The long-term goal of the proposed research is to further our understanding of N-type Ca2+ channel modulation by opioid receptor-like 1 (NOP, or OP4) opioid receptors in rat stellate ganglion (SG) neurons involved in pain signaling. This project will focus on identifying the specific signal transduction elements that contribute to NOP receptor desensitization, the pharmacological profile of constitutively active receptors and N-type Ca2+ channel inhibition. The NOP receptor is activated by the endogenous peptide nociceptin FQ (N/OFQ). N/OFQ-activated NOP receptors can exert algesic or analgesic effects in animal pain models. Clinical studies have shown that SG blockade can be used to treat patients that suffer from chronic facial pain or headaches. A combination of electrophysiological, immunofluorescence, and molecular techniques will be used to probe the mechanisms by which NOP receptors modulate N-type Ca2+ channels.
The specific aims of this proposal are to: i) identify the specific Gb and Gg subunits that mediate N-type Ca2+ channel inhibition for N/OFQ-stimulated ii) identify the G protein-coupled receptor kinase (GRK) isoform that mediates desensitization of NOP receptors iii) to determine the interaction of GRK and Gb proteins with constitutively active NOP receptors, as well as to examine the pharmacological profile of the receptors. NOP receptors and N-type Ca2+ channels are known to participate in pain transmission. Thus, the proposed studies will help to clarify the signaling mechanisms underlying these processes and aid in the development of novel agents for the treatment of pain, such as those associated with chronic headache and complex region pain syndrome, and at the same time prevent opioid tolerance and addiction.

Public Health Relevance

The purpose of this grant proposal is to examine the cellular mechanisms by which opiate receptors that are involved in pain processes regulate the entry of Ca2+ ions into nerves. We will identify specific cellular proteins that affect the functional response of these receptors, and we will also study the pharmacology of these receptors. These studies will lead to new information that can be employed to help treat pain without developing tolerance or opiate addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA025574-06
Application #
7777836
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Hillery, Paul
Project Start
2009-04-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
6
Fiscal Year
2010
Total Cost
$268,711
Indirect Cost
Name
Pennsylvania State University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Freet, Christopher S; Alexander, Danielle N; Imperio, Caesar G et al. (2017) Heroin-induced suppression of saccharin intake in OPRM1 A118G mice. Brain Res Bull :
Mahmoud, Saifeldin; Farrag, Mohamed; Ruiz-Velasco, Victor (2016) G?7 proteins contribute to coupling of nociceptin/orphanin FQ peptide (NOP) opioid receptors and voltage-gated Ca(2+) channels in rat stellate ganglion neurons. Neurosci Lett 627:77-83
Freet, Christopher S; Ballard, Sarah M; Alexander, Danielle N et al. (2015) Cocaine-induced suppression of saccharin intake and morphine modulation of Ca²? channel currents in sensory neurons of OPRM1 A118G mice. Physiol Behav 139:216-23
Farrag, Mohamed; Laufenberg, Lacee J; Steiner, Jennifer L et al. (2015) Modulation of voltage-gated Ca2+ channels by G protein-coupled receptors in celiac-mesenteric ganglion neurons of septic rats. PLoS One 10:e0125566
Laufenberg, Lacee J; Weller, Gregory E; Lang, Charles H et al. (2013) Nociceptin receptor signaling in sympathetic neurons from septic rats. J Surg Res 184:973-80
Mahmoud, Saifeldin; Yun, Jong K; Ruiz-Velasco, Victor (2012) G?2 and G?4 participate in the opioid and adrenergic receptor-mediated Ca2+ channel modulation in rat sympathetic neurons. J Physiol 590:4673-89
Margas, Wojciech; Mahmoud, Saifeldin; Ruiz-Velasco, Victor (2010) Muscarinic acetylcholine receptor modulation of mu (mu) opioid receptors in adult rat sphenopalatine ganglion neurons. J Neurophysiol 103:172-82
Mahmoud, Saifeldin; Margas, Wojciech; Trapella, Claudio et al. (2010) Modulation of silent and constitutively active nociceptin/orphanin FQ receptors by potent receptor antagonists and Na+ ions in rat sympathetic neurons. Mol Pharmacol 77:804-17