dynorphins and Hypothermia

Genetic and early environmental factors interact to influence ethanol's motivational effects. To explore these issues, a reciprocal cross-fostering paradigm was applied to Fischer and Lewis rats. The adult female offspring received vehicle or the kappa opioid antagonist nor-BNI (1 mg/kg) followed by assessments of conditioned taste aversion (CTA), blood alcohol concentrations (BACs) and hypothermia induced by 1.25 g/kg intraperitoneal ethanol. CTA acquisition in the in-fostered Fischer and Lewis animals did not differ; however, the Fischer maternal environment produced stronger acquisition in the cross-fostered Lewis rats versus their in-fostered counterparts. CTAs in the Fischer rats were not affected by cross-fostering. In extinction, the in-fostered Lewis animals displayed stronger aversions than the Fischer groups on two trials (of 12) whereas the cross-fostered Lewis differed from the Fischer groups on nine trials. Despite these CTA effects, Lewis rats exhibited higher BACs and stronger hypothermic responses than Fischer with no cross-fostering effects in either strain. No phenotypes were affected by nor-BNI. These data extend previous findings dissociating the aversive and peripheral physiological effects of ethanol in female Fischer and Lewis rats, and highlight the importance of genetic and early environmental factors in shaping subsequent responses to alcohol's motivational effects in adulthood.

Topics: Animals; Avoidance Learning; Central Nervous System Depressants; Conditioning, Operant; Data Interpretation, Statistical; Dynorphins; Ethanol; Extinction, Psychological; Female; Hypothermia; Maternal Behavior; Motivation; Naltrexone; Rats; Receptors, Opioid, kappa; Taste

Regulations of hormonal stress responses entail the initiation, amplitude and termination of the reaction, as well as its integration with other stress response systems. This study investigates the role of endogenous opioids in the regulation and integration of behavioral, thermal and hormonal stress responses, as these neuromodulators and their receptors are expressed in limbic structures responsible for stress responses. For this purpose, we subjected mice with selective deletion of beta-endorphin, enkephalin or dynorphin to the zero-maze test, a mildly stressful situation, and registered behaviors and stress hormone levels. Behavioral stress reactivity was assessed using zero-maze, light-dark and startle-reactivity paradigms. Animals lacking enkephalin displayed increased anxiety-related behavioral responses in each three, dynorphin knockouts in two models, whereas the responses of beta-endorphin knockouts indicated lower anxiety level in the zero-maze test. All knockout strains showed marked changes in hormonal stress reactivity. Increase in ACTH level after zero-maze test situation, unlike in wild type animals, failed to reach the level of significance in Penk1(-/-) and Pdyn(-/-) mice. Corticosterone plasma levels rapidly increased in all strains, with a lower peak response in knockouts. In wild-type and beta-endorphin-deficient mice, corticosterone levels returned to baseline within 60min after stress exposure. In contrast, mice lacking dynorphin and enkephalin showed longer-lasting elevated corticosterone levels, indicating a delayed termination of the stress reaction. Importantly, the behavioral and hormonal responses correlated in wild-type but not in knockout mice. Hyperthermia elicited by stress was reduced in animals lacking dynorphin and absent in Penk1(-/-) mice, despite of the heightened behavioral anxiety level of these strains. These results demonstrate an important role on the endogenous opioid system in the integration of behavioral and hormonal stress responses.

Topics: Adrenocorticotropic Hormone; Amygdala; Analysis of Variance; Animals; Anxiety; beta-Endorphin; Corticosterone; Dynorphins; Enkephalins; Exploratory Behavior; Hypothermia; Limbic System; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Opioid Peptides; Paraventricular Hypothalamic Nucleus; Protein Precursors; Proto-Oncogene Proteins c-fos; Reflex, Startle; Stress, Psychological; Time Factors

Prodynorphin-derived peptides were tested for their effects on body temperature after intracerebroventricular administration to unrestrained male rats. Dynorphin A (Dyn A) (5 and 10 nmol) and Dynorphin A-(1-32) (Dyn A-(1-32) (2.5 and 5 nmol) lowered body temperature with a maximum approximately 30 min after administration. Dyn B (up to 50 nmol) did not induce hypothermia. Lower doses of all peptides did not alter body temperature. The hypothermic effect was significantly, but not completely prevented by MR1452 (30 nmol), a preferential antagonist of the kappa receptor, administered intracerebroventricularly. Naloxone, a mu receptor antagonist, naltrexone, its long acting analog up to doses of 100 nmol, as well as MR1453, the (+)-enantiomer of kappa antagonist MR1452 with no opioid binding properties, did not prevent the hypothermic effect. Moreover, episodic barrel rolling and bizarre postures elicited by Dyn A and Dyn A-(1-32) were reduced in rats pretreated i.c.v. with MR1452 (30 nmol), but not with naloxone (up to 100 nmol). Interestingly, des-Tyr-Dynorphin A (Dyn A-(2-17)), a fragment with virtually no opioid binding potential, was 4 times less potent that Dyn A in inducing hypothermia. These findings are consistent with the hypothesis that prodynorphin-derived peptides effects are not exclusively opioids in nature.

Topics: Animals; Benzomorphans; Body Temperature; Dynorphins; Endorphins; Hypothermia; Kinetics; Male; Motor Activity; Naloxone; Naltrexone; Peptide Fragments; Rats; Rats, Inbred Strains; Receptors, Opioid