Behavioral and Accumbal Responses During an Affective Go/No-Go Task Predict Adherence to Injectable Naltrexone Treatment in Opioid Use Disorder.

Adherence is a major factor in the effectiveness of the injectable extended-release naltrexone as a relapse prevention treatment in opioid use disorder. We examined the value of a variant of the Go/No-go paradigm in predicting extended-release naltrexone adherence in 27 detoxified opioid use disorder patients who were offered up to 3 monthly extended-release naltrexone injections. Before extended-release naltrexone, participants performed a Go/No-go task that comprised positively valenced Go trials and negatively valenced No-go trials during a functional magnetic resonance imaging scan. Errors of commission and neural responses to the No-go vs Go trials were independent variables. Adherence, operationalized as the completion of all 3 extended-release naltrexone injections, was the outcome variable. Fewer errors of commission and greater left accumbal response during the No-go vs Go trials predicted better adherence. These findings support the clinical potential of the behavioral and neurophysiological correlates of response inhibition in the prediction of extended-release naltrexone treatment outcomes in opioid use disorder.

Gestational changes in buprenorphine exposure: A physiologically-based pharmacokinetic analysis.

AIMS: Buprenorphine (BUP) is approved by the US Food and Drug Administration for the treatment of opioid addiction. The current dosing regimen of BUP in pregnant women is based on recommendations designed for nonpregnant adults. However, physiological changes during pregnancy may alter BUP exposure and efficacy. The objectives of this study were to develop a physiologically-based pharmacokinetic (PBPK) model for BUP in pregnant women, to predict changes in BUP exposure at different stages of pregnancy, and to demonstrate the utility of PBPK modelling in optimizing BUP pharmacotherapy during pregnancy. METHODS: A full PBPK model for BUP was initially built and validated in healthy subjects. A fetoplacental compartment was included as a combined compartment in this model to simulate pregnancy induced anatomical and physiological changes. Further, gestational changes in physiological parameters were incorporated in this model. The PBPK model predictions of BUP exposure in pregnancy and during the postpartum period were compared to published data from a prospective clinical study. RESULTS: The predicted BUP plasma concentration-time profiles in the virtual pregnant populations are consistent with the observed data in the 2nd and 3rd trimesters, and the postpartum period. The differences in the predicted means of dose normalized area under the plasma drug concentration-time curve up to 12 h, average concentration and maximum concentration were within ±25% of the corresponding observed means with the exception of average concentration in the 3rd trimester (-26.3%). CONCLUSION: PBPK model-based simulation may be a useful tool to optimize BUP pharmacotherapy during pregnancy, obviating the need to perform pharmacokinetic studies in each trimester and the postpartum period that normally require intensive blood sampling.

The Efficacy of Peripheral Opioid Antagonists in Opioid-Induced Constipation and Postoperative Ileus: A Systematic Review of the Literature.

Opioid-induced constipation has a negative impact on quality of life for patients with chronic pain and can affect more than a third of patients. A related but separate entity is postoperative ileus, which is an abnormal pattern of gastrointestinal motility after surgery. Nonselective µ-opioid receptor antagonists reverse constipation and opioid-induced ileus but cross the blood-brain barrier and may reverse analgesia. Peripherally acting µ-opioid receptor antagonists target the µ-opioid receptor without reversing analgesia. Three such agents are US Food and Drug Administration approved. We reviewed the literature for randomized controlled trials that studied the efficacy of alvimopan, methylnaltrexone, and naloxegol in treating either opioid-induced constipation or postoperative ileus. Peripherally acting µ-opioid receptor antagonists may be effective in treating both opioid-induced bowel dysfunction and postoperative ileus, but definitive conclusions are not possible because of study inconsistency and the relatively low quality of evidence. Comparisons of agents are difficult because of heterogeneous end points and no head-to-head studies.

100-Hz Electroacupuncture but not 2-Hz Electroacupuncture is Preemptive Against Postincision Pain in Rats.

Preemptive analgesia involves introducing an analgesic before noxious stimulation. Electroacupuncture (EA) activates descending mechanisms that modulate nociceptive inputs into the spinal dorsal horn. This study evaluated whether preoperative EA is more effective than postoperative EA in reducing incision pain in rats. The nociceptive threshold to mechanical stimulation was utilized to examine the effects of an intraperitoneal injection of saline (0.1 mL/kg) or naloxone (1 mg/kg) on antinociception induced by a 20-minute period of 2-Hz or 100-Hz EA applied to the Zusanli (ST36) and Sanyinjiao (SP6) acupoints before surgical incision, or 10 minutes after or 100 minutes after surgical incision of the hind paw. The extent of mechanical hyperalgesia after the incision was significantly attenuated by the application of 100-Hz EA preoperatively, but not by its application at 10 minutes or 100 minutes postoperatively. By contrast, 2-Hz EA was effective against postoperative hyperalgesia when applied 10 minutes or 100 minutes after surgery but not when it was applied preoperatively. Only the effect of 2-Hz EA applied 10 minutes after surgery was sensitive to naloxone. The present study showed for the first time that 100-Hz EA, but not 2-Hz EA, exerts a nonopioidergic preemptive effect against postincision pain in rats.

Baclofen prevents the elevated plus maze behavior and BDNF expression during naloxone precipitated morphine withdrawal in male and female mice.

In previous studies we have shown that baclofen, a selective GABAB receptor agonist, prevents the somatic expression and reestablishes the dopamine and µ-opioid receptors levels, modified during naloxone-precipitated morphine withdrawal syndrome in male and female mice. There are no previous reports regarding sex differences in the elevated plus maze (EPM) and the expression of BDNF in morphine-withdrawn mice. The present study analyses the behavioral and biochemical variations during morphine withdrawal in mice of both sexes, and whether these variations are prevented with baclofen. Swiss-Webster albino prepubertal mice received morphine (2 mg/kg, i.p.) twice daily, for 9 consecutive days. On the 10th day, one group of morphine-treated mice received naloxone (opioid receptor antagonist; 6 mg/kg, i.p.) 1 h after the last dose of morphine to precipitate withdrawal. A second group received baclofen (2 mg/kg, i.p.) before naloxone administration. The EPM behavior was measured during 15 min after naloxone injection. The expression of BDNF-positive cells was determined by immunohistochemistry. Withdrawn male mice showed a higher percentage of time spent and number of entries to the open arms compared to withdrawn female mice. Baclofen prevented this behavior in both sexes. BDNF expression decreased in the AcbC, BNST, CeC, and CA3 of the hippocampus while increased in the BLA of morphine withdrawn male. Baclofen pretreatment prevented the BDNF expression observed in morphine withdrawn male mice in all the brain areas studied except in the CeC. Baclofen prevention of the EPM behavior associated to morphine withdrawal could be partially related to changes in BDNF expression.

Treating Opioid Dependence With Injectable Extended-Release Naltrexone (XR-NTX): Who Will Respond?

OBJECTIVES: Once-monthly intramuscular extended-release naltrexone (XR-NTX) has demonstrated efficacy for the prevