The delta (DOR) and mu (MOR) subtypes of G protein-coupled opioid receptors are widely distributed in the central and peripheral nervous system. These receptors are targeted both by endogenous opioid peptides and by a host of exogenous opiate agonists, including morphine. Despite years of research, there are still numerous unanswered questions concerning the differential contribution of the DOR and MOR to the complex behaviors influenced by opioid agonists, including pain control, addiction and reward. In part, the lack of progress reflects the tools that are available to study the expression, interaction and function of the receptors in different CNS circuits. To this end, we have developed a delta opioid receptor (DOReGFP) reporter mouse that led to a complete reappraisal of the circuits that are influenced by agonists that act at the DOR. Contrary to the prevailing view, we find that the DOR and the MOR are expressed in non-overlapping subsets of dorsal root ganglia (DRG) "pain" transmission neurons (nociceptors) and regulate distinct pain modalities. The DOR is expressed in myelinated sensory neurons and in a subset of the non-peptidergic unmyelinated nociceptors and regulates mechanical pain and the mechanical hypersensitivity produced in the setting of injury. The MOR predominates in the peptidergic nociceptors, which express the capsaicin and heat responsive channel, TRPV1, and regulates heat pain. The present proposal builds upon these observations. Studies in Specific Aim 1 will use neuroanatomical methods to assess the extent to which segregation of the DOR and MOR also occurs in the spinal cord and brain, in the normal animal and in the setting of tissue or nerve injury.
Specific Aim 2 uses a combination of behavioral, pharmacological and genetic methods to determine the differential contribution of the DRG and spinal cord neuron expression of the DOR and MOR to nociceptive processing and to the antinociceptive effects of opioid compounds. Finally, Specific Aim 3 will extend the pharmacological analysis to the differential contribution of DOR and MOR agonist action at supraspinal targets. Taken together these studies will not only provide new information as to the organization of endogenous opioid receptor systems, but will also assess the extent to which different modalities of pain can be controlled by opioid agonists that selectively target these receptors, in the peripheral and central nervous systems. Information derived from these studies will be an important contributor to the development of pain-relieving drugs with better side effect profiles.

Public Health Relevance

Although it is well established that opioid receptors, which are widely distributed in the central and peripheral nervous system, mediate the pain relieving effects of drugs such as morphine, recent studies in our laboratory demonstrated that the mu and delta opioid receptor subtypes regulate, independently, distinct modalities of pain (e.g. thermal vs. mechanical and the mechanical hypersensitivity that occurs in the setting of injury). By examining the contribution of these receptor subtypes at all levels of the pain pathway, studies in this proposal will provide critical information for the development of new pain therapeutics, with improved side effect profiles.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA029204-04
Application #
8637952
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Rapaka, Rao
Project Start
2011-07-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$379,243
Indirect Cost
$123,988
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Bardoni, Rita; Tawfik, Vivianne L; Wang, Dong et al. (2014) Delta opioid receptors presynaptically regulate cutaneous mechanosensory neuron input to the spinal cord dorsal horn. Neuron 81:1312-27
Braz, João; Solorzano, Carlos; Wang, Xidao et al. (2014) Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control. Neuron 82:522-36
Gibbs, Jennifer L; Urban, Rochelle; Basbaum, Allan I (2013) Paradoxical surrogate markers of dental injury-induced pain in the mouse. Pain 154:1358-67
Zhang, Jie; Cavanaugh, Daniel J; Nemenov, Michael I et al. (2013) The modality-specific contribution of peptidergic and non-peptidergic nociceptors is manifest at the level of dorsal horn nociresponsive neurons. J Physiol 591:1097-110