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1.  Involvement of spinal cord opioid mechanisms in the acute antinociceptive effect of hyperbaric oxygen in mice1 
Brain research  2013;1540:10.1016/j.brainres.2013.09.050.
Earlier research has demonstrated that treatment with hyperbaric oxygen (HBO2) can elicit an antinociceptive response in models of acute pain. We have demonstrated that this antinociceptive effect is centrally-mediated and is dependent on opioid receptors. The purpose of the present study was to examine the role of endogenous opioid peptides and opioid receptors specifically in the spinal cord in the acute antinociceptive effect of HBO2 in mice. Male NIH Swiss mice were exposed to HBO2 (100% oxygen @ 3.5 atmospheres absolute) for 11 min and their antinociceptive responsiveness was determined using the glacial acetic acid-induced abdominal constriction test. HBO2-induced antinociception was sensitive to antagonism by intrathecal (i.t.) pretreatment with the κ- and μ-selective opioid antagonists norbinaltorphimine and β-funalrexamine, respectively, but not the δ-selective antagonist naltrindole. The antinociceptive effect of HBO2 was also significantly attenuated by i.t. pretreatment with a rabbit antiserum against rat dynorphin1-13 but not antisera against β-endorphin or methionine-enkephalin. Based on these experimental findings, the acute antinociceptive effect of HBO2 appears to involve neuronal release of dynorphin and activation of κ and μ opioid receptors in the spinal cord.
PMCID: PMC3867933  PMID: 24113418
Hyperbaric oxygen; antinociception; opioid receptors; endogenous opioid peptides; spinal cord; mouse
2.  Involvement of brain opioid receptors in the anti-allodynic effect of hyperbaric oxygen in rats with sciatic nerve crush-induced neuropathic pain 
Brain research  2013;1537:10.1016/j.brainres.2013.08.050.
Earlier research has demonstrated that hyperbaric oxygen (HBO2) can produce an antinociceptive effect in models of acute pain. Recent studies have revealed that HBO2 can produce pain relief in animal models of chronic pain as well. The purpose of the present investigation was to ascertain whether HBO2 treatment might suppress allodynia in rats with neuropathic pain and whether this effect might be blocked by the opioid antagonist naltrexone (NTX). Male Sprague Dawley rats were subjected to a sciatic nerve crush under anesthesia and mechanical thresholds were assessed using an electronic von Frey anesthesiometer. The time course of the HBO2-induced anti-allodynic effect in different treatment groups was plotted, and the area-under-the-curve (AUC) was determined for each group. Seven days after the nerve crush procedure, rats were treated with HBO2 at 3.5 atmospheres absolute (ATA) for 60 min and exhibited an anti-allodynic effect, compared to nerve crush-only control rats. Twenty-four hours before HBO2 treatment, another group of rats was implanted with Alzet® osmotic minipumps that continuously released NTX into the lateral cerebral ventricle for 7 days. These NTX-infused, HBO2-treated rats exhibited an allodynic response comparable to that exhibited by rats receiving nerve crush only. Analysis of the AUC data showed that HBO2 significantly reduced the nerve crush-induced allodynia; this anti-allodynic effect of HBO2 was reversed by NTX. These results implicate opioid receptors in the pain relief induced by HBO2.
PMCID: PMC3827781  PMID: 23998986
Hyperbaric oxygen; anti-allodynia; naltrexone; opioid receptors; neuropathic pain; sciatic nerve crush; rat
3.  An anxiolytic-like effect of hyperbaric oxygen in the mouse light/dark exploration test 
Life Sciences  2011;90(7-8):267-271.
We studied whether hyperbaric oxygen (HBO2) treatment, which is known to increase production of nitric oxide (NO) in the brain, might also produce an NO-dependent anxiolytic-like behavioral response.
Main methods
Male NIH Swiss mice (20–25 g) were subjected to a 60-min HBO2 treatment at different absolute atmospheres, and anxiety was assessed using the light/dark exploration test at different time intervals following the cessation of HBO2 treatment. To ascertain the underlying mechanism of action, other groups of mice were pretreated with the NO synthase inhibitor NG-monomethyl-L-arginine acetate, the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide (carboxy-PTIO), the soluble guanylyl cyclase-inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or the benzodiazepine antagonist flumazenil to determine their influence on the HBO2-induced anxiolytic-like effect.
Key findings
A 60-min HBO2 treatment at 3.0 absolute atmospheres increased the time spent by mice in the light compartment that lasted up to 90 min following the end of HBO2 treatment. This anxiolytic effect of HBO2 was significantly reduced by pretreatment with L-NMMA, carboxy-PTIO, ODQ and flumazenil.
Based on these findings, we conclude that a 60-min HBO2 treatment is capable of inducing an anxiolytic effect that possibly involves NO, cyclic GMP and the benzodiazepine binding site.
PMCID: PMC3268913  PMID: 22154905
hyperbaric oxygen; anxiolysis; light/dark exploration test; nitric oxide; cyclic GMP; benzodiazepine binding site; mouse
4.  Involvement of a NO–cyclic GMP–PKG signaling pathway in nitrous oxide-induced antinociception in mice 
European journal of pharmacology  2011;654(3):249-253.
The antinociceptive effect of nitrous oxide (N2O) 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 N2O action involves sequential activation of NO synthase, soluble guanylyl cyclase and protein kinase G to induced an antinociceptive effect in mice. The antinociceptive responsiveness of male NIH Swiss mice to N2O 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 N2O 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 N2O was progressively shifted to the right by increasing doses of each pretreatment drug. On the other hand, N2O-induced antinociception was enhanced by systemic pretreatment with T 0156; the dose-response curve for N2O was shifted to the left. The ATP-sensitive potassium channel blocker glibenclamide was without influence on the anti-nociceptive effect of N2O. These results support the hypothesis that N2O-induced antinociception in mice is mediated by a NO–cyclic GMP–PKG pathway.
PMCID: PMC3050811  PMID: 21238450
Nitrous oxide; antinociception; nitric oxide; cyclic GMP; protein kinase G; mice
5.  Nitrous oxide-induced NO-dependent neuronal release of β-endorphin from the rat arcuate nucleus and periaqueductal gray 
Brain research  2010;1366:38-43.
Nitrous oxide (N2O)-induced antinociception is thought to result from nitric oxide (NO)-dependent neuronal release of endogenous opioid peptides in the central nervous system. The present study employed microdialysis to determine whether exposure to N2O stimulates proopiomelanocortin (POMC) neurons to release β-endorphin in the arcuate nucleus (ARC) of the hypothalamus and the periaqueductal gray (PAG) of the midbrain. Male Sprague Dawley rats were stereotaxically implanted with microdialysis probes in the ARC or PAG. Exposure to 70% N2O significantly increased dialysate levels of oxidation products of NO as well as β-endorphin, compared to levels in fractions collected under room air. These increases in the ARC and PAG were abolished by systemic pretreatment with L-NG-nitro arginine methyl ester (L-NAME). These findings suggest an association between increased NO activity and the stimulated release of β-endorphin during exposure of rats to N2O.
PMCID: PMC2993853  PMID: 20937263
Nitrous oxide; microdialysis; β-endorphin; nitric oxide; arcuate nucleus; periaqueductal gray; rat
6.  Hyperbaric Oxygen Treatment Induces a Two-Phase Antinociceptive Response of Unusually Long Duration in Mice 
Hyperbaric oxygen (HBO2) therapy is approved by the FDA for limited clinical indications but is reported to produce pain relief in several chronic pain conditions. However, there have been no studies to explain this apparent analgesic effect of HBO2. Research conducted in our laboratory demonstrates that four daily 60-min HBO2 treatments at 3.5 ATA induced an unparalleled antinociceptive response that consists of 1) an early phase that lasted at least six hours after the HBO2 treatment before dissipating; and 2) a late phase that emerged about 18 hours after the early phase and lasted for up to three weeks. The early phase was sensitive to antagonism by acutely intracerebroventricular (i.c.v.)-administered opioid antagonist naltrexone and the nitric oxide synthase (NOS)-inhibitor L-NAME. The late phase was inhibited by treatment with i.c.v. naltrexone or L-NAME during the four HBO2 treatments but was not antagonized by either naltrexone or L-NAME following acute pretreatment two weeks after HBO2 treatment. These experimental results implicate a novel mechanism that is activated by HBO2, resulting in an antinociceptive response of unusually long duration that is of potential interest in the clinical management of pain.
Hyperbaric oxygen treatment of mice can induce a two-phase antinociceptive response of unusually long duration. Nitric oxide and opioid receptors appear to initiate or mediate both phases of the antinociceptive response. Further elucidation of the underlying mechanism may potentially identify molecular targets that cause long-lasting activation of endogenous analgesic systems.
PMCID: PMC2910818  PMID: 20418186
Hyperbaric oxygen; antinociception; nitric oxide; opioid receptors; mice
7.  Antagonism of the Antinociceptive Effect of Nitrous Oxide by Inhibition of Enzyme Activity or Expression of Neuronal Nitric Oxide Synthase in the Mouse Brain and Spinal Cord 
European journal of pharmacology  2009;626(2-3):234-238.
Previous studies have implicated nitric oxide (NO) in the antinociceptive response to the anesthetic gas nitrous oxide (N2O). The present study was conducted to confirm this NO involvement using pharmacological and gene knockdown and knockout strategies to inhibit the supraspinal and spinal production of NO. Antinociceptive responsiveness to 70% N2O was assessed using the acetic acid (0.6%) abdominal constriction test in NIH Swiss mice following intracerebroventricular (i.c.v.) or intrathecal (i.t.) pretreatment with the NOS-inhibitor L-NG-nitro arginine methyl ester (L-NAME) or an antisense oligodeoxynucleotide (AS-ODN) directed against neuronal NOS (nNOS). Experiments were also conducted in mice homozygous for a defective nNOS gene (nNOS−/−). Mice that were pretreated i.c.v. or i.t. with L-NAME (1.0 μg) both exhibited 80-90% reduction in the magnitude of the N2O-induced antinociceptive response. Mice that were pretreated i.c.v. or i.t. with nNOS AS-ODN (3×25 μg) exhibited a 60-80% antagonism of the antinociceptive response. Compared to wild-type mice, nNOS knockout mice showed a 60% reduction in N2O-induced antinociception. These findings consistently demonstrate that transient or developmental suppression of nNOS expression significantly reduces antinociceptive responsiveness to N2O. NO of both supraspinal and spinal origin, therefore, plays an important role in the antinociceptive response to N2O.
PMCID: PMC2790018  PMID: 19818753
Nitrous oxide; Nitric oxide; Antinociception; NOS-inhibitor; Antisense; Transgenic mice
8.  Exposure to nitrous oxide stimulates a nitric oxide-dependent neuronal release of β-endorphin in ventricular-cisternally-perfused rats 
Brain research  2009;1300:37-40.
We have previously shown that the antinociceptive effect of nitrous oxide (N2O) in the rat hot plate test is sensitive to antagonism by antisera against the endogenous opioid peptide β-endorphin. Moreover, N2O-induced antinociception is reduced by inhibition of nitric oxide (NO) production in the brain. To test the hypothesis that N2O might stimulate an NO-dependent neuronal release of β-endorphin, we conducted a ventricular-cisternal perfusion with artificial cerebrospinal fluid (aCSF) in urethane-anesthetized Sprague Dawley rats. Ten-min fractions of aCSF perfusate were collected from separate groups of room air-exposed rats, N2O-exposed rats, and L-NAME-pretreated, N2O-exposed rats; they were then analyzed for their content of NO metabolites and β-endorphin. Compared to room air control, exposure to 70% N2O increased perfusate levels of the NO metabolites nitrite and nitrate as well as β-endorphin. Pretreatment of rats with L-NG-nitro arginine methyl ester, an inhibitor of NO synthase, prevented the N2O-induced increases in nitrite, nitrate and β-endorphin. These findings demonstrate in an in vivo rat model that N2O may stimulate an NO-dependent neuronal release of β-endorphin.
PMCID: PMC2783921  PMID: 19747467
Nitrous oxide; nitric oxide; β-endorphin; ventricular-cisternal perfusion; rats
9.  A Prolonged NO-Dependent, Opioid-Mediated Antinociceptive Effect of Hyperbaric Oxygen in Mice 
Hyperbaric oxygen (HBO2) therapy is reported to cause pain relief in several conditions of chronic pain. A single 60-min session of HBO2 treatment produced a prolonged antinociceptive effect in mice that persisted for 90 min after cessation of treatment. The HBO2-induced antinociception was significantly attenuated by pretreatment prior to HBO2 exposure with the opioid antagonist naltrexone, the non-specific nitric oxide synthase (NOS)-inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and the selective neuronal NOS-inhibitor S-methyl-L-thiocitrulline (SMTC) but not the selective endothelial NOS-inhibitor N5-(1-iminoethyl)-L-ornithine (L-NIO). The antinociception was also significantly reduced by central pretreatment with a rabbit antiserum against dynorphin1-13 but not by rabbit antisera against either β-endorphin or methionine-enkephalin. The prolonged antinociceptive effect at 90 min after HBO2-induced treatment was also significantly attenuated by naltrexone but not L-NAME administered 60 min following HBO2 treatment but prior to nociceptive testing. These findings indicate that the antinociception that persists for 90 min after HBO2 exposure is mediated by nitric oxide (NO) and opioid mechanisms but that the NO involvement is critical during the HBO2 treatment and not at the time of nociceptive testing. These results are consistent with the concept that HBO2 may induce an NO-dependent release of opioid peptide to cause a long-acting antinociceptive effect.
PMCID: PMC2650380  PMID: 18976963
Hyperbaric Oxygen; Nitric Oxide; Opioid; Antinociception; Mice
10.  Nitrous oxide-antinociception is mediated by opioid receptors and nitric oxide in the periaqueductal gray region of the midbrain 
Previous studies have shown that nitrous oxide (N2O)-induced antinociception is sensitive to antagonism by blockade of opioid receptors and also by inhibition of nitric oxide (NO) production. The present study was conducted to determine whether these occur within the same brain site. Mice were stereotaxically implanted with microinjection cannulae in the periaqueductal gray (PAG) area of the midbrain. In saline-pretreated mice, exposure to 70% N2O resulted in a concentration-dependent antinociceptive effect in the mouse abdominal constriction test. Pretreatment with an opioid antagonist in the PAG significantly antagonized the antinociceptive effect. Pretreatment with an inhibitor of NO production in the PAG also significantly antagonized the antinociceptive effect. These findings suggest that N2O acts in the PAG via an NO-dependent, opioid receptor-mediated mechanism to induce antinociception.
PMCID: PMC2279102  PMID: 17683915
Nitrous oxide; antinociception; periaqueductal gray; opioid receptors; nitric oxide
11.  Genomic loci and candidate genes underlying inflammatory nociception 
Pain  2010;152(3):599-606.
Heritable genetic factors contribute significantly to inflammatory nociception. To determine candidate genes underlying inflammatory nociception, the current study used a mouse model of abdominal inflammatory pain. BXD recombinant inbred (RI) mouse strains were administered the intraperitoneal (IP) acetic acid test and genome-wide quantitative trait locus (QTL) mapping was performed on the mean number of abdominal contraction and extension movements in three distinct groups of BXD RI mouse strains in two separate experiments. Combined mapping results detected two QTLs on chromosomes (Chr) 3 and 10 across experiments and groups of mice; an additional sex-specific QTL was detected on Chr 16. The results replicate previous findings of a significant QTL, Nociq2, on distal Chr 10 for formalin-induced inflammatory nociception and will aid in identification of the underlying candidate genes. Comparisons of sensitivity to IP acetic acid in BXD RI mouse strains with microarray mRNA transcript expression profiles in specific brain areas detected covarying expression of candidate genes that are also found in the detected QTL confidence intervals. The results indicate that common and distinct genetic mechanisms underlie heritable sensitivity to diverse inflammatory insults, and provide a discrete set of high priority candidate genes to investigate further in rodents and human association studies.
PMCID: PMC3039031  PMID: 21195549
inflammation; nociception; acetic acid; quantitative trait locus mapping; microarray; transcript abundance
12.  The acute antinociceptive effect of HBO2 is mediated by a NO–cyclic GMP–PKG–KATP channel pathway in mice 
Brain research  2010;1368:102-107.
Previous research has found that hyperbaric oxygen (HBO2) produces an acute antinociceptive effect that is dependent on nitric oxide (NO). The present study was undertaken to determine whether HBO2-induced acute antinociception might involve a NO–cyclic GMP–protein kinase G–ATP-sensitive potassium (KATP) channel pathway. Male NIH Swiss mice were subjected to a 5-min HBO2 treatment (100% oxygen at 3.5 absolute atmospheres) and antinociception was assessed over the next 6 min still under HBO2 using the acetic acid abdominal constriction test. Pretreatment with 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide (carboxy-PTIO, an NO scavenger), 1H-[1,2,4]-oxadiazolo-[4,3-a]quinoxalin-1-one) (a soluble guanylyl cyclase-inhibitor, Rp-8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphorothioate (a protein kinase G-inhibitor) or glibenclamide (an ATP-sensitive potassium channel-inhibitor) all led to antagonism of the HBO2-induced acute antinociception in a dose-dependent manner. These findings suggest that HBO2-induced acute antinociception might be due to activation of a NO–cyclic GMP–protein kinase G–KATP channel pathway.
