Female rats express heroin-induced and -conditioned suppression of peripheral nitric oxide production in response to endotoxin challenge

Opioids and opioid-conditioned stimuli (CS) negatively alter host immunity, impairing the response to pathogens during opioid use and following drug cessation. Using male rats, our laboratory has determined that heroin or heroin-CS exposure preceding a lipopolysaccharide (LPS) challenge markedly suppresses normal induction of peripheral pro-inflammatory biomarkers. Presently, it is unknown if these heroin-induced and -conditioned effects extend to the female immune response. To begin this venture, the current study tested the direct effects of heroin and heroin-CS on LPS-induced peripheral nitric oxide (NO) production in female rats. We focused investigations on peripheral NO as it is a critical pro-inflammatory molecule necessary for pathogen resistance. In Experiment 1, male and female Lewis rats were administered 0 (Saline), 1, or 3 mg/kg heroin subcutaneously (s.c). Sixty minutes later, animals were injected with LPS (1 mg/kg, s.c.). Spleen and plasma samples were collected 6 h later to examine NO production through inducible NO synthase (iNOS) expression and nitrate/nitrite concentration, respectively. In Experiment 2, female Lewis rats underwent five, 60-minute context conditioning sessions with heroin (1 mg/kg, s.c.) or saline. On test day, CS-exposed and control (home cage) animals were injected with LPS (1 mg/kg, s.c.). Tissue was collected 6 h later to examine splenic iNOS expression and plasma nitrate/nitrite concentration. Both heroin administration alone and exposure to heroin-CS suppressed LPS-induced indices of NO production in spleen and plasma. Our results are the first to indicate that, similar to males, female rats express heroin-induced and -conditioned immunomodulation to a LPS challenge.     

Selective scalp block decreases short term post-operative pain scores and opioid use after craniotomy: A case series

There is no consensus on the management of post-craniotomy pain. Several randomized controlled trials have examined the use of a regional scalp block for post-craniotomy pain. We aim to investigate whether scalp block affected short or long-term pain levels and opioid use after craniotomy. This study prospectively administered selective scalp blocks (lesser occipital, preauricular nerve block + pin site block) in 20 consecutive patients undergoing craniotomy for semicircular canal dehiscence. Anesthesia, pain, and opioid outcomes in these patients were compared to 40 consecutive historic controls. There was no significant difference in patient demographics between the two groups and no complications related to selective scalp block. The time between the end of procedure and end of anesthesia decreased in the scalp block group (16 vs 21 min, P = 0.047). Pain scores were significantly less in the scalp block group for the first 4 h, after which there was no statistically significant difference. Time to opioid rescue was longer in the scalp block group (3.6 vs 1.8 h, HR 0.487, P = 0.0361) and opioid use in the first 7 h was significantly less in the scalp block group. Total opioid use, outpatient opioid use, and length of stay did not differ. Selective scalp block is a safe and effective tool for short-term management of postoperative pain after craniotomy and decreases the medication requirement during emergence and recovery. Selective scalp block can speed up OR turnover but is not efficacious in the treatment of postoperative pain beyond this point.     

Effects of prenatal opioid exposure on functional networks in infancy

Prenatal opioid exposure has been linked to altered neurodevelopment and visual problems such as strabismus and nystagmus. The neural substrate underlying these alterations is unclear. Resting-state functional connectivity MRI (rsfMRI) is an advanced and well-established technique to evaluate brain networks. Few studies have examined the effects of prenatal opioid exposure on resting-state network connectivity in infancy. In this pilot study, we characterized network connectivity in opioid-exposed infants (n = 19) and controls (n = 20) between 4–8 weeks of age using both a whole-brain connectomic approach and a seed-based approach. Prenatal opioid exposure was associated with differences in distribution of betweenness centrality and connection length, with positive connections unique to each group significantly longer than common connections. The unique connections in the opioid-exposed group were more often inter-network connections while unique connections in controls and connections common to both groups were more often intra-network. The opioid-exposed group had smaller network volumes particularly in the primary visual network, but similar network strength as controls. Network topologies as determined by dice similarity index were different between groups, particularly in visual and executive control networks. These results may provide insight into the neural basis for the developmental and visual problems associated with prenatal opioid exposure.     

Suppression of ethanol responding by centrally administered CTOP and naltrindole in AA and Wistar rats

BACKGROUND: Both mu- and delta-opioid receptors have been implicated in the reinforcing actions of ethanol. However, selective opioid receptor antagonists have not altered ethanol intake in all rodent strains consistently, which suggests that genotype may modulate their suppressive effects. Therefore, we tested the effects of the selective mu-antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) and the selective delta-antagonist naltrindole in both high-drinking AA (Alko, Alcohol) and heterogeneous Wistar rats. METHODS: AA and Wistar rats were trained to respond for ethanol (10% w/v) in a two-lever operant condition by using a saccharin fading procedure. After stable baseline responding was established, rats were implanted stereotaxically either with a guide cannula above the lateral ventricle or with bilateral cannulas above the nucleus accumbens, basolateral amygdala, or ventral tegmental area. After postoperative recovery, AA and Wistar animals were tested after intracerebroventricular microinjections of either CTOP (0-3 microg) or naltrindole (0-30 microg) or subcutaneous injections of naloxone (0-1 g/kg), which was used as a reference antagonist. Effects of intracerebral microinjections of CTOP and naltrindole (both 0-500 ng) were tested only in Wistar rats. RESULTS: Subcutaneous naloxone and intracerebroventricular CTOP and naltrindole suppressed ethanol self-administration in a similar manner in AA and Wistar rats. Cumulative response patterns indicated that naloxone and naltrindole had no effect on the initiation of responding but suppressed it later during the session, whereas CTOP also affected initiation. In Wistar rats, naltrindole microinjections into both the nucleus accumbens and basolateral amygdala decreased ethanol responding, whereas CTOP was effective only in the amygdala. Injections of these antagonists into the ventral tegmental area had little effect on ethanol intake. CONCLUSIONS: The results confirm previous results which showed that both mu- and delta-opioid receptors are involved in the regulation of ethanol self-administration and indicate that genetic differences between AA and Wistar rats produced by selection do not modify the effects of opioid antagonists. The nucleus accumbens and the basolateral amygdala may be important central sites for the mediation of their suppressive effects.     

