Editors' ChoiceBehavior

Opioid-Related Peptides for Treating Anxiety

Sci. Signal.  17 Dec 2013:
Vol. 6, Issue 306, pp. ec308
DOI: 10.1126/scisignal.2005005

Subcapsular hyperplasia (SCH) of the adrenal glands is a common feature of aging in rodents and humans. Ikeda et al. examined various aspects of mouse physiology and behavior in male and female mice with and without SCH. The transcript for proenkephalin A, which can be cleaved to produce various bioactive peptides, including those acting on opioid receptors, and various proenkephalin A–derived peptide fragments were abundant in SCH cells. Secretion of the stress-responsive hormone glucocorticoid is circadian, and female, but not male, mice with SCH exhibited an increase in the amount of glucocorticoid secreted at Zeitgeber time 12 (ZT12) but no change in the phase or amount of glucocorticoid secreted at other times. This change in the amplitude of glucocorticoid secretion in females with SCH was not present in mice genetically deficient for proenkephalin A (Penk–/–). Female mice with SCH exhibited less anxiety than age-matched female mice in behavioral tests, and this anxiolytic effect of SCH was not present in Penk–/– mice and was abolished in mice given a low-dose course of a glucocorticoid receptor antagonist. A screen of proenkephalin-derived peptide fragments showed that glucocorticoid secretion from H295 cells was stimulated by BAM22 and peptide E, both of which contain the MetEnk (methionine enkephalin) sequence that would enable activation of opioid receptors. The opioid peptide MetEnk did not stimulate glucocorticoid secretion, and a mutant form of BAM22 that could not bind to opioid receptors did stimulate glucocorticoid secretion, indicating that these peptides were not acting through opioid receptors. Screening G protein–coupled receptors (GPCRs) in adrenocortical cells with a β-arrrestin recruitment assay identified CXCR7 as a specific receptor for BAM22, peptide E, and peptide I. In situ hybridization revealed that, in females, Cxcr7 mRNA was abundant in the region that produces glucocorticoids, whereas in males, expression was weaker and in a different region, which explained the gender-based differences in the effects of SCH. In cultured cells or adrenal slices or both, BAM22 or a CXCR7 agonist enhanced glucocorticoid secretion in the presence of the hormone ACTH (adrenocorticotropic hormone). Injection of the CXCR7 agonist into female mice enhanced circulating glucocorticoid concentration at ZT12, but not ZT10, and reduced anxiety in behavioral tests. This effect was not present in male mice. Thus, proenkephalin was cleaved to form bioactive ligands for the β-arrestin–coupled GPCR CXCR7. In females, because this receptor is abundant in the adrenal cells that produce glucocorticoids, CXCR7 agonists may be an effective treatment for anxiety and stress-related disorders (see Rando and Schibler for commentary).

Y. Ikeda, H. Kumagai, A. Skach, M. Sato, M. Yanagisawa, Modulation of circadian glucocorticoid oscillation via adrenal opioid-CXCR7 signaling alters emotional behavior. Cell 155, 1323–1336 (2013). [PubMed]

G. Rando, U. Schibler, Glucocorticoid rhythm renders female mice more daring. Cell 155, 1211–1212 (2013). [PubMed]

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