Prescription drug misuse among U.S. active duty military personnel: a secondary analysis of the 2008 DoD survey of health related behaviors.

OBJECTIVES: This study identifies predictors of prescription drug misuse among U.S. active duty service members (ADSM). The 2008 Department of Defense Survey of Health-Related Behaviors (HRB) Among Active Duty Military Personnel indicated that ADSM misuse pain relievers, tranquilizers, sedatives, and stimulants at levels ranging from 2% to 17%. METHODS: Secondary, multivariate analyses of HRB survey data examined predictors of self-reported prescription drug misuse for 4 distinct drug categories. RESULTS: Receipt of a pain reliever prescription in the past month, year, or previous year were strong predictors (adjusted odds ratio above 2.0) of misuse for all drug categories; receipt of a prescription for anxiety or depression medication in the past year was the strongest predictor of sedative misuse (adjusted odds ratio = 4.46, 95% confidence intervals 3.18-6.24). Absence of a drug testing program was significantly related to the likelihood of drug misuse for all drug categories. CONCLUSIONS: ADSM with a history of treatment for pain and mood disorders, and who self-report headaches, sleep disorders, and fatigue are at higher risk for misusing prescription drugs, perhaps in an effort to self-manage symptoms. The results should be interpreted as a starting place for future exploration, not as the sole basis for policy or program development.

The involvement of hypothalamic sleep pathways in general anesthesia: testing the hypothesis using the GABAA receptor beta3N265M knock-in mouse.

The GABA(A) receptor has been identified as the single most important target for the intravenous anesthetic propofol. How effects at this receptor are then translated into a loss of consciousness, however, remains a mystery. One possibility is that anesthetics act on natural sleep pathways. Here, we test this hypothesis by exploring the anesthetic sensitivities of GABAergic synaptic currents in three specific brain nuclei that are known to be involved in sleep. Using whole-cell electrophysiology, we have recorded GABAergic IPSCs from the tuberomammillary nucleus (TMN), the perifornical area (Pef), and the locus ceruleus (LC) in brain slices from both wild-type mice and mice that carry a specific mutation in the GABA(A) receptor beta(3) subunit (N265M), which greatly reduces their sensitivity to propofol, but not to the neurosteroid alphaxalone. We find that this in vivo pattern of anesthetic sensitivity is mirrored in the hypothalamic TMN and Pef nuclei, consistent with their role as direct anesthetic targets. In contrast, anesthetic sensitivity in the LC was unaffected by the beta(3)N265M mutation, ruling out this nucleus as a major target for propofol. In support of the hypothesis that orexinergic neurons in the Pef are involved in propofol anesthesia, we further show that these neurons are selectively inhibited by GABAergic drugs in vivo during anesthesia, and that a modulation in the activity of Pef neurons alone can affect loss of righting reflex. Overall, our results support the idea that GABAergic anesthetics such as propofol exert their effects, at least in part, by modulating hypothalamic sleep pathways.

Role of endogenous sleep-wake and analgesic systems in anesthesia.

Classical anesthetics of the gamma-aminobutyric acid type A receptor (GABA(A))-enhancing class (e.g., pentobarbital, chloral hydrate, muscimol, and ethanol) produce analgesia and unconsciousness (sedation). Dissociative anesthetics that antagonize the N-methyl-D-aspartate (NMDA) receptor (e.g., ketamine, MK-801, dextromethorphan, and phencyclidine) produce analgesia but do not induce complete loss of consciousness. To understand the mechanisms underlying loss of consciousness and analgesia induced by general anesthetics, we examined the patterns of expression of c-Fos protein in the brain and correlated these with physiological effects of systemically administering GABAergic agents and ketamine at dosages used clinically for anesthesia in rats. We found that GABAergic agents produced predominantly delta activity in the electroencephalogram (EEG) and sedation. In contrast, anesthetic doses of ketamine induced sedation, followed by active arousal behaviors, and produced a faster EEG in the theta range. Consistent with its behavioral effects, ketamine induced Fos expression in cholinergic, monoaminergic, and orexinergic arousal systems and completely suppressed Fos immunoreactivity in the sleep-promoting ventrolateral preoptic nucleus (VLPO). In contrast, GABAergic agents suppressed Fos in the same arousal-promoting systems but increased the number of Fos-immunoreactive neurons in the VLPO compared with waking control animals. All anesthetics tested induced Fos in the spinally projecting noradrenergic A5-7 groups. 6-hydroxydopamine lesions of the A5-7 groups or ibotenic acid lesions of the ventrolateral periaqueductal gray matter (vlPAG) attenuated antinociceptive responses to noxious thermal stimulation (tail-flick test) by both types of anesthetics. We hypothesize that neural substrates of sleep-wake behavior are engaged by low-dose sedative anesthetics and that the mesopontine descending noradrenergic cell groups contribute to the analgesic effects of both NMDA receptor antagonists and GABA(A) receptor-enhancing anesthetics.

Gastroenteropancreatic hormones and metabolism in fish.

