Female preproenkephalin-knockout mice display altered emotional responses

Abstract

The endogenous opioid system has been implicated in sexual behavior, palatable intake, fear, and anxiety. The present study examined whether ovariectomized female transgenic preproenkephalin-knockout (PPEKO) mice and their wild-type and heterozygous controls displayed alterations in fear and anxiety paradigms, sucrose intake, and lordotic behavior. To examine stability of responding, three squads of the genotypes were tested across seasons over a 20-month period. In a fear-conditioning paradigm, PPEKO mice significantly increased freezing to both fear and fear + shock stimuli relative to controls. In the open field, PPEKO mice spent significantly less time and traversed significantly less distance in the center of an open field than wild-type controls. Further, PPEKO mice spent significantly less time and tended to be less active on the light side of a dark-light chamber than controls, indicating that deletion of the enkephalin gene resulted in exaggerated responses to fear or anxiety-provoking environments. These selective deficits were observed consistently across testing squads spanning 20 months and different seasons. In contrast, PPEKO mice failed to differ from corresponding controls in sucrose, chow, or water intake across a range (0.0001-20%) of sucrose concentrations and failed to differ in either lordotic or female approach to male behaviors when primed with estradiol and progesterone, thereby arguing strongly for the selectivity of a fear and anxiety deficit which was not caused by generalized and nonspecific debilitation. These transgenic data strongly suggest that opioids, and particularly enkephalin gene products, are acting naturally to inhibit fear and anxiety.

Pronociceptive and Antinociceptive Effects of Estradiol through Endogenous Opioid Neurotransmission in Women

“…In this regard, it has been suggested that progesterone may induce opposite effects to those of estradiol on both -opioid receptor binding and in the capacity to release endogenous opioids activating those receptors (Ratka et al, 1991;Shen et al, 1995;Ragnauth et al, 2001;Sinchak and Micevych, 2001;Mills et al, 2004). Additional investigation into these processes appears necessary in view of the results obtained here.…”

An Anxiolytic Role for CRF Receptor Type 1 in the Globus Pallidus

“…In a previous study, it was shown that CRF, when delivered into the GP, induces the release of enkephalin (Sirinathsinghji et al, 1989), an anxiolytic endogenous opioid (König et al, 1996;Kang et al, 2000;Ragnauth et al, 2001) that is released in the GPe by afferent neurons in the striatum. Based on these results, we suggest a mechanism in which reduced CRFR1 expression increases anxiety-like behavior in part by affecting enkephalin release.…”

Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways

“…This discovery is of crucial importance from a physiological and physiopathological point of view when the extent of the functions mediated by the endogenous opioidergic pathways are considered. Indeed, the endogenous opioid peptides, in particular the enkephalins, have a pivotal role in the control of pain perception and mood-related states, including modulation of emotional and͞or motivational responses (5,6,19). Endogenous Opiorphin could facilitate adaptative responses to threat-inducing stimuli by potentiating analgesic and antidepressive-like behavior, induced by endogenous enkephalinergic systems, in humans.…”