The aims of this project are based on three hypothesis. Hypothesis 1 is that the opioid delta receptor may exist as subtypes. An antisense strategy will be employed in NG 108-15 cells, in primary DRG cultures and in an antinociceptive model in vivo. Antisense oligodeoxynucleotide (ODN) """"""""knock-down"""""""" of delta receptors in NG108-15 cells will be studied using ODNs directed at the DOR-1 clone and at a conserved sequence in the opioid mu, delta and kappa receptors (conserved opioid receptor; COR). Cellular uptake and ODN translocation, time-course, concentration-dependence and inhibition of the delta receptor expression will be determined with fluorescence microscopy and radioligand binding; control ODN sequences will be emphasized. In DRG cultures DOR or COR antisense ODN will be used to evaluate ODN uptake and morphological distribution and to validate the DOR ODN selectivity against delta mu and kappa receptors. In rats, DOR/COR ODNs will be used to elucidate the distribution of spinal ODNs and """"""""knock-down"""""""" of opioid receptors and possible differential sensitivity of putative delta subtype selective agonists (but not mu or kappa agonists), to DOR-1 antisense ODN effects as well as time-course and recovery of the antinociceptive effect. Hypothesis 2 is that activation of supraspinal opioid delta receptors will produce antinociception not necessarily dependent on the descending pathway characterized for opioid mu receptor agonists. Localized microinjection of opioid subtype selective agonists and antagonists into selected supraspinal loci will be employed to establish receptor selective antinociceptive activity. The involvement of descending pathways following activation of confirmed supraspinal delta antinociception will be studied by examining suppression of nociceptive induced behavior and c-FOS expression in the spinal cord in control rats, or in animals with lesions of the dorsolateral funiculus (DLF). Hypothesis 3 is that activation of both supraspinal and spinal opioid delta receptors will result in a synergistic antinociceptive effect. Analysis of antinociception elicited by supraspinal/spinal co-administration of subtype-selective agonists in a fixed-ratio paradigm with isobolographic methods will be used. These experiments should yield significant new information about the role of the delta receptor in nociception and the bossibility of subtypes of this receptor in vitro and in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
2P01DA006284-08A1
Application #
6237907
Study Section
Project Start
1997-05-15
Project End
1998-03-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
8
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Remesic, Michael; Macedonio, Giorgia; Mollica, Adriano et al. (2018) Cyclic biphalin analogues with a novel linker lead to potent agonist activities at mu, delta, and kappa opioid receptors. Bioorg Med Chem 26:3664-3667
Mowlazadeh Haghighi, Saghar; Zhou, Yang; Dai, Jixun et al. (2018) Replacement of Arg with Nle and modified D-Phe in the core sequence of MSHs, Ac-His-D-Phe-Arg-Trp-NH2, leads to hMC1R selectivity and pigmentation. Eur J Med Chem 151:815-823
Sandweiss, A J; McIntosh, M I; Moutal, A et al. (2018) Genetic and pharmacological antagonism of NK1 receptor prevents opiate abuse potential. Mol Psychiatry 23:1745-1755
Bannister, Kirsty; Qu, Chaoling; Navratilova, Edita et al. (2017) Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain. Pain 158:2386-2395
Vardanyan, Ruben S; Cain, James P; Haghighi, Saghar Mowlazadeh et al. (2017) Synthesis and Investigation of Mixed ?-Opioid and ?-Opioid Agonists as Possible Bivalent Ligands for Treatment of Pain. J Heterocycl Chem 54:1228-1235
Cai, Minying; Marelli, Udaya Kiran; Mertz, Blake et al. (2017) Structural Insights into Selective Ligand-Receptor Interactions Leading to Receptor Inactivation Utilizing Selective Melanocortin 3 Receptor Antagonists. Biochemistry 56:4201-4209
Remesic, Michael; Lee, Yeon Sun; Hruby, Victor J (2016) Cyclic Opioid Peptides. Curr Med Chem 23:1288-303
Ramos-Colon, Cyf N; Lee, Yeon Sun; Remesic, Michael et al. (2016) Structure-Activity Relationships of [des-Arg7]Dynorphin A Analogues at the ? Opioid Receptor. J Med Chem 59:10291-10298
Hall, Sara M; Lee, Yeon Sun; Hruby, Victor J (2016) Dynorphin A analogs for the treatment of chronic neuropathic pain. Future Med Chem 8:165-77
Deekonda, Srinivas; Cole, Jacob; Sunna, Sydney et al. (2016) Enkephalin analogues with N-phenyl-N-(piperidin-2-ylmethyl)propionamide derivatives: Synthesis and biological evaluations. Bioorg Med Chem Lett 26:222-7

Showing the most recent 10 out of 268 publications