PMCID: PMC3023906  PMID: 20977894
Hyperbaric oxygen; antinociception; nitric oxide; cyclic GMP; protein kinase G; potassium channels; mice
13.  An Elective Course to Engage Student Pharmacists in Elementary School Science Education 
Objective. To develop and assess the impact of an elective course (HealthWISE) on student pharmacists’ skills in communication and health promotion and elementary school students’ knowledge of and attitudes toward science.
Design. Three colleges and schools of pharmacy collaborated to develop a 1-credit elective course that used online and classroom teaching and learning techniques to prepare student pharmacists to teach science in elementary school classrooms. Student pharmacists delivered 6 science lessons to elementary students over the course of 2 months.
Assessment. In weekly journal reflections and a final paper, student pharmacists reported improved communication and health promotion skills. Elementary teachers reported they were satisfied with student pharmacists’ performance in the classroom. On pretest and posttest evaluations, elementary students demonstrated increased science knowledge and enhanced enthusiasm for science following the lessons taught by student pharmacists.
Conclusions. The HealthWISE elective course provided positive benefit for student pharmacists, elementary school teachers, and elementary students.
PMCID: PMC3279034  PMID: 22345722
service-learning; communication skills; health promotion; STEM education
14.  Homeostatic Synapse-driven Membrane Plasticity in Nucleus Accumbens Neurons 
Stable brain function relies on homeostatic maintenance of the functional output of individual neurons. In general, neurons function by converting synaptic input to output as action potential firing. To determine homeostatic mechanisms that balance this input-output/synapse-membrane interaction, we focused on nucleus accumbens (NAc) neurons and demonstrated a novel form of synapse-to-membrane homeostatic regulation, homeostatic synapse-driven membrane plasticity (hSMP). Through hSMP, NAc neurons adjusted their membrane excitability to functionally compensate for basal shifts in excitatory synaptic input. Furthermore, hSMP was triggered by synaptic N-methyl-D-aspartate receptors (NMDARs) and expressed by the modification of SK-type Ca2+-activated potassium channels. Moreover, hSMP in NAc neurons was abolished in rats during a short- (2 days) or long-term (21 days) withdrawal from repeated intraperitoneal injections of cocaine (15 mg/kg/day, 5 days). These results suggest that hSMP is a novel form of synapse-to-membrane homeostatic plasticity and dysregulation of hSMP may contribute to cocaine-induced cellular alterations in the NAc.
PMCID: PMC2743333  PMID: 19420249
Homeostatic plasticity; NMDA receptor; accumbens; SK channel; cocaine; excitatory synapse; membrane excitability
15.  Advances in Understanding the Actions of Nitrous Oxide 
Anesthesia Progress  2007;54(1):9-18.
Nitrous oxide (N2O) 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 N2O, but the mechanisms involved in its anxiolytic and anesthetic actions remain less clear. Findings to date indicate that the analgesic effect of N2O is opioid in nature, and, like morphine, may involve a myriad of neuromodulators in the spinal cord. The anxiolytic effect of N2O, on the other hand, resembles that of benzodiazepines and may be initiated at selected subunits of the γ-aminobutyric acid type A (GABAA) receptor. Similarly, the anesthetic effect of N2O may involve actions at GABAA 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 N2O.
PMCID: PMC1821130  PMID: 17352529
Nitrous oxide; Pharmacology; Anesthesia; Analgesia; Anxiolysis
16.  Combination Effects of Chloral Hydrate and Nitrous Oxide/Oxygen in the Mouse Staircase Test 
Anesthesia Progress  1988;35(3):116-120.
The effects of chloral hydrate and/or nitrous oxide were assessed in the mouse staircase test. In this paradigm, the number of steps ascended is thought to reflect locomotor activity, whereas the number of rears is an index of anxiety. Chloral hydrate alone produced a dose-dependent decrease in the number of rears but no change in the number of steps ascended except at the highest dose. Nitrous oxide alone produced a concentration-related increase in the number of steps ascended but no change in rearing. When the two drugs were combined, nitrous oxide appeared to potentiate the rearing suppressant activity of chloral hydrate. Analysis of our experimental findings suggests that chloral hydrate exerts a specific anxiolytic drug effect that can be potentiated by concurrent treatment with nitrous oxide.
PMCID: PMC2168025  PMID: 3166349

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