Absence of Opioid Stress-Induced Analgesia in Mice Lacking β -Endorphin by Site-Directed Mutagenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 9; pp. 3995 - 4000
• Main Authors: Rubinstein, Marcelo, Mogil, Jeffrey S., Japón, Miguel, Chan, E. Cheng, Allen, Richard G., Low, Malcolm J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 30-04-1996; National Acad Sciences; National Academy of Sciences
• Subjects: Alleles; Amino Acid Sequence; Analgesia; Analgesics; Analgesics, Opioid - pharmacology; Animals; Base Sequence; beta-Endorphin - deficiency; beta-Endorphin - genetics; beta-Endorphin - physiology; Circadian Rhythm; Codon; DNA Primers; Female; Genes; Genotypes; Hypothalamo-Hypophyseal System - physiology; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular Sequence Data; Morphine; Morphine - pharmacology; Mutagenesis, Site-Directed; Naloxone - pharmacology; Neurology; Neurons; Opioid analgesics; Pain; Pain - physiopathology; Peptides; Pituitary-Adrenal System - physiology; Polymerase Chain Reaction; Pro-Opiomelanocortin - genetics; Protein Biosynthesis; Rodents; Sex Characteristics; Stem Cells; Stress, Psychological; Tyrosine
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.9.3995

A physiological role for β -endorphin in endogenous pain inhibition was investigated by targeted mutagenesis of the proopiomelanocortin gene in mouse embryonic stem cells. The tyrosine codon at position 179 of the proopiomelanocortin gene was converted to a premature translational stop codon. The resulting transgenic mice display no overt developmental or behavioral alterations and have a normally functioning hypothalamic-pituitary-adrenal axis. Homozygous transgenic mice with a selective deficiency of β -endorphin exhibit normal analgesia in response to morphine, indicating the presence of functional μ -opiate receptors. However, these mice lack the opioid (naloxone reversible) analgesia induced by mild swim stress. Mutant mice also display significantly greater nonopioid analgesia in response to cold water swim stress compared with controls and display paradoxical naloxone-induced analgesia. These changes may reflect compensatory upregulation of alternative pain inhibitory mechanisms.