Antinociceptive effects of novel melatonin receptor agonists in mouse models of abdominal pain

AIM: To characterize the antinociceptive action of the novel melatonin receptor(MT) agonists, Neu-P11 and Neu-P12 in animal models of visceral pain. METHODS: Visceral pain was induced by intracolonic(ic) application of mustard oil or capsaicin solution or by intraperitoneal(ip) administration of acetic acid. Neu-P11, Neu-P12, or melatonin were given ip or orally and their effects on pain-induced behavioral responses were evaluated. To identify the receptors involved, thenon-selective MT1/MT2 receptor antagonist luzindole, the MT2 receptor antagonist 4-P-PDOT, or the μ-opioid receptor antagonist naloxone were injected ip or intracerebroventricularly(icv) prior to the induction of pain. RESULTS: Orally and ip administered melatonin, Neu-P11, and Neu-P12 reduced pain responses in a dose-dependent manner. Neu-P12 was more effective and displayed longer duration of action compared to melatonin. The antinociceptive effects of Neu-P11 or Neu-P12 were antagonized by ip or icv. administered naloxone. Intracerebroventricularly, but not ip administration of luzindole or 4-P-PDOT blocked the antinociceptive actions of Neu-P11 or Neu-P12. CONCLUSION: Neu-P12 produced the most potent and long-lasting antinociceptive effect. Further development of Neu-P12 for future treatment of abdominal pain seems promising.     

Ethanol alters opioid regulation of Ca(2+) influx through L-type Ca(2+) channels in PC12 cells

Background: Studies at the behavioral and synaptic level show that effects of ethanol on the central nervous system can involve the opioid signaling system. These interactions may alter the function of a common downstream target. In this study, we examined Ca²⁺ channel function as a potential downstream target of interactions between ethanol and μ or κ opioid receptor signaling. Methods: The studies were carried out in a model system, undifferentiated PC12 cells transfected with μ or κ opioid receptors. The PC12 cells express L‐type Ca²⁺ channels, which were activated by K⁺ depolarization. Ca²⁺ imaging was used to measure relative Ca²⁺ flux during K⁺ depolarization and the modulation of Ca²⁺ flux by opioids and ethanol. Results: Ethanol, μ receptor activation, and κ receptor activation all reduced the amplitude of the Ca²⁺ signal produced by K⁺ depolarization. Pretreatment with ethanol or combined treatment with ethanol and μ or κ receptor agonists caused a reduction in the amplitude of the Ca²⁺ signal that was comparable to or smaller than that observed for the individual drugs alone, indicating an interaction by the drugs at a downstream target (or targets) that limited the modulation of Ca²⁺ flux through L‐type Ca²⁺ channels. Conclusions: These studies provide evidence for a cellular mechanism that could play an important role in ethanol regulation of synaptic transmission and behavior through interactions with the opioid signaling.     

Opioidergic modulation of ethanol self-administration in the ventral pallidum

Background: Striatopallidal medium spiny neurons have been viewed as a final common path for drug reward and the ventral pallidum as an essential convergent point for hedonic and motivational signaling in the brain. The medium spiny neurons are GABAergic, but they colocalize enkephalin. Purpose of this study was to investigate the role of the opioidergic mechanisms of the ventral pallidum in ethanol self‐administration behavior. Methods: Effects of bilateral microinjections of μ‐, δ‐, and κ‐opioid receptor agonists and antagonists into the ventral pallidum on voluntary ethanol consumption were monitored in alcohol‐preferring Alko Alcohol (AA) rats using the 90‐minute limited access paradigm. Results: Stimulation of μ‐opioid receptors with DAMGO (0.01 to 0.1 μg) or morphine (1 to 10 μg) in the ventral pallidum decreased ethanol intake dose‐dependently. Conversely, blocking μ‐receptors with CTOP (0.3 to 3 μg) increased ethanol intake significantly. Unlike CTOP, DAMGO also increased locomotor activity. Consumption of ethanol was not modified significantly by a broad‐spectrum opioid receptor antagonist naltrexone, by δ‐opioid receptor agonist DPDPE or antagonist naltrindole, or by a κ‐opioid receptor agonist U50,488H or antagonist nor‐BNI. Conclusions: The study provides evidence for μ‐ but not δ‐ or κ‐opioid receptors in the ventral pallidum playing a role in the regulation of voluntary ethanol consumption. Furthermore, present findings give support to earlier work, suggesting an essential role of pallidal opioidergic transmission in drug reward.