Nitrous Oxide: Mechanism of Its Antinociceptive Action

Nitrous oxide (N2O) is an anesthetic gas known to produce an analgesic effect at sub-anesthetic concentrations. This analgesic property of N2O can be clinically exploited in a broad range of conditions where pain relief is indicated. The mechanism of this analgesic effect was long thought to be nonspecific in nature, but a landmark study by Berkowitz and others in 1976 first implicated an opioid mechanism of action, possibly via N2O-stimulated neuronal release of endogenous opioid peptides to activate opioid receptors. N2O-induced release of opioid peptide has been demonstrated in both in vivo and in vitro preparations. Reversal of N2O-induced antinociception in animals by narcotic antagonists has been reported by a number of laboratories. Subsequent studies have utilized more selective opioid antagonists to identify the opioid receptor subtypes involved in the antinociceptive effect of N2O. Extensive pharmacological testing in the mouse abdominal constriction and rat hot plate paradigms have established that N2O-induced antinociception is mediated by κ-opioid receptors in the former and by µ- and -opioid receptors in the latter. Current studies focus on two recent developments. The poor responsiveness of the DBA/2J mouse strain to N2O has led to pharmacogenetic studies that hope to identify the underlying genetic basis for antinociceptive responsiveness to N2O. Other research suggests an involvement of nitric oxide (NO) in mediating the antinociceptive effects of N2O in both rats and mice

Detection and Mapping of Quantitative Trait Loci that Determine Responsiveness

Exposure to 70% N2O evokes a robust antinociceptive effect in C57BL/6 (B6) but not in DBA/2 (D2) inbred mice. This study was conducted to identify quantitative trait loci (QTL) in the mouse genome that might determine responsiveness to N2O. Offspring from the F2 generation bred from B6 and D2 progenitors exhibited a broad range of responsiveness to N2O antinociception as determined by the acetic acid-induced abdominal constriction test. QTL analysis was then used to dissect this continuous trait distribution into component loci, and to map them to broad chromosomal regions. To this end, 24 spleens were collected from each of the following four groups: male and female F2 mice responding to 70% N2O in oxygen with 100% response (high-responders); and male and female F2 mice responding with 0% response (low-responders). Genomic DNA was extracted from the spleens and genotyped with simple sequence length polymorphism MapPairs markers. Findings were combined with findings from the earlier QTL analysis from BXD recombinant inbred mice [Brain Res 725 (1996) 23]. Combined results revealed two significant QTL that influence responsiveness to nitrous oxide on proximal chromosome 2 and distal chromosome 5, and one suggestive QTL on midchromosome 18. The chromosome 2 QTL was evident only in males. A significant interaction was found between a locus on chromosome 6 and another on chromosome 13 with a substantial effect on N2O antinociception

Diversity and evolution of amphibian pupil shapes

Pupil constriction has important functional consequences for animal vision, yet the evolutionary mechanisms underlying diverse pupil sizes and shapes are poorly understood. We aimed to quantify the diversity and evolution of pupil shapes among amphibians and to test for potential correlations to ecology based on functional hypotheses. Using photographs, we surveyed pupil shape across adults of 1294 amphibian species, 74 families and three orders, and additionally for larval stages for all families of frogs and salamanders with a biphasic ontogeny. For amphibians with a biphasic life history, pupil shape changed in many species that occupy distinct habitats before and after metamorphosis. In addition, non-elongated (circular or diamond) constricted pupils were associated with species inhabiting aquatic or underground environments, and elongated pupils (with vertical or horizontal long axes) were more common in species with larger absolute eye sizes. We propose that amphibians provide a valuable group within which to explore the anatomical, physiological, optical and ecological mechanisms underlying the evolution of pupil shape

Non-Motor and Motor Features in LRRK2 Transgenic Mice

10.1371/journal.pone.0070249PLoS ONE87-POLN

A New Threat to Honey Bees, the Parasitic Phorid Fly Apocephalus borealis

Honey bee colonies are subject to numerous pathogens and parasites. Interaction among multiple pathogens and parasites is the proposed cause for Colony Collapse Disorder (CCD), a syndrome characterized by worker bees abandoning their hive. Here we provide the first documentation that the phorid fly Apocephalus borealis, previously known to parasitize bumble bees, also infects and eventually kills honey bees and may pose an emerging threat to North American apiculture. Parasitized honey bees show hive abandonment behavior, leaving their hives at night and dying shortly thereafter. On average, seven days later up to 13 phorid larvae emerge from each dead bee and pupate away from the bee. Using DNA barcoding, we confirmed that phorids that emerged from honey bees and bumble bees were the same species. Microarray analyses of honey bees from infected hives revealed that these bees are often infected with deformed wing virus and Nosema ceranae. Larvae and adult phorids also tested positive for these pathogens, implicating the fly as a potential vector or reservoir of these honey bee pathogens. Phorid parasitism may affect hive viability since 77% of sites sampled in the San Francisco Bay Area were infected by the fly and microarray analyses detected phorids in commercial hives in South Dakota and California's Central Valley. Understanding details of phorid infection may shed light on similar hive abandonment behaviors seen in CCD

Involvement of a NO–cyclic GMP–PKG signaling pathway in nitrous oxide-induced antinociception in mice

The antinociceptive effect of nitrous oxide (N 2O) is dependent on nitric oxide (NO); however, the next step in the pathway activated by NO is undetermined. The present study was conducted to test the hypothesis that a N 2O action involves sequential activation of NO synthase, soluble guanylyl cyclase and protein kinase G to induce an antinociceptive effect in mice. The antinociceptive responsiveness of male NIH Swiss mice to N 2O was assessed using the acetic acid abdominal constriction test. Different groups of mice were pretreated with either saline, the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide (carboxy-PTIO), the guanylyl cyclase-inhibitor 1H-[1,2,4]-oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), the protein kinase G-inhibitor Rp-isomer of 8-(4-chlorophenylthio)-guanosine-3′,5′-cyclic monophosphorothioate (Rp-8-pCPT-cGMPS) or the selective phosphodiesterase V-inhibitor 1,2-dihydro-2-[(2-methyl-4-pyridinyl)methyl]-1-oxo-8-(2-pyrimidinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (T 0156). Vehicle (saline)-pretreated mice responded to N 2O in a concentration-dependent manner. This antinociceptive effect was antagonized by systemic pretreatment with carboxy-PTIO and ODQ and central pretreatment with Rp-8-pCPT-cGMPS. In each case, the dose–response curve for N 2O was progressively shifted to the right by increasing the dose of each pretreatment drug. On the other hand, N 2O-induced antinociception was enhanced by systemic pretreatment with T 0156; the dose–response curve for N 2O was shifted to the left. The ATP-sensitive potassium channel blocker glibenclamide was without influence on the antinociceptive effect of N 2O. These results support the hypothesis that N 2O-induced antinociception in mice is mediated by a NO–cyclic GMP–PKG pathway. [Display omitted

Advances in Understanding the Actions of Nitrous Oxide

Nitrous oxide (N 2 O) has been used for well over 150 years in clinical dentistry for its analgesic and anxiolytic properties. This small and simple inorganic chemical molecule has indisputable effects of analgesia, anxiolysis, and anesthesia that are of great clinical interest. Recent studies have helped to clarify the analgesic mechanisms of N 2 O, but the mechanisms involved in its anxiolytic and anesthetic actions remain less clear. Findings to date indicate that the analgesic effect of N 2 O is opioid in nature, and, like morphine, may involve a myriad of neuromodulators in the spinal cord. The anxiolytic effect of N 2 O, on the other hand, resembles that of benzodiazepines and may be initiated at selected subunits of the γ-aminobutyric acid type A (GABA A ) receptor. Similarly, the anesthetic effect of N 2 O may involve actions at GABA A receptors and possibly at N-methyl-D-aspartate receptors as well. This article reviews the latest information on the proposed modes of action for these clinicaleffects of N 2 O