Metabolism of vertebrates integrates a vast array of systems and processes, including the pursuit and capture of food, feeding and digestion of ingested food, absorption and transport of nutrients, assimilation, partitioning and utilization of energy, and the processing and elimination of wastes. Fish, which are the most diverse group of vertebrates and occupy a wide range of habitats and display numerous life history patterns, have proven to be important models for the study of the structure, biosynthesis, evolution, and function of gastroenteropancreatic (GEP) hormones. Food intake is promoted by galanin, neuropeptide Y, and pancreatic polypeptide (PP), while cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) inhibit food intake. Digestion of ingested food is facilitated by CCK, PP, and secretin by coordinating gastrointestinal tract motility and regulation of exocrine secretion. Somatostatins (SS), on the other hand, generally inhibit exocrine secretions. Insulin facilitates assimilation by promoting the uptake of nutrient molecules (e.g., glucose, amino acids, and fatty acids) into cells. Insulin also is generally anabolic and stimulates the synthesis and deposition of energy reserves (e.g., glycogen, triacylglycerol) as well as of proteins, thereby facilitating organismal growth. Insulin-like growth factors (e.g., IGF-1) also promote cell proliferation and organismal growth. Breakdown and mobilization of stored energy reserves is stimulated by glucagon, GLP-1, and SS. Somatostatins also affect metabolism and reproduction via their effects on the thyroid axis as well as growth via effects on growth hormone (GH) release and perhaps directly via modulation of GH sensitivity. Studies in fish have revealed that GEP hormones play an important role in coordinating the various aspects of metabolism with each other and with the physiological and developmental status of the animal as well as with the environment.

Insulin and growth hormone stimulate somatostatin receptor (SSTR) expression by inducing transcription of SSTR mRNAs and by upregulating cell surface SSTRs.

This study examined the effects of insulin (INS) and growth hormone (GH) on mRNA and functional expression of somatostatin receptors (SSTRs). Rainbow trout liver was used as a model system to evaluate the direct effects of INS and GH on mRNA expression of three SSTR subtypes characterized previously from this species: SSTR1A, SSTR1B, and SSTR2. INS and GH directly stimulated steady-state levels of all SSTR mRNAs in a concentration- and time-dependent manner; however, the pattern of expression was hormone and SSTR subtype specific. INS stimulated SSTR2 expression to a greater extent than SSTR1A or SSTR1B expression, whereas GH stimulated SSTR2 and SSTR1B expression to a similar extent, with SSTR2 and SSTR1B expression being more responsive to GH than SSTR1A. Whether INS- or GH-stimulated SSTR expression resulted from altered rates of transcription and/or changes in mRNA stability also was investigated. Formation of nascent SSTR transcripts in nuclei isolated from rainbow trout hepatocytes was significantly stimulated by INS and GH. Neither INS nor GH, however, affected the stability of SSTR mRNAs. Functional expression of SSTRs was studied in Chinese hamster ovary (CHO-K1) cells stably transfected with SSTR1A or SSTR1B. Surface expression of functional SSTRs was stimulated by INS and GH. These findings indicate that INS and GH stimulate SSTR expression by regulating transcription of SSTR mRNAs and by increasing functional SSTRs on the cell surface, and they suggest that regulation of SSTRs may be important for the coordination of growth, development, and metabolism of vertebrates.

Regulation of somatostatins and their receptors in fish.

The multifunctional nature of the somatostatin (SS) family of peptides results from a multifaceted signaling system consisting of many forms of SS peptides that bind to a variety of receptor (SSTR) subtypes. Research in fish has contributed important information about the components, function, evolution, and regulation of this system. Somatostatins or mRNAs encoding SSs have been isolated from over 20 species of fish. Peptides and deduced peptides differ in their amino acid chain length and/or composition, and most species of fish possess more than one form of SS. The structural heterogeneity of SSs results from differential processing of the hormone precursor, preprosomatostatin (PPSS), and from the existence of multiple genes that give rise to multiple PPSSs. The PPSS genes appear to have arisen through a series of gene duplication events over the course of vertebrate evolution. The numerous PPSSs of fish are differentially expressed, both in terms of the distribution among tissues and in terms of the relative abundance within a tissue. Accumulated evidence suggests that nutritional state, season/stage of sexual maturation, and many hormones [insulin (INS), glucagon, growth hormone (GH), insulin-like growth factor-I (IGF-I), and 17beta-estradiol (E2)] regulate the synthesis and release of particular SSs. Fish and mammals possess multiple SSTRs; four different SSTRs have been described in fish and several of these occur as isoforms. SSTRs are also wide spread and are differentially expressed, both in terms of distribution of tissues as well as in terms of relative abundance within tissues. The pattern of distribution of SSTRs may underlie tissue-specific responses of SSs. The synthesis of SSTR mRNA and SS-binding capacity are regulated by nutritional state and numerous hormones (INS, GH, IGF-I, and E2). Accumulated evidence suggests the possibility of both tissue- and subtype-specific mechanisms of regulation. In many instances, there appears to be coordinate regulation of PPSS and of SSTR; such regulation may prove important for many processes, including nutrient homeostasis and growth control.

