Biomedical subjects
Publications and source records attributed to M Kavaliers.
Intracerebroventricular administration of 0.01-1.0 micrograms of the peptide FMRFamide (Phe-Met-Arg-Phe-NH2) to mice suppressed feeding induced by the specific kappa opiate agonist, U-50, 488H. This suggests that FMRFamide, or FMRFamide-like neuropeptides, may have a role in the control of kappa opioid mediated feeding in the mouse.
An exposure for 60 min to a 0.5 Hz rotating magnetic field (1.5-90 G) significantly attenuated the daytime analgesic effects of the mu and kappa opiate agonists, morphine and U50,488H, respectively, and significantly inhibited the analgesic actions of the delta agonist, D-Ala2-D-Leu5-enkephalin, in mice. The magnetic stimuli had no significant effects on the analgesic effects of the prototypic sigma opiate agonist (+/-) SKF-10,047. These results show that exposure to relatively weak magnetic stimuli has significant and differential inhibitory influences on various opioid systems.
The effects of prolyl-leucyl-glycinamide (MIF-1, PLG), tyrosine-prolyl-leucyl-glycinamide (Tyr-MIF-1, YPLG) and the exogenous opiate antagonist, naloxone, on aggressive interactions and defeat-induced analgesia were examined in male mice. All three substances reduced the number of bites required to obtain defeat in subordinate mice during aggressive encounters, as well as blocking subsequent defeat-induced analgesia. Tyr-MIF-1 had significantly greater inhibitory effects than MIF. These results suggest that both MIF and Tyr-MIF-1 may function as endogenous opioid antagonists and have inhibitory influences on aggression, with the antagonistic effects of Tyr-MIF-1 being more potent than those of MIF-1.
The effects of prolyl-leucyl-glycinamide (MIF-1, PLG), tyrosine-prolyl-leucyl-glycinamide (Tyr-MIF-1, YPLG) and naloxone on morphine and warm and cold stress-induced increases in the latency of the thermal (40 degrees C hot plate) avoidance behaviors of the terrestrial snail, Cepaea nemoralis, were examined. All three substances blocked the morphine- and warm stress-induced opioid analgesia, while having no effects on non-opioid cold stress-induced analgesia. Tyr-MIF-1 had a significantly greater inhibitory effect than MIF-1. These results indicate that MIF-1 and Tyr-MIF-1 antagonize the antinociceptive effects of exogenous opiates and opioid-mediated analgesia in snails in a manner analogous to that described for mammals. This raises the possibility of an evolutionary conservation of functional opioid antagonists.
Two mammalian FMRF-NH2-like peptides have been isolated from bovine brain; an octapeptide with the structure Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (F-8-F-NH2) and an octadecapeptide, Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro-Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe- NH2 (A-18-F-NH2). In the present study determinations were made of the effects of intracerebroventricular administration of IgG prepared from antisera raised against these peptides on nociception and morphine- and immobilization-induced opioid analgesia in mice. Both F-8-F-NH2-IgG and A-18-F-NH2-IgG antisera increased nociception (thermal response latency) and significantly augmented morphine- and immobilization-induced analgesia in a naloxone reversible manner, with F-8-F-NH2-IgG antisera having a greater effect than A-18-F-NH2-IgG antisera. These results provide further evidence that mammalian FMRF-NH2-like peptides function as endogenous opiate antagonists and have a role in the mediation of antinociception.
The effects of body rotation in a horizontal plane and various opiate antagonists on the nociceptive responses of a day-active microtine rodent, the meadow vole, Microtus pennsylvanicus, were examined. Intermittent rotation (70 rpm, schedule of 30 sec on, 30 sec off) for 30 min induced significant analgesic responses in the voles for 15 min after rotation. These increases in thermal response latency were blocked by intraperitoneal pretreatment with either naloxone or the irreversible mu opiate receptor antagonist beta-funaltrexamine (beta-FNA; 10 mg/kg; 24 hr pretreatment). This antagonistic effect of beta-FNA indicates mu opioid involvement in the mediation of rotation-induced analgesia. The antiopiate peptides MIF-1 (Pro-Leu-Gly-NH2) and Tyr-MIF-1 also significantly reduced, though did not completely block, body rotation-induced opiate analgesia. This suggests that Tyr-MIF-1 and MIF-1 have significant antagonistic effects on mu opioid systems that are involved in the mediation of stress (rotation)-induced analgesia.
The effects of two endogenous mammalian FMRFamide (Phe-Met-Arg-Phe-NH2)-related peptides, an octapeptide F8Fa (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) and an octadecapeptide A18Fa (Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro-Phe-Trp-Ser-Leu-Ala-Pro-Gln-Arg-Phe-NH2 ), and IgG from serum against them on the responses to aggression and defeat-induced analgesia were examined in subordinate mice in "resident-intruder" pairings. Intracerebroventricular (ICV) administrations of F8Fa and A18Fa (0.10-10 micrograms) reduced, in a dose-dependent manner, the number of bites to obtain defeat in the subordinate mice during the agonistic encounters, as well as attenuating defeat-induced analgesia, with F8Fa having a greater inhibitory effect than A18Fa. Peripheral administration of naloxone (1.0 mg/kg) had a similar inhibitory effect on the number of bites to defeat and the level of defeat-induced analgesia. In contrast, ICV administrations of F8Fa-IgG and A18Fa-IgG antisera increased the number of bites to defeat and augmented the levels of defeat-induced analgesia, with F8Fa-IgG having a greater effect than A18Fa-IgG. These results provide further evidence that the peptides, F8Fa and A18Fa, are involved in the modulation of opioid-mediated analgesia accompanying biological stressors and suggest that these endogenous FMRF-NH2-related peptides may also be associated with the expression of opioid-sensitive components of aggressive behavior.
There is accumulating evidence that pertussis toxin-sensitive G proteins are associated with the transduction of opioid-mediated antinociception in mammals. The present study examined the effects of hemocel injections of pertussis toxin (0.10 microgram) on the day-night rhythm of nociception and mu and kappa opioid-mediated antinociception in a mollusc, the land snail, Cepaea nemoralis. Five days after treatment, pertussis toxin significantly reduced the naloxone-sensitive, opioid-mediated nocturnal peak in the day-night rhythm of nociception [as measured by the latency of response to a thermal (40 degrees C) stimulus] in Cepaea, without affecting the daytime response latency. Pertussis toxin also significantly decreased the antinociceptive effects of the mu agonist, DAMGO, and blocked those of the kappa opioid agonist, U-69,593. These results suggest that G protein substrates of pertussis toxin are associated with the transduction of opioid-mediated nociception and antinociception in the snail, Cepaea.
There is evidence suggesting that the endogenous tetrapeptide, Tyr-MIF-1 (Tyr-Prol-Leu-Gly-amide), has antagonistic or modulatory effects on opioid-mediated analgesia. There is also substantial evidence for sex differences in opioid effects, whereby male rodents display greater levels of opioid-mediated analgesia than females. In the present study, determinations were made of the effects of Tyr-MIF-1 on morphine- and restraint stress-induced opioid analgesia in adult male and female deer mice, Peromyscus maniculatus. Intraperitoneal treatment with Tyr-MIF-1 (0.10-10 mg/kg) reduced morphine- and stress-induced analgesia in both male and female mice, with Tyr-MIF-1 having markedly greater antagonistic effects in male than female mice. These results indicate that there are sex differences in the modulatory (antiopiate) effects of Tyr-MIF-1 on opioid-mediated analgesia.
There is evidence suggesting that the endogenous mammalian octapeptide FLFQPQRFamide (F8Fa or neuropeptide FF, NPFF) has modulatory effects on opioid-mediated analgesia in rodents. There is also substantial evidence for sex differences in opioid analgesia, whereby male rats and mice display greater levels of opioid-mediated analgesia than females. In the present study, determinations were made of the effects of NPFF and IgG from antiserum against NPFF on morphine- and restraint stress-induced opioid analgesia in male and female deer mice. Intracerebroventricular (ICV) administrations of NPFF (0.10-10 micrograms) reduced in a dose-dependent manner morphine- and stress-induced analgesia in both male and female mice, with NPFF having markedly greater antagonistic effects in the male than female mice. Additionally, ICV administrations of NPFF-IgG increased the levels of morphine- and stress-induced analgesia and significantly reduced basal nociceptive sensitivity in male mice, whereas, in female mice, NPFF-IgG had no significant effects on either opioid-mediated analgesia or nociceptive sensitivity. These results indicate that there are sex differences in the modulatory effects of NPFF on opioid-mediated analgesia.
Reproductive adult male and female deer mice that received daily (7 days) injections of either the prototypic exogenous opiate antagonist, naloxone (1.0 mg/kg), or the endogenous putative antiopioid tetrapeptide, Tyr-MIF-1 (Tyr-Pro-Leu-Gly amide; 1.0 and 10 mg/kg), followed by determinations of thermal nociceptive sensitivity (hot-plate response) developed hypoalgesia. There were significant sex differences in this opioid blockade-induced or associated analgesia, with male mice displaying significantly greater hypoalgesia than females. Mice that received daily injections of either naloxone or Tyr-MIF-1 for 7 days without any accompanying determinations of nociceptive sensitivity (days 2-6 of treatment) failed to show any hypoalgesia on day 7 when they received the antagonist followed by a measurement of nociception. These results indicate that there are sex differences in both naloxone- and Tyr-MIF-1-induced hypoalgesia, and suggest that this pattern may be associated with sexually dimorphic opioid modulation of aversive conditioning.
In vertebrates the effects of endogenous opioid peptides are limited by proteolytic enzymes such as endopeptidase 24.11 (enkephalinase), which cleaves the Gly-Phe bonds in both methionine- and leucine-enkephalin. SCH 34826 ((S)-N-[n-[1-[(2,2-dimethyl-1,3-dioxolan-4yl) methoxy]carbonyl]-2-phenylethyl]-L-phenylalanine-B-alanine) is a potent, highly specific, enkephalinase inhibitor that has marked analgesic effects in mammals. The present study examined the effects of SCH 34826 on opioid-mediated aversive thermal (nociceptive) response of an invertebrate, the land snail, Cepaea nemoralis. SCH 34828 had significant, dose-related antinociceptive effects in Cepaea that were reduced by naloxone and completely blocked by the specific data opiate antagonist, ICI-174,864, and only weakly affected by the specific kappa opiate antagonist nor-binaltrophimine. These findings with SCH 34826 suggest that an enkephalinase similar to that in vertebrates is present and involved in the mediation of opioid (enkephalin) activity in the snail, Cepaea.
Day-night rhythms in feeding behavior and response to the putative sigma opiate agonist, N-allylnormetazocine (+/- SKF-10,047, 0.10-10 mg/kg), were measured in young (1-2 months), mature (8-12 months) and old (24-30 months) male CF-1 mice. The mice consumed more food at night than in the day-time, though this nocturnal peak was markedly reduced in the mature and old animals. The young mice also displayed a significant nocturnal enhancement in SKF-10,047 (0.10-1.0 mg/kg) stimulated feeding, that could, in part, be suppressed by the opiate antagonist naloxone (1.0 mg/kg). The day-night rhythm in ingestive responses to SKF-10,047 (0.10-1.0 mg/kg) was reduced in the mature animals and absent in the old animals. The old mice failed to show any significant increase in ingestive response following opiate administration. A higher dose of SKF-10,047 (10 mg/kg) had no significant ingestive effects in any of the age groups of mice; the excitatory, psychotomimetic-related effects, being also reduced in the old animals.
Although conditioned taste aversion (CTA) has been investigated and described in laboratory rodents and domestic animals, less is known regarding wild rodents. Here, we describe CTA in males and females of a "wild" species of rodent, the deer mouse (Peromyscus maniculatus). In addition, as CTA has often been induced by exposure to intense electromagnetic, X or gamma, radiation, in a second study, we also investigated the effects of a specifically designed, pulsed extremely low-frequency and low-intensity magnetic field on the flavor preferences of male and female deer mice. The results of these investigations showed that: (i) deer mice quickly developed a marked CTA for a novel flavor after a single pairing with LiCl; (ii) although the intensity of the CTA was the same in males and females, there was a sex difference in the duration of the flavor aversion, with males displaying it for a longer period (4 days) than females (3 days); (iii) both males and females showed a rapid and complete extinction of the aversion, in contrast to what has been reported for laboratory rodents; (iv) there was no recovery of CTA on re-test 10 days after extinction; (v) neither male or female deer mice developed a taste aversion as a consequence of exposure to a weak electromagnetic field; and (vi) there was a sex difference in response to the magnetic field, with exposure to the magnetic field significantly enhancing novel taste preference in male but not in female deer mice. Overall, our results show that there are several sex differences in the behavior of deer mice, both in the characteristics of the CTA and in the response to magnetic field exposure. The sex differences are discussed in terms of a sexually dimorphic sensitivity to experimental manipulation and the induction of stress and/or anxiety.