Effects of dynorphins on body temperature of rats

Evidence indicates that endogenous opioids play a role in body temperature (Tb) regulation in mammals but no data exist about the involvement of the specific opioid receptors, mu, kappa and delta, in the reduction of Tb induced by hypoxia. Thus, we investigated the participation of these opioid receptors in the anteroventral preoptic region (AVPO) in hypoxic decrease of Tb. To this end, Tb of unanesthetized Wistar rats was monitored by temperature data loggers before and after intra-AVPO microinjection of the selective kappa-opioid receptor antagonist nor-binaltorphimine dihydrochloride (nor-BNI; 0.1 and 1.0 μg/100 nL/animal), the selective mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂ cyclic (CTAP; 0.1 and 1.0 μg/100 nL/animal), and the selective delta-opioid receptor antagonist Naltrindole (0.06 and 0.6 μg/100 nL/animal) or saline (vehicle, 100 nL/animal), during normoxia and hypoxia (7% inspired O₂). Under normoxia, no effect of opioid antagonists on Tb was observed. Hypoxia induced Tb to reduce in vehicle group, a response that was inhibited by the microinjection intra-AVPO of nor-BNI. In contrast, CTAP and Naltrindole did not change Tb during hypoxia but caused a longer latency for the return of Tb to the normoxic values just after low O₂ exposure. Our results indicate the kappa-opioid receptor in the AVPO is important for the reduction of Tb during hypoxia while the mu and delta receptors are involved in the increase of Tb during normoxia post-hypoxia.

Few environmental factors have a larger influence on animal energetics than temperature, a fact that makes thermoregulation a very important process for survival. In general, endothermic species, i.e., mammals and birds, maintain a constant body temperature (Tb) in fluctuating environmental temperatures using autonomic and behavioural mechanisms. Most of the knowledge on thermoregulatory physiology has emerged from studies using mammalian species, particularly rats. However, studies with all vertebrate groups are essential for a more complete understanding of the mechanisms involved in the regulation of Tb. Ectothermic vertebrates–fish, amphibians and reptiles–thermoregulate essentially by behavioural mechanisms. With few exceptions, both endotherms and ectotherms develop fever (a regulated increase in Tb) in response to exogenous pyrogens, and regulated hypothermia (anapyrexia) in response to hypoxia. This review focuses on the mechanisms, particularly neuromediators and regions in the central nervous system, involved in thermoregulation in vertebrates, in conditions of euthermia, fever and anapyrexia.

Background and aim: Cholestatic animals display abnormal hypothalamic responses to pyrogenic stimuli and decreased febrile response to lipopolysaccharide. The present study was undertaken to determine if obstructive cholestasis was associated with abnormal thermoregulation under thermoneutral conditions. Methods: Male Sprague–Dawley rats weighing 200–250 g were randomly divided into 21 groups. Three sets of seven groups were unoperated control, sham-operated and bile duct-ligated rats. The groups of unoperated control, sham-operated and bile duct-ligated rats were treated with daily administration of isotonic saline solution, N(ω)-nitro-l-arginine methyl ester (l-NAME) (3, 10, or 20 mg/kg), naltrexone (10 or 20 mg/kg) or aminoguanidine (150 mg/kg). Body temperatures were measured before and 1, 3, 5 and 7 days after the surgery. Results: Bile duct-ligated rats had lower body temperature than sham-operated animals at 3 (P < 0.001) and 5 (P < 0.01) days after surgery. l-NAME, a non-selective inhibitor of nitric oxide synthase (NOS) (10, 20 mg/kg, i.p.) or aminoguanidine, a selective iNOS inhibitor (150 mg/kg, i.p.), completely reversed this hypothermia (P > 0.05). Naltrexone, a non-selective opioid antagonist (20 mg/kg, i.p.), also completely corrected this hypothermia (P > 0.05). There was a drop in temperature in the first day after the surgery in sham and BDL groups compared to unoperated controls, which was significant in some groups demonstrating the effect of surgery and anesthetic drugs on the body temperature. Conclusions: Cholestatic rats show impaired thermoregulation suggesting the involvement of nitrergic and opioidergic systems.

Previous studies demonstrated that intracerebroventricular (icv) injection of a kappa opioid receptor agonist decreased, and a mu agonist increased, body temperature (T_b) in rats. A dose–response study with the selective kappa antagonist nor-binaltorphimine (nor-BNI) showed that a low dose (1.25 nmol, icv) alone had no effect, although a high dose (25 nmol, icv) increased T_b. It was hypothesized that the hyperthermia induced by nor-BNI was the result of the antagonist blocking the kappa opioid receptor and releasing its inhibition of mu opioid receptor activity. To determine whether the T_b increase caused by nor-BNI was a mu receptor-mediated effect, we administered the selective mu antagonist CTAP (1.25 nmol, icv) 15 min after nor-BNI (25 nmol, icv) and measured rectal T_b in unrestrained rats. CTAP significantly antagonized the T_b increase induced by icv injection of nor-BNI. Injection of 5 or 10 nmol of CTAP alone significantly decreased the T_b, and 1.25 nmol of nor-BNI blocked that effect, indicating that the CTAP-induced hypothermia was kappa-mediated. The findings strongly suggest that mu antagonists, in blocking the basal hyperthermia mediated by mu receptors, can unmask the endogenous kappa receptor-mediated hypothermia, and that there is a tonic balance between mu and kappa opioid receptors that serves as a homeostatic mechanism for maintaining T_b.

The selective δ-opioid receptor agonist deltorphin II (25.0–100.0 μg, i.c.v.) produced biphasic effects on core temperature in rats, in which hypothermia was followed by hyperthermia. Pretreatment with the selective δ-opioid receptor antagonist, naltrindole (25.0 μg, i.c.v.), blocked hypothermia produced by deltorphin II and had a tendency to potentiate the hyperthermic effect of deltorphin II. The non-selective opioid receptor antagonist naloxone (1.5 mg kg⁻¹, s.c.) potentiated hypothermia, and blocked hyperthermia, produced by deltorphin II (100.0 μg). Also, naloxone potentiated hypothermia produced by a lower dose of deltorphin II (25.0 μg), which did not produce hyperthermia. A similar pattern was found for the selective μ-opioid receptor antagonist, β-funaltrexamine (5.0 μg, i.c.v.), which potentiated and blocked deltorphin II-induced hypo- and hyperthermia, respectively. The selective κ-opioid receptor antagonist nor-binaltorphimine (20.0 μg, i.c.v.) had no effects on deltorphin II-induced temperature changes. The present results suggest that deltorphin II produces hypothermia through activation of δ-opioid receptors, whereas the hyperthermic effect of deltorphin II involves activation of μ-opioid receptors. This μ-opioid receptor stimulatory effect of deltorphin II is furthermore more pronounced than was anticipated based on the reported in vitro properties of this compound. The biphasic effect of deltorphin II implies a negative interaction between δ- and μ-opioid receptors in thermoregulation in rats.

Previous studies have shown that the κ-opioid effects are sensitive to pertussis toxin (PTX) and affected by Ca²⁺ fluxes. However, the possible involvement of Ca²⁺ channels in PTX-induced inhibition of κ-opioid effects has not been reported. The effect of intracerebroventricular (i.c.v.) treatment of pertussis toxin (1 μg/rat, PTX) or saline on the κ-opioid agonist, U-50,488H (U5H) induced tail-flick analgesia and hypothermia in rats was determined. The effect of nimodipine (NIM), a dihydropyridine (DHP)-sensitive Ca²⁺ channel blocker (CCB), on PTX-induced modulation of U5H effects was examined. The DHP ligand, [³H]PN200–110 binding was also determined in both PTX and saline treated rats to study the possible involvement of L-type Ca²⁺ channels in PTX modulation of κ-opioid agonist effects. The analgesia and change in colonic temperature were determined using tail-flick analgesiometer and telethermometer, respectively. U5H (40 mg/kg, i.p.) produced significant analgesic and hypothermic responses. PTX treatment significantly (P<0.01) antagonized the analgesic and hypothermic effects of U5H. Acute pretreatment of NIM (1 mg/kg, i.p.) 15 min prior significantly (P<0.01) reversed the PTX-induced antagonism of U5H effects. In the binding study, PTX treatment (72 h before) resulted in a significant (P<0.005) upregulation (+45% vs. saline control) of DHP binding (B_max) with no change in affinity (K_d). The results showed significant upregulation of DHP binding in accordance with PTX-induced antagonism of U5H effects and this blockade was reversed by NIM. Thus, present results suggest that U5H-induced analgesia and hypothermia may be mediated through PTX-sensitive transducer G-proteins (G_i/o) coupled to L-type Ca²⁺ channels.