The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects.

BACKGROUND: The authors investigated whether the sedative, or hypnotic, action of the general anesthetic dexmedetomidine (a selective alpha -adrenoceptor agonist) activates endogenous nonrapid eye movement (NREM) sleep-promoting pathways. METHODS: c-Fos expression in sleep-promoting brain nuclei was assessed in rats using immunohistochemistry and hybridization. Next, the authors perturbed these pathways using (1) discrete lesions induced by ibotenic acid, (2) local and systemic administration of gamma-aminobutyric acid receptor type A (GABA ) receptor antagonist gabazine, or (3) alpha2-adrenoceptor antagonist atipamezole in rats, and (4) genetic mutation of the alpha -adrenoceptor in mice. RESULTS: Dexmedetomidine induced a qualitatively similar pattern of c-Fos expression in rats as seen during normal NREM sleep, a decrease in the locus ceruleus (LC) and tuberomammillary nucleus (TMN) and an increase in the ventrolateral preoptic nucleus (VLPO). These changes were attenuated by atipamezole and were not seen in mice lacking functional alpha2a-adrenoceptors, which do not show a sedative response to dexmedetomidine. Bilateral VLPO lesions attenuated the sedative response to dexmedetomidine, and the dose-response curve to dexmedetomidine was shifted right by gabazine administered systemically or directly into the TMN. VLPO lesions and gabazine pretreatment altered c-Fos expression in the TMN but in not the LC after dexmedetomidine administration, indicating a hierarchical sequence of changes. CONCLUSIONS: The authors propose that endogenous sleep pathways are causally involved in dexmedetomidine-induced sedation; dexmedetomidine's sedative mechanism involves inhibition of the LC, which disinhibits VLPO firing. The increased release of GABA at the terminals of the VLPO inhibits TMN firing, which is required for the sedative response.

Evidence for the involvement of spinal cord alpha1 adrenoceptors in nitrous oxide-induced antinociceptive effects in Fischer rats.

BACKGROUND: In a previous study, the authors found that nitrous oxide (N2O) exposure induces c-Fos (an immunohistochemical marker of neuronal activation) in spinal cord gamma-aminobutyric acid-mediated (GABAergic) neurons in Fischer rats. In this study, the authors sought evidence for the involvement of alpha1 adrenoceptors in the antinociceptive effect of N2O and in activation of GABAergic neurons in the spinal cord. METHODS: Adult male Fischer rats were injected intraperitoneally with alpha1 adrenoceptor antagonist, alpha2 adrenoceptor antagonist, opioid receptor antagonist, or serotonin receptor antagonist and, 15 min later, were exposed to either air (control) or 75% N2O. In some animals, nociception was investigated with the plantar test after 30 min of exposure, while in other animals, gas exposure was continued for 90 min and the spinal cord was examined for c-Fos immunostaining. In a separate experiment, animals were exposed to the above gases alone, after which the spinal cords were examined immunohistochemically for c-Fos and alpha1 adrenoceptor by double-staining methods. RESULTS: The antinociceptive effect of N2O was attenuated by prazosin (an alpha1 adrenoceptor antagonist), yohimbine (an alpha2 adrenoceptor antagonist), and naloxone (an opioid receptor antagonist) but not by methysergide and tropisetron (serotonin receptor antagonists). N2O exposure induced c-Fos expression in the spinal cord, which was blocked by prazosin and naloxone but not by other drugs. N2O-induced c-Fos expression was colocalized with alpha1 adrenoceptor immunoreactivity in laminae III-IV. CONCLUSIONS: These findings support the hypothesis that N2O activates GABAergic interneurons through alpha1 adrenoceptors to produce its antinociceptive effect.

Nitrous oxide exerts age-dependent antinociceptive effects in Fischer rats.

Nitrous oxide (N(2)O) is an inhalational anesthetic/analgesic gas that has been used for clinical practice for more than a century. While its anesthetic mechanisms remain largely unknown, the underlying analgesic mechanisms are now being unraveled. It has been proposed that N(2)O induces opioid peptide release in the midbrain, leading to the activation of descending noradrenergic inhibitory neurons, which modulates pain processing within the spinal cord. Because descending noradrenergic inhibitory neurons are not functional at birth we posit that N(2)O only becomes an effective analgesic/antinociceptive agent in young patients when the descending noradrenergic inhibitory neurons become fully functional. In the present study, we have examined the age-dependence of N(2)O-induced antinociceptive effects on the formalin test. Fischer rats of various ages (7-, 15-, 19-, 23-, and 29-day-old, and adult) were injected 5% formalin into the hind paw during exposure to 75% N(2)O. Both their behavioral responses and changes in Fos-like immunoreactivity in the spinal cord were assessed as markers of N(2)O's antinociceptive effect. Adult-like antinociceptive responses to N(2)O, both behaviorally and immunohistochemically, were only present in rats older than 3 weeks (23- and 29-day-old). These findings support our hypothesis that N(2)O lacks antinociceptive effects in the very young animals.