Location of fatal prescription opioid-related deaths in 12 states, 2008-2010: Implications for prevention programs.

INTRODUCTION: Prescription opioid pain reliever overdose is a major public health issue in the United States. To characterize the location of drug-related deaths, we examined fatal prescription opioid and illicit drug-related deaths reported in 12 states. METHODS: Data are from the Substance Abuse and Mental Health Services Administration's Drug Abuse Warning Network (DAWN). Medical examiners or coroners in 12 states (MA, MD, ME, NH, NM, OK, OR, RI, UT, VA, VT, WV) reported details of state-wide drug-related mortality during 2008-2010. DAWN data included location and manner of death, age, race, and drugs involved. Deaths were coded into three categories: prescription opioid-related, illicit drug-related, and cases that involved both a prescription opioid and an illicit drug. RESULTS: During a 3-year period, there were 14,091 opioid or illicit drug-related deaths in 12 states. More than half of the prescription opioid-related deaths in all states, except Maryland, occurred at home, rather than in public or in a health care facility. Although it was still the predominant category, lower percentages of illicit drug-related deaths occurred at home. CONCLUSION: Prescription opioid overdoses have increased substantially, and the location of the person at the time of death can have important public health implications for interventions. PRACTICAL APPLICATIONS: This paper highlights that bystander support can be a critical lifesaving factor in drug related deaths but may be more likely for illicit drug-related deaths than for prescription opioid-related deaths.

Enantiomeric propanolamines as selective N-methyl-D-aspartate 2B receptor antagonists.

Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11-64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC 50 values between 30-100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties.

The CRF1 receptor antagonist, R121919, attenuates the severity of precipitated morphine withdrawal.

Corticotropin-releasing factor (CRF) regulates the hypothalamic-pituitary-adrenal axis, coordinates the mammalian stress response, and acting primarily via the CRF(1) receptor, has been strongly implicated in the pathophysiology of depression and anxiety. Furthermore, the behavioral and autonomic activation that occurs following withdrawal in drug dependent animals resembles the mammalian stress response. Concordant with this view is evidence of enhanced CRF transcription, release and activity following withdrawal from several drugs of abuse. Conversely, CRF receptor antagonists have been demonstrated to reduce the severity of many drug withdrawal symptoms, implicating a specific role for activation of CRF neurons in mediating the anxiogenic and stress-like reactions observed during withdrawal. To extend these findings, we investigated whether pretreatment with a selective CRF(1) receptor antagonist, R121919, is capable of similarly decreasing the autonomic, behavioral and neuroendocrine activation observed following precipitation of morphine withdrawal in dependent rats. The results indicate that pretreatment with R121919 attenuates the global severity of the precipitated morphine withdrawal syndrome as measured by the Gellert-Holtzman scale. In addition, rats pretreated with R121919 prior to precipitation of morphine withdrawal demonstrated decreased hypothalamic-pituitary-adrenal axis activation, as measured by plasma ACTH concentrations, and decreased early expression of the CRF gene in the paraventricular nucleus of the hypothalamus, as measured by CRF heteronuclear RNA. These findings suggest that activation of CRF neuronal systems via the CRF(1) receptor may be one element of the neurobiological mechanisms activated during drug withdrawal and that CRF(1) receptor antagonists may have a potential therapeutic role in the treatment of human drug withdrawal syndromes.

Maternal separation alters ICSS responding in adult male and female rats, but morphine and naltrexone have little affect on that behavior.

Prior research has provided evidence that the early postnatal environment can have long lasting effects on both the physiology and behavior of offspring. This is modeled in rats by using a maternal separation paradigm in which pups are separated from their mother for a few hours daily during their first two postnatal weeks. While this model has been used extensively to study stress effects and anxiety, less research has been done to examine how these separations affect measures of reward and reinforcement in adulthood. The current study investigated the impact of maternal separation (MS) on intracranial self-stimulation (ICSS) maintained responding in male and female offspring, and the effects of morphine (0.3-3.0 mg/kg) and naltrexone (0.1-10 mg/kg) on that responding. Rearing condition (MS or non-handled, NH) significantly altered response rates during acquisition in both sexes, with NH offspring exhibiting the highest rates. Group differences in baseline responding on a progressive ratio (PR-2) schedule of reinforcement were evident only in females, with MS females having response rates 50% lower than NH females. Neither morphine nor naltrexone differentially affected either rearing group. Sex impacted NH offspring: males acquired responding more readily, but females had higher response rates and breakpoints during all other phases of the experiment. In MS offspring, no sex differences were observed during acquisition, but during all other phases males had higher response rates and breakpoints than females. These results indicate that maternal separation during the first two postnatal weeks can have long-term effects on responding for ICSS, but these effects do not appear tied to endogenous opioid systems in the lateral hypothalamus.

