids and adrenergic alpha2C receptors. Neuroscience 148:250-65

Showing the most recent 10 out of 24 publications