Peripherally acting opioids are desirable for producing analgesia while eliminating debilitating central side effects, such as tolerance, dependence and addiction. However, peripheral opioid efficacy is significantly reduced in the absence of tissue inflammation. The long-term goal of this research project is to understand how inflammation enhances peripheral opioid efficacy. For example, in the absence of inflammation the delta opioid receptor (DOR) is less responsive to agonist activation. However, inflammatory mediators have been shown to enhance receptor responsiveness and increase peripheral opioid efficacy. Therefore, the constitutively desensitized receptor becomes primed for activation following inflammation. A gap in knowledge exists concerning the mechanism regulating constitutive DOR incompetence. This represents an important opportunity to identify new pharmaceutical targets to enhance opioid efficacy. The overall objective of this project is to identify that G protein-coupled receptor kinase 2 (GRK-2) chronically associates with DOR to govern receptor competence. The central hypothesis for this application is that GRK-2 constitutively desensitizes DOR and that its dissociation from the receptor enhances DOR responsiveness. This hypothesis will be addressed through three specific aims that (1) identify whether the association of GRK-2 with DOR governs receptor competence, (2) determine whether AKAP mediates constitutive association of GRK-2 with DOR, and (3) investigate whether PLC activity drives DOR priming. The role of GRK-2 on DOR competence will be investigated using a combination of biochemical, molecular, genetic, imaging, and behavioral techniques. The contribution of this research is significant because it will identify new targets t increase opioid agonist efficacy. Research results will demonstrate that reducing chronic GRK-2 association with DOR can significantly enhance DOR competence and improve analgesic efficacy.

Public Health Relevance

The proposed research is relevant to public health because current therapies aimed to reduce chronic inflammatory pain are ineffective in certain populations or have debilitating side effects, like tolerance and addiction. Thus, an unmet need exists for the identification of novel targets that influence analgesic activity in order to improv therapeutic utility. Experiments proposed in this application will identify mechanisms of anti- nociceptive competency of opioid receptors to improve pharmacotherapy.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Predoctoral Individual National Research Service Award (F31)
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NIDR Special Grants Review Committee (DSR)
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Frieden, Leslie A
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University of Texas Health Science Center
Schools of Medicine
San Antonio
United States
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Gomez, Ruben; Kohler, Dorothy M; Brackley, Allison D et al. (2018) Serum response factor mediates nociceptor inflammatory pain plasticity. Pain Rep 3:e658
Brackley, Allison Doyle; Sarrami, Shayda; Gomez, Ruben et al. (2017) Identification of a signaling cascade that maintains constitutive ?-opioid receptor incompetence in peripheral sensory neurons. J Biol Chem 292:8762-8772
Por, Elaine D; Sandoval, Melody L; Thomas-Benson, Chiquita et al. (2017) Repeat low-level blast exposure increases transient receptor potential vanilloid 1 (TRPV1) and endothelin-1 (ET-1) expression in the trigeminal ganglion. PLoS One 12:e0182102
Brackley, Allison Doyle; Gomez, Ruben; Guerrero, Kristi A et al. (2017) A-Kinase Anchoring Protein 79/150 Scaffolds Transient Receptor Potential A 1 Phosphorylation and Sensitization by Metabotropic Glutamate Receptor Activation. Sci Rep 7:1842
Brackley, Allison Doyle; Gomez, Ruben; Akopian, Armen N et al. (2016) GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity. Cell Rep 16:2686-2698