Modeling the onset of drug dependence: a consideration of the requirement for protein synthesis.

It has been proposed, with some supporting evidence, that development of opiate tolerance and dependence requires protein synthesis. However, a quantitative, biologically based model within which to analyse and support the data has been lacking. Utilizing such a framework or model, we recently compared the time course of onset of opiate dependence in laboratory animals, with the mathematical time course of general changes in protein levels. Not only did the time course of onset of dependence parallel the time course of increasing levels of a protein, but also the half-life of the putative protein required by the model was very similar to those of many brain proteins. In this study, we have more extensively tested the model by producing and examining a much more detailed and surprisingly complex time course of the onset of dependence. Applying the protein synthesis time course model to the data suggested the presence of two distinct components of dependence, an early transient component and a later long-lasting component. These components appear to correspond to acute and chronic dependence, respectively. The protein synthesis hypothesis more readily applies to the chronic dependence portion. Because consideration of the model can generate components that correspond to accepted and well-known components of dependence, both the utility of the model as well as the hypothesis that opiate dependence at least partially requires protein synthesis are supported. It is also possible that individual components of the withdrawal syndrome have individual and unique rate limiting mechanisms. In any case, time course analysis may be helpful in revealing underlying mechanisms of change.

In rats, acute morphine dependence results in antagonist-induced response suppression of intracranial self-stimulation.

RATIONALE: Lower (0.001-1.0 mg/kg) doses of the opioid antagonist naltrexone produce few behavioral effects in otherwise drug-free rats responding for ICSS, but reduce response rates by up to 75% after a single dose of morphine. OBJECTIVES: The present study represents an effort to verify that other opioid antagonists produce this acute opioid dependence effect, and to characterize their relative pharmacological profiles. METHODS: We implanted bipolar electrodes in the lateral hypothalamus of adult male rats, and then trained them to lever-press on an "autotitration" ICSS schedule, where responding on a "reset" lever allows the rat to control the frequency of stimulation; performance stabilized at approximately 1.5 responses/s. RESULTS: During twice-weekly test sessions, cumulative doses of five of seven opioid antagonists produced significant response rate decreases (30-80%) in saline-pretreated rats; nalorphine (ED25=15.6 mg/kg)> naltrexone (ED25=13.1 mg/kg)>naloxone (ED25=7.3 mg/kg)>levallorphan (ED25=13.96 mg/kg)>(-)cyclazocine (ED25=0.028 mg/kg). A single MOR pretreatment (10 mg/kg, 4 h) significantly enhanced the rate-decreasing effects of six of the seven agonists tested; by 10-fold (-) cyclazocine>13-fold (nalorphine)>93-fold (levallorphan)>972-fold (naloxone)>2190-fold (naltrexone). The pure non-selective antagonist diprenorphine potently decreased rates after MOR pretreatment (ED25= 0.01 mg/kg), but did not after saline pretreatment. The mixed opioid agonist-antagonist drug nalbuphine (1.0-30 mg/kg) did not affect responding after either saline or MOR. CONCLUSIONS: Antagonists with a high affinity for, and a lack of intrinsic activity at, the micro-opioid receptor precipitate the greatest behavioral changes in rats acutely dependent on MOR.

Long-lasting changes in morphine-induced locomotor sensitization and tolerance in Long-Evans mother rats as a result of periodic postpartum separation from the litter: a novel model of increased vulnerability to drug abuse?

Daily postpartum separations from the litter produce enduring changes in anxiety and sensitivity to the antinociceptive effects of morphine in Long-Evans dams. We tested whether postpartum experience alters sensitivity to the effects of morphine on locomotor activity. Dams were tested 4-6 weeks after their pups were weaned, and had one of the following backgrounds: daily separation from the litter on postpartum days 2-14 for either 3 h (prolonged separation-LS) or 15 min (brief separation-BS), or no separation (nonhandled control-NH). After 2 consecutive days (B1-2) of baseline activity measurements, subjects were tested daily after s.c. injections of either morphine (10 mg/kg) or saline for 7 days and again on day 10. Beginning 5 days later, saline and 1.0-10 mg/kg of morphine were tested in all dams. On B1, LS and BS dams habituated slower than NH controls, yielding higher horizontal counts. LS dams failed to habituate across baseline days and were more active than other dams on B2. Sensitization, a progressive increase in horizontal activity, was more rapid and robust in LS and BS dams compared to NH animals. LS was the only group that developed tolerance to morphine-induced decreases in vertical activity. In LS dams with the history of morphine treatment, injection of saline resulted in higher horizontal activity and center time compared to saline-treated counterparts, indicative of conditioning. Among animals with a history of saline treatment, LS dams were more sensitive to morphine challenges than BS and NH dams. As a result of the robust and long-lasting increases in the ability of morphine to induce behavioral sensitization in litter-separated dams, periodic postpartum separation may represent a new animal model of increased vulnerability to substance abuse.

Early neonatal experience of Long-Evans rats results in long-lasting changes in reactivity to a novel environment and morphine-induced sensitization and tolerance.

In Long-Evans rats, daily 3-h separation from the dam during the neonatal period results in enduring alterations in behavioral and neuroendocrine responses to stressors and sensitivity to antinociceptive effects of acute and chronic morphine. We tested whether early neonatal experience alters sensitivity to effects of morphine on locomotor activity. The subjects were adult rats that had one of the following backgrounds: daily separation from the dam on postnatal days 2-14 for either 3 h (maternal separation (MS)) or 15 min (handled control (H)) or no separation from the dam (non-handled control (NH)). After two consecutive days of baseline activity measurements, subjects were tested daily after SC injections of either morphine (10 mg/kg) or saline for seven days and again on day 10. Beginning five days later, saline and 1.0-10 mg/kg of morphine were tested in all animals. On the baseline days, MS animals had higher horizontal and vertical activity than did NH controls, whereas H animals spent more time in the center of the testing chamber. In MS and H animals but not in NH controls, daily injections of morphine produced progressive increases in all locomotor activity measures, indicative of sensitization (horizontal counts, center time) and tolerance (vertical counts). MS animals with a history of morphine treatment had significantly higher horizontal and vertical activity after a saline injection than did their counterparts with a history of saline treatment, indicative of conditioning. They also exhibited greater locomotor sensitization to 1.0 mg/kg of morphine than did H and NH controls. These results provide further evidence that environmental manipulation in the form of maternal separation early in life results in enduring changes in sensitivity to effects of morphine that could reflect altered endogenous opioid systems.

Long-lasting changes in stress-induced corticosterone response and anxiety-like behaviors as a consequence of neonatal maternal separation in Long-Evans rats.

Early neonatal environmental factors appear to have powerful and long-lasting influences on an organism's physiology and behavior. Long-Evans male rats separated from their dam for 3 h daily over the first 2 weeks of life (maternally separated, MS rats) when tested as adults exhibit exaggerated behavioral and neuroendocrine responses to stress compared to 15-min separated (handled, H) animals. The purpose of this study was to compare male and female adult rats that were MS, H or were undisturbed (nonhandled, NH) as neonates in anxiety-like behaviors, in the elevated plus-maze, and in response to startle-inducing auditory stimuli. We confirmed that MS males oversecrete corticosterone (CORT; 2.5-5 times) in response to mild handling stress. MS males and females were less likely to explore open arms of the plus-maze. MS males exhibited 35% higher startle amplitudes compared to controls. Furthermore, MS males were more likely to emit ultrasonic vocalizations in response to startle than were H controls. However, MS and control females did not differ in auditory startle response or in startle-induced ultrasonic vocalizations. Therefore, experiencing maternal separation results in a long-lasting increase in anxiety-like behaviors that occurs in a sex-dependent manner.