Chaim G. Pick

NG-Nitro-L-arginine prevents morphine tolerance

NMDA receptor antagonists, such as MK-801, prevent the development of tolerance to morphine. Since many NMDA actions involve the production of nitric oxide, we examined the effects of a nitric oxide synthase inhibitor on morphine tolerance. The analgesic response to morphine (5 mg/kg s.c.) given daily diminishes from 60% in naive animals to 0% within 5 days. Coadministration of NG-nitro-L-arginine (8 mg/kg per day) along with morphine prevents the demonstration of appreciable tolerance for at least 11 days. These results suggest that morphine tolerance involves the activation of NMDA receptors followed by the subsequent release of nitric oxide.

Alterations in Hippocampal Cholinergic Receptors and Hippocampal Behaviors After Early Exposure to Nicotine

Mice were exposed to nicotine prenatally by injecting the mother with 1.5 mg/kg nicotine SC twice daily on gestation days 9-18 (PreN mice) or neonatally by daily SC injections of 1.5 mg/kg nicotine on postnatal days 2-21 (NeoN mice). At age 50 days, hippocampal muscarinic receptors Bmax of PreN and NeoN mice were 58% and 79% above control, respectively (p less than 0.01); Kd was unaffected by early nicotine exposure. Eight-arm maze performance of nicotine-exposed animals fell behind control level. Both PreN and NeoN made approximately 10% less correct responses in the first eight trials than controls throughout the test period (p less than 0.01). By the last day of testing, PreN needed 23% and NeoN 31% more trials than controls to enter all arms (p less than 0.001). In addition, PreN needed 35 and NeoN 42% more days than controls to reach criterion (p less than 0.05). Similarly, while 61% of controls reached criterion by day 6 only 17% of PreN and 25% of NeoN reached criterion (p less than 0.01). In the Morris maze, PreN needed from 43-119% more time to reach the platform (p less than 0.001). In the spatial probe test, PreN animals made 35% fewer crosses over the area of the missing platform (p less than 0.001). The study suggests that nicotine administered to the fetus or neonate alters septohippocampal chemistry and induces deficits in hippocampus-related behaviors. The possible reversal of the behavioral changes by manipulating the cholinergic innervations should be the subject of future investigations.

Genetic influences in opioid analgesic sensitivity in mice

Studies of various strains of mice revealed marked differences in their analgesic sensitivity towards morphine (mu), U50,488H (kappa 1) and naloxone benzoylhydrazone (NalBzoH; kappa 3). Sensitivity to mu and kappa analgesia varied independently of the other. Analgesic sensitivity to morphine remained relatively consistent among 3 different nociceptive assays for each strain. However, the sensitivity of an individual strain to NalBzoH remained highly dependent upon the assay used. CD-1 mice were sensitive to NalBzoH in all 3 assays, but in BALB/c mice NalBzoH produced analgesia only in the hot plate and cold water tail-flick assays. In Swiss-Webster mice, NalBzoH was active in the radiant heat and cold water tail-flicks but inactive in the hot plate. Although the levels of mu, kappa 1 and kappa 3 binding in whole brain homogenates did vary somewhat, they did not correlate with analgesic sensitivity. These results suggests that the genetic controls over mu and kappa analgesia operate independently and further illustrate the many difficulties in evaluating potential analgesics.

The antinociceptive effect of fluvoxamine

The authors conducted a study in order to evaluate the antinociceptive effects of the serotonin-selective reuptake inhibitor (SSRI) antidepressant fluvoxamine and its interaction with various opioid receptor subtypes. Male ICR mice were tested with a hotplate analgesia meter. Fluvoxamine elicited antinociceptive effect in a dose-dependent manner following i.p., i.t. and i.c.v. injection. Naloxone 10 mg/kg s.c. did not abolish the fluvoxamine antinociceptive effect. At the next stage fluvoxamine was administered together with various agonists of opioid receptors. When administered together with opiates, fluvoxamine significantly potentiated analgesia at the kappa(3)-opioid receptor subtype (P < .005) and to a lesser extent, at the mu-, delta-, and kappa(1)-opioid receptors. We conclude that fluvoxamine alone induces an antinociceptive effect. This effect is mediated by non-opioid mechanism of action. These results suggest a potential role for fluvoxamine in the management of pain when co-administered with opioids at low doses.

Potentiation of opioid analgesia by the antidepressant nefazodone.

Nefazodone is a new antidepressant related structurally to trazodone. In addition to its activity in preclinical assays for antidepressant activity, nefazodone was a potent analgesic in the mouse hotplate assay. At 50 mg/kg s.c. nefazodone doubled baseline latencies in 40% of mice but was inactive in the tailflick test at any dose tested. The hotplate analgesia seen with nefazodone alone was not reversed by naloxone (10 mg/kg s.c.). In the tailflick assay, nefazodone (50 mg/kg s.c.) enhanced morphines analgesic response, shifting morphines ED50 from 3.1 mg/kg alone to 0.86 mg/kg in conjunction with nefazodone (P less than 0.05). Two days after implantation of a morphine pellet (75 mg) no mice remained analgesic in the tailflick assay. Administration of nefazodone (50 mg/kg s.c.) restored analgesia to 60% of mice (P less than 0.03). In selective analgesic assays, nefazodone enhanced mu 1, mu 2 and delta analgesia, but not kappa 1 or kappa 3 analgesia. Nefazodone did not affect morphines LD50 and, in assays of gastrointestinal transit, nefazodone increased morphines potency only slightly. In conclusion, nefazodone alone is analgesic in certain animal models. In conjunction with morphine, nefazodone potentiated analgesia with no effect on lethality and little effect on gastrointestinal transit, resulting in an increase in morphines therapeutic index. These results suggest that nefazodone and similar agents may have a significant role in the management of pain.

Entrapment of the distal suprascapular nerve

SummaryTwenty-five shoulders were dissected in cadavers in order to observe the presence of the inferior transverse ligament, the spinoglenoid ligament, and its relationship to the spinoglenoid notch and the suprascapular nerve. The ligament was found to be absent in 50% of females and rudimentary in one female, but absent in only 13% of the male shoulders. The distance between the ligament and the bone, and from the ligament to the nerve was similar in males and females, but the variation was greater in males. These findings may explain the observation that distal suprascapular nerve entrapment occurs mostly in men.RésuméLes auteurs ont disséqué vingt-cinq épaules de cadavres afin de vérifier la présence dun ligament transversal inférieur, le ligament spinoglénoïdien, ainsi que ses rapports avec léchancrure spino-glénoïdienne et le nerf sus-scapulaire. Labsence de ce ligament a été constatée chez 50% des sujets féminins et il était rudimentaire chez lun dentre eux. Chez les sujets masculins, il nétait absent que dans 13% des cas. La distance entre le ligament et los, et entre le ligament et le nerf était semblable chez les hommes et chez les femmes, mais les variations étaient plus importantes chez les hommes. Ces observations peuvent expliquer que la compression distale du nerf sus-scapulaire survienne plus fréquemment chez lhomme.

Alterations in septohippocampal cholinergic innervations and related behaviors after early exposure to heroin and phencyclidine

Mice were exposed to diacetylmorphine (heroin) or phencyclidine (PCP) prenatally or neonatally. At a later age, they were tested for hippocampus-related behavioral deficits and concomitant alterations in the septohippocampal cholinergic innervations. Actually, this is an application of the previously established phenobarbital neuroteratogenicity model to heroin and PCP. Prenatal exposure was accomplished transplacentally by injecting the mother 10 mg/kg heroin or PCP on gestation days 9-18. Neonatal administrations were applied directly by injections of 10 mg/kg of either drug to the pups between neonatal days 2-21. At the age of 50 days, mice exposed to heroin and PCP prenatally exhibited a 107% and 159% increase in their muscarinic cholinergic receptors Bmax, respectively. Neonatal exposure to heroin or PCP caused an 83% and 76% increase in the receptors respectively. On the behavioral level, both prenatal and neonatal exposure to heroin or PCP reduced performance in the hippocampus related eight-arm maze and Morris mazes. Depending on the drug, the test and the period of drug administration, the reduction ranged between 10% and 75%. The results suggest that heroin and PCP induce alterations in the septohippocampal cholinergic innervations and in related behavioral performance. Further studies are necessary in order to connect the biochemical and behavioral events in causal relationships.

EIGHT ARM MAZE FOR MICE

Certain behaviors have been found to be mediated by the brain. Eight-arm maze behavior is a measure of spatial-memory, and the integrity of this has been connected with the integrity of the hippocampus in rats (Olton & Samuelson, 1976). Mice are useful animals in neuropharmacological research, but an apparatus for mice has not yet been developed, perhaps because mice were thought incapable of executing intricate tasks as compared with rats. We developed an eight-arm-maze adapted for mice to be used for such an experiment and also developed a procedure that was found to be highly useful and easy for mice to carry out, in order to increase their motivation to work in the apparatus. In our early studies we had shown that neonatal exposure to phenobarbital destroyed hippocampal neurons (Yanai & Bergman, 1981). Consequently, we used a sensitive eight-arm-maze to show that even small differences in performance can be clearly shown in this maze.

Neuron transplantation reverses phenobarbital-induced behavioral birth defects in mice

Mice were exposed to phenobarbital prenatally on gestation days 9–18 (B mice), and were tested at adulthood for behavioral changes. B mice showed deficits in the eight‐arm maze, a behavior related to the septohippocampal pathways. Consequently, transplantation of septal (mostly cholinergic) and locus coeruleus (mostly noradrenergic) neurons was applied to reverse the behavioral deficits. Most (75%) of the controls but none of the B mice reached a specific criterion in the eight‐arm maze. However, transplantation of fetal septal tissue into the hippocampus of B mice enabled 55% of them to reach criterion. Transplantation of locus coeruleus tissue did not improve the performance of B mice. The viability of the transplants was confirmed in cytochemical studies. The results suggest that transplantation of neurons can be applied to reverse phenobarbital‐induced behavioral birth defects.

Long term reduction in eight arm maze performance after early exposure to phenobarbital

Performance in the hippocampal eight arm maze was studied in mice after early exposure to phenobarbital (PhB). since previous studies suggested that these animals suffered neural deficits in the hippocampus. For prenatal exposure pregnant mothers were fed 3 g PhB/kg milled food on gestation days 9–18. Neonates were injected daily with 50 mg PhB/kg. on postnatal days 2–21. After a week of water deprivation, the animals were tested at age 50 days for 5 days preceded by 1 day of habituation. Deficits in eight arm maze performance were demonstrated in early treated mice on every testing day. For example, on day 5 of testing the number of correct entries during the first eight attempts in the prenatally treated group were 12% below control level (P<0.01), the respective reduction in the neonatal group was 10% (P< 0.001). The number of trials needed to enter all arms on day 5 was 27% above control level among prenatally treated mice (P< 0.001), and 13% in neonatally treated mice (P< 0.05). It took prenatal PhB animals twice the time to reach criterion than their controls (P< 0.001) and four times as long for neonatally treated mice (P< 0.001).