International Journal of Neuropsychopharmacology (2014), 17, 1355. doi:10.1017/S1461145714001060
© CINP 2014
E D I TO R I A L
Editorial
Thematic Section – Effects of Opiates
CHARLES P. FRANCE, Ph.D. Department of Pharmacology The University of Texas Health Science Center at San Antonio USA
Downloaded from http://ijnp.oxfordjournals.org/ by guest on November 14, 2015
Recent estimates are that opioids account for more than half of illicit drug-related deaths worldwide and the thematic section this month includes 5 basic science reports on opioid abuse and dependence. The first three papers used rats to study pharmacokinetic factors and cell signaling mechanisms that play a role in opioid abuse and dependence, respectively. A fourth paper that is relevant to the treatment of opioid abuse compared buprenorphine to a combination of buprenorphine and naloxone in mice. A final paper used brain imaging to explore the effects of heroin on a measure of impulsivity in heroin abusers. Collectively, these papers provide new information on mechanisms contributing to opioid abuse and suggest potential novel targets for treating this growing public health crisis. Diacetylmorphine (heroin) is metabolized to 6monoacetylmorphine and further to morphine. Gottås and colleagues measured concentrations of heroin, 6monoacetylmorphine, and morphine in blood and brain and the extracellular concentration of dopamine in striatum in rats treated with an opioid. Increases in dopamine occurred shortly after heroin administration and were attributed to the activity of 6-monoacetylmorphine because similar increases were observed after administration of heroin or 6-monoacetylmorphine and not after administration of morphine. The authors conclude that because 6-monoacetylmorphine plays a major role in the effects of heroin, factors impacting blood concentrations of 6-monoacetylmorphine will significantly impact the behavioral effects of heroin. A study by Lai and colleagues compared the effects of the phosphodiesterase-4 inhibitor rolipram on heroin self-administration, reinstatement of responding, and on the expression of phosphorylated cAMP response element-binding protein (CREB) in the nucleus accumbens of rats. Rolipram did not affect responding under a fixed-ratio schedule of heroin self-administration but decreased responding under a progressive-ratio schedule of heroin self-administration and decreased both cue- and heroin-induced reinstatement. Decreased reinstatement responding was correlated with increased expression of CREB, leading these authors to conclude that phophodiesterase-4 could be a target for treating the high rate of relapse that occurs in heroin abusers. Yang and colleagues studied hydrogen sulfide (H2S), an endogenously produced gas that is thought to be a
signaling molecule, for its ability to prevent behavioral and cellular changes that emerge during acute opioid withdrawal. After three hourly injections of the opioid receptor agonist DAMGO, a subsequent injection of naloxone caused hyperalgesia as well as increased phosphorylation of CREB and upregulation of the signaling molecules calcitonin gene-related peptide (CGRP) and cAMP. These behavioral and cellular changes were attenuated in rats that received H2S with each injection of DAMGO. H2S also inhibited forskolin-stimulated cAMP production and adenylate cyclase activity in SH-SY5Y neuronal cells as well as naloxone-stimulated activation of protein kinase Cα, Raf-1, and extracellular signalregulated kinase 1/2. The authors suggest that H2S might be a novel target for preventing hyperalgesia in opioid withdrawal. Canestrelle and colleagues used a conditioned place preference (CPP) procedure in mice to compare buprenorphine alone with combinations of buprenorphine and naloxone, both of which are used to treat opioid abuse. Buprenorphine alone produced only CPP whereas a combination of buprenorphine and naloxone produced CPP when a 30-min conditioning session was used but a conditioned place aversion when a 5-min conditioning session was used. These results could be relevant to discrepancies in the literature regarding the abuse of combinations of buprenorphine and naloxone in opioid abusers. Finally, a double-blind placebo-controlled study in heroin-dependent humans examined acutely administered heroin using both functional magnetic resonance imaging to investigate interactions between the dorsal anterior cingulate cortex and the bilateral inferior frontal gyri and a Go/No-Go task to compare brain activation to response inhibition. Schmidt and colleagues report that heroin deceased activity of the anterior cingulate cortex. Moreover, response inhibition was associated with activation of several brain regions including the anterior cingulate cortex; there was a significant positive correlation between activity of the dorsal anterior cingulate cortex and false alarm rates after placebo but not after heroin. Prepared by:
© CINP 2014
E D I TO R I A L
Editorial
Thematic Section – Effects of Opiates
CHARLES P. FRANCE, Ph.D. Department of Pharmacology The University of Texas Health Science Center at San Antonio USA
Downloaded from http://ijnp.oxfordjournals.org/ by guest on November 14, 2015
Recent estimates are that opioids account for more than half of illicit drug-related deaths worldwide and the thematic section this month includes 5 basic science reports on opioid abuse and dependence. The first three papers used rats to study pharmacokinetic factors and cell signaling mechanisms that play a role in opioid abuse and dependence, respectively. A fourth paper that is relevant to the treatment of opioid abuse compared buprenorphine to a combination of buprenorphine and naloxone in mice. A final paper used brain imaging to explore the effects of heroin on a measure of impulsivity in heroin abusers. Collectively, these papers provide new information on mechanisms contributing to opioid abuse and suggest potential novel targets for treating this growing public health crisis. Diacetylmorphine (heroin) is metabolized to 6monoacetylmorphine and further to morphine. Gottås and colleagues measured concentrations of heroin, 6monoacetylmorphine, and morphine in blood and brain and the extracellular concentration of dopamine in striatum in rats treated with an opioid. Increases in dopamine occurred shortly after heroin administration and were attributed to the activity of 6-monoacetylmorphine because similar increases were observed after administration of heroin or 6-monoacetylmorphine and not after administration of morphine. The authors conclude that because 6-monoacetylmorphine plays a major role in the effects of heroin, factors impacting blood concentrations of 6-monoacetylmorphine will significantly impact the behavioral effects of heroin. A study by Lai and colleagues compared the effects of the phosphodiesterase-4 inhibitor rolipram on heroin self-administration, reinstatement of responding, and on the expression of phosphorylated cAMP response element-binding protein (CREB) in the nucleus accumbens of rats. Rolipram did not affect responding under a fixed-ratio schedule of heroin self-administration but decreased responding under a progressive-ratio schedule of heroin self-administration and decreased both cue- and heroin-induced reinstatement. Decreased reinstatement responding was correlated with increased expression of CREB, leading these authors to conclude that phophodiesterase-4 could be a target for treating the high rate of relapse that occurs in heroin abusers. Yang and colleagues studied hydrogen sulfide (H2S), an endogenously produced gas that is thought to be a
signaling molecule, for its ability to prevent behavioral and cellular changes that emerge during acute opioid withdrawal. After three hourly injections of the opioid receptor agonist DAMGO, a subsequent injection of naloxone caused hyperalgesia as well as increased phosphorylation of CREB and upregulation of the signaling molecules calcitonin gene-related peptide (CGRP) and cAMP. These behavioral and cellular changes were attenuated in rats that received H2S with each injection of DAMGO. H2S also inhibited forskolin-stimulated cAMP production and adenylate cyclase activity in SH-SY5Y neuronal cells as well as naloxone-stimulated activation of protein kinase Cα, Raf-1, and extracellular signalregulated kinase 1/2. The authors suggest that H2S might be a novel target for preventing hyperalgesia in opioid withdrawal. Canestrelle and colleagues used a conditioned place preference (CPP) procedure in mice to compare buprenorphine alone with combinations of buprenorphine and naloxone, both of which are used to treat opioid abuse. Buprenorphine alone produced only CPP whereas a combination of buprenorphine and naloxone produced CPP when a 30-min conditioning session was used but a conditioned place aversion when a 5-min conditioning session was used. These results could be relevant to discrepancies in the literature regarding the abuse of combinations of buprenorphine and naloxone in opioid abusers. Finally, a double-blind placebo-controlled study in heroin-dependent humans examined acutely administered heroin using both functional magnetic resonance imaging to investigate interactions between the dorsal anterior cingulate cortex and the bilateral inferior frontal gyri and a Go/No-Go task to compare brain activation to response inhibition. Schmidt and colleagues report that heroin deceased activity of the anterior cingulate cortex. Moreover, response inhibition was associated with activation of several brain regions including the anterior cingulate cortex; there was a significant positive correlation between activity of the dorsal anterior cingulate cortex and false alarm rates after placebo but not after heroin. Prepared by:
