It is now generally accepted that G protein coupled receptors (GPCRs) can form multimeric complexes with the same (homomers) or different (heteromers) GPCR partners. We have learned a vast amount about these GPCR oligomers from studies conducted with heterologous expression systems where individual receptor protomers can be labeled and high-resolution microscopy techniques can be applied along with rigorous biochemical and cell signaling methods. As a result of studies in heterologous systems, we know that GPCR oligomers can be considered as unique receptor entities as they have distinct pharmacological properties and distinct signaling characteristics that can differ from those of the individual GPCR protomers. However, there are relatively few studies of GPCR oligomers in native systems, owing in large part to a lack of methods that are applicable to the study of these oliogomeric complexes in physiologically relevant systems. Our lack of understanding of roles for receptor heteromers in physiologically relevant systems represents a critical gap in our knowledge as these oligomeric receptors may be valuable targets for development of selective drugs for pharmacotherapy. Recently, we published the first evidence for functional opioid receptor heteromers between delta (DOR) and kappa (KOR) receptors in a physiologically relevant system - adult rat peripheral pain-sensing neurons (nociceptors). We believe this system, comprised of in vivo behavioral pain assays along with complementary ex vivo culture of nociceptors, provides an excellent opportunity to validate approaches to enable further study of the role of DOR-KOR heteromers in peripheral mechanisms of analgesia. Thus, the goal of this R21 exploratory application is to use these nociceptor model systems to validate approaches to study DOR-KOR heteromers in native systems.
The specific aims are: to disrupt DOR-KOR heteromer formation using TM-TAT peptides that interfere with the association of DOR and KOR at the cell surface. 2) to disrupt DOR-KOR heteromer formation by knock-out of either DOR or KOR expression using genetically-modified mice and 3) to block DOR-KOR heteromer function using a DOR-KOR heteromer-selective antagonist, KDN- 21. Results from this project will allow for us to study the pharmacological and signaling mechanisms of DOR- KOR heteromers expressed in peripheral pain-sensing neurons and their role in regulating pain signaling by these neurons. Moreover, approaches used to disrupt DOR-KOR heteromers can be applied to the study of other receptor heteromers to aid in understanding the physiological and pharmacological relevance of these novel oligomeric receptors.

Public Health Relevance

G protein coupled receptors (GPCRs) can form multimeric complexes with the same (homomers) or different (heteromers) GPCR partners. However, there are relatively few studies of GPCR oligomers in native systems, largely due to a lack of validated methods to study them. In this application, we propose to validate approaches to disrupt the formation or function of delta-kappa opioid receptor heteromers expressed by pain-sensing neurons in vivo and ex vivo.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Rapaka, Rao
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center
Schools of Medicine
San Antonio
United States
Zip Code
Berg, Kelly A; Clarke, William P (2018) Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity. Int J Neuropsychopharmacol 21:962-977
Jacobs, Blaine A; Pando, Miryam M; Jennings, Elaine et al. (2018) Allosterism within ? Opioid-? Opioid Receptor Heteromers in Peripheral Sensory Neurons: Regulation of ? Opioid Agonist Efficacy. Mol Pharmacol 93:376-386