Targeted disruption of the orphanin FQ/nociceptin gene increases stress susceptibility and impairs stress adaptation in mice.
The neuropeptide orphanin FQ (also known as nociceptin; OFQ/N) has been implicated in modulating stress-related behavior. OFQ/N was demonstrated to reverse stress-induced analgesia and possess anxiolytic-like activity after central administration. To further study physiological functions of OFQ/N, we have generated OFQ/N-deficient mice by targeted disruption of the OFQ/N gene. Homozygous mice display increased anxiety-like behavior when exposed to a novel and threatening environment. OFQ/N-null mice show elevated basal pain threshold but develop normal stress-induced analgesia. Interestingly, these mice show impaired adaptation to repeated stress when compared with wild-type mice, whereas their performance in spatial learning remained unaffected. Basal and poststress plasma corticosterone levels were found to be elevated in OFQ/N-deficient animals. Thus, OFQ/N appears to be crucially involved in the neurobiological regulation of stress-coping behavior and fear.
Köster
A
A
F. Hoffmann-La Roche AG, Pharma Division, CNS Research, CH-4070 Basel, Switzerland.
Montkowski
A
A
Schulz
S
S
Stübe
E M
EM
Knaudt
K
K
Jenck
F
F
Moreau
J L
JL
Nothacker
H P
HP
Civelli
O
O
Reinscheid
R K
RK
D000698:Analgesia; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000503:physiopathology; D003345:Corticosterone / Q000097:blood; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D018782:Maze Learning; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D018847:Opioid Peptides / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D010146:Pain / Q000503:physiopathology*; D010465:Perception; D011957:Receptors, Opioid / Q000502:physiology; D013028:Space Perception; D013315:Stress, Psychological / Q000235:genetics* / Q000503:physiopathology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D003345:Corticosterone; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C000722287:Oprl1 protein, mouse