Changes in opioid receptor selectivity following processing of peptide E: Effect on gut motility

Thomas P Davis, Terrence J. Gillespie, Jennifer Shook, Thomas H. Kramer, Gifford Hoyer, Kumiko Hawkins, Peg Davis, Henry I. Yamamura, Thomas F. Burks

Research output: Contribution to journalArticle

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Abstract

Peptide E is a μ-selective opioid peptide derived from proenkephalin A which contains [Met5]-enkephalin at the amino end and [Leu5]-enkephalin at the carboxyl end. Peptide E is further processed both centrally and peripherally to a [Leu5]-enkephalincontaining fragment which was investigated to determine if processing leads to alterations in receptor selectivity. Peptide E-(15-25) inhibited electrically stimulated contractions in both the mouse vas deferens, longitudinal muscle, myenteric (IC50 = 459 nmol/ L), and guinea pig ileum (IC50 = 2630 nmol/L), indicating a sixfold δ-receptor selectivity. When administered intracerebroventricularly to mice, peptide E-(15-25) also produced potent analgesia which was completely antagonized by naloxone pretreatment, but the peptide had no effect on intestinal transit as measured by the radiochromium geometric center method. This is consistent with earlier findings that intracerebroventricular δ-opioid-selective agents are analgesic but do not inhibit intestinal transit. In vitro radioligand binding assays were performed using male Sprague-Dawley rat whole brain homogenates. The IC50 for peptide E against [3H]naloxone was 1.8 nmol/L compared with the δ-opioid ligand, [3H] [d-Pen2, d-Pen5]-enkephalin of 38.8 nmol/L. The IC50 for peptide E-(15-25) against [3H]naloxone was 497 nmol/L, but for [3H] [d-Pen2, d-Pen5]-enkephalin it was 50.6 nmol/L. Therefore, peptide E loses μ-opioid receptor affinity (1.8-497 nmol/L) after proteolytic processing and the loss of the amino terminal tyrosine but maintains a high δ-opioid affinity (38.8-50.6 nmol/L). These studies demonstrate that enzymatic peptide processing of peptide E to peptide E-(15-25) leads to a shift from μ to δ-receptor selectivity and a different spectrum of biological effects on gut motility.

Original languageEnglish (US)
Pages (from-to)1603-1615
Number of pages13
JournalGastroenterology
Volume100
Issue number6
StatePublished - 1991

Fingerprint

Opioid Receptors
Enkephalins
Inhibitory Concentration 50
Naloxone
Opioid Analgesics
peptide E (adrenal medulla)
Radioligand Assay
Peptides
Vas Deferens
Opioid Peptides
Ileum
Analgesia
Sprague Dawley Rats
Tyrosine
Analgesics
Guinea Pigs
Ligands
Muscles
Brain

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Davis, T. P., Gillespie, T. J., Shook, J., Kramer, T. H., Hoyer, G., Hawkins, K., ... Burks, T. F. (1991). Changes in opioid receptor selectivity following processing of peptide E: Effect on gut motility. Gastroenterology, 100(6), 1603-1615.

Changes in opioid receptor selectivity following processing of peptide E : Effect on gut motility. / Davis, Thomas P; Gillespie, Terrence J.; Shook, Jennifer; Kramer, Thomas H.; Hoyer, Gifford; Hawkins, Kumiko; Davis, Peg; Yamamura, Henry I.; Burks, Thomas F.

In: Gastroenterology, Vol. 100, No. 6, 1991, p. 1603-1615.

Research output: Contribution to journalArticle

Davis, TP, Gillespie, TJ, Shook, J, Kramer, TH, Hoyer, G, Hawkins, K, Davis, P, Yamamura, HI & Burks, TF 1991, 'Changes in opioid receptor selectivity following processing of peptide E: Effect on gut motility', Gastroenterology, vol. 100, no. 6, pp. 1603-1615.
Davis TP, Gillespie TJ, Shook J, Kramer TH, Hoyer G, Hawkins K et al. Changes in opioid receptor selectivity following processing of peptide E: Effect on gut motility. Gastroenterology. 1991;100(6):1603-1615.
Davis, Thomas P ; Gillespie, Terrence J. ; Shook, Jennifer ; Kramer, Thomas H. ; Hoyer, Gifford ; Hawkins, Kumiko ; Davis, Peg ; Yamamura, Henry I. ; Burks, Thomas F. / Changes in opioid receptor selectivity following processing of peptide E : Effect on gut motility. In: Gastroenterology. 1991 ; Vol. 100, No. 6. pp. 1603-1615.
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abstract = "Peptide E is a μ-selective opioid peptide derived from proenkephalin A which contains [Met5]-enkephalin at the amino end and [Leu5]-enkephalin at the carboxyl end. Peptide E is further processed both centrally and peripherally to a [Leu5]-enkephalincontaining fragment which was investigated to determine if processing leads to alterations in receptor selectivity. Peptide E-(15-25) inhibited electrically stimulated contractions in both the mouse vas deferens, longitudinal muscle, myenteric (IC50 = 459 nmol/ L), and guinea pig ileum (IC50 = 2630 nmol/L), indicating a sixfold δ-receptor selectivity. When administered intracerebroventricularly to mice, peptide E-(15-25) also produced potent analgesia which was completely antagonized by naloxone pretreatment, but the peptide had no effect on intestinal transit as measured by the radiochromium geometric center method. This is consistent with earlier findings that intracerebroventricular δ-opioid-selective agents are analgesic but do not inhibit intestinal transit. In vitro radioligand binding assays were performed using male Sprague-Dawley rat whole brain homogenates. The IC50 for peptide E against [3H]naloxone was 1.8 nmol/L compared with the δ-opioid ligand, [3H] [d-Pen2, d-Pen5]-enkephalin of 38.8 nmol/L. The IC50 for peptide E-(15-25) against [3H]naloxone was 497 nmol/L, but for [3H] [d-Pen2, d-Pen5]-enkephalin it was 50.6 nmol/L. Therefore, peptide E loses μ-opioid receptor affinity (1.8-497 nmol/L) after proteolytic processing and the loss of the amino terminal tyrosine but maintains a high δ-opioid affinity (38.8-50.6 nmol/L). These studies demonstrate that enzymatic peptide processing of peptide E to peptide E-(15-25) leads to a shift from μ to δ-receptor selectivity and a different spectrum of biological effects on gut motility.",
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AU - Davis, Thomas P

AU - Gillespie, Terrence J.

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AU - Kramer, Thomas H.

AU - Hoyer, Gifford

AU - Hawkins, Kumiko

AU - Davis, Peg

AU - Yamamura, Henry I.

AU - Burks, Thomas F.

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N2 - Peptide E is a μ-selective opioid peptide derived from proenkephalin A which contains [Met5]-enkephalin at the amino end and [Leu5]-enkephalin at the carboxyl end. Peptide E is further processed both centrally and peripherally to a [Leu5]-enkephalincontaining fragment which was investigated to determine if processing leads to alterations in receptor selectivity. Peptide E-(15-25) inhibited electrically stimulated contractions in both the mouse vas deferens, longitudinal muscle, myenteric (IC50 = 459 nmol/ L), and guinea pig ileum (IC50 = 2630 nmol/L), indicating a sixfold δ-receptor selectivity. When administered intracerebroventricularly to mice, peptide E-(15-25) also produced potent analgesia which was completely antagonized by naloxone pretreatment, but the peptide had no effect on intestinal transit as measured by the radiochromium geometric center method. This is consistent with earlier findings that intracerebroventricular δ-opioid-selective agents are analgesic but do not inhibit intestinal transit. In vitro radioligand binding assays were performed using male Sprague-Dawley rat whole brain homogenates. The IC50 for peptide E against [3H]naloxone was 1.8 nmol/L compared with the δ-opioid ligand, [3H] [d-Pen2, d-Pen5]-enkephalin of 38.8 nmol/L. The IC50 for peptide E-(15-25) against [3H]naloxone was 497 nmol/L, but for [3H] [d-Pen2, d-Pen5]-enkephalin it was 50.6 nmol/L. Therefore, peptide E loses μ-opioid receptor affinity (1.8-497 nmol/L) after proteolytic processing and the loss of the amino terminal tyrosine but maintains a high δ-opioid affinity (38.8-50.6 nmol/L). These studies demonstrate that enzymatic peptide processing of peptide E to peptide E-(15-25) leads to a shift from μ to δ-receptor selectivity and a different spectrum of biological effects on gut motility.

AB - Peptide E is a μ-selective opioid peptide derived from proenkephalin A which contains [Met5]-enkephalin at the amino end and [Leu5]-enkephalin at the carboxyl end. Peptide E is further processed both centrally and peripherally to a [Leu5]-enkephalincontaining fragment which was investigated to determine if processing leads to alterations in receptor selectivity. Peptide E-(15-25) inhibited electrically stimulated contractions in both the mouse vas deferens, longitudinal muscle, myenteric (IC50 = 459 nmol/ L), and guinea pig ileum (IC50 = 2630 nmol/L), indicating a sixfold δ-receptor selectivity. When administered intracerebroventricularly to mice, peptide E-(15-25) also produced potent analgesia which was completely antagonized by naloxone pretreatment, but the peptide had no effect on intestinal transit as measured by the radiochromium geometric center method. This is consistent with earlier findings that intracerebroventricular δ-opioid-selective agents are analgesic but do not inhibit intestinal transit. In vitro radioligand binding assays were performed using male Sprague-Dawley rat whole brain homogenates. The IC50 for peptide E against [3H]naloxone was 1.8 nmol/L compared with the δ-opioid ligand, [3H] [d-Pen2, d-Pen5]-enkephalin of 38.8 nmol/L. The IC50 for peptide E-(15-25) against [3H]naloxone was 497 nmol/L, but for [3H] [d-Pen2, d-Pen5]-enkephalin it was 50.6 nmol/L. Therefore, peptide E loses μ-opioid receptor affinity (1.8-497 nmol/L) after proteolytic processing and the loss of the amino terminal tyrosine but maintains a high δ-opioid affinity (38.8-50.6 nmol/L). These studies demonstrate that enzymatic peptide processing of peptide E to peptide E-(15-25) leads to a shift from μ to δ-receptor selectivity and a different spectrum of biological effects on gut motility.

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