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Blockade of a Novel Neuropeptide Receptor System, BigLEN‐GPR171, Reduces Adverse Effects of Prolonged Morphine Administration
Author(s) -
Bobeck Erin N,
Pena Darlene,
Gomes Ivone,
Fakira Amanda,
Devi Lakshmi
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.985.8
Subject(s) - conditioned place preference , nucleus accumbens , morphine , basolateral amygdala , brain stimulation reward , pharmacology , chemistry , opioid , neuropeptide , dynorphin , receptor , antagonist , medicine , opioid peptide , biochemistry
ProSAAS derived peptides, such as BigLEN, are abundantly expressed throughout the brain. We recently identified BigLEN as the endogenous peptide for the orphan receptor GPR171. Immunohistochemical analysis shows that both BigLEN and GPR171 are highly expressed in areas of the brain involved in opioid function, such as nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and basolateral amygdala (BLA). C57bl/6 mice showed an increase in GPR171 mRNA expression in NAc and BLA following conditioned place preference to morphine. Whereas there was no change in GPR171 expression under these conditions in the mPFC, but there was a reduction in BigLEN expression and enhanced cAMP signaling. Next we examined the role of GPR171 in the BLA of mice using lentiviral‐mediated local knockdown and found that this leads to a reduction in conditioned place preference to morphine. We have recently identified MS21570 as a selective antagonist of GPR171 by in silico screening of a library of small molecules using a homology model of GPR171. Pretreatment with MS21570 (5 mg/kg, i.p. in 6% DMSO) prior to 4 morphine (10 mg/kg, s.c.) pairings, reduced conditioned place preference to morphine. In addition, mice were made tolerant by twice daily morphine injections for 5 days. We found that MS21570 pretreatment reduced the development of morphine tolerance and withdrawal. Together, these data support the idea that the BigLEN‐GPR171 system plays an important role in the regulation of some of the adverse effects associated with prolonged opioid exposure. Support or Funding Information Supported by NIH grants, DA019521 and NS026880 (to LAD) and NIDA postdoctoral training grant DA007135 (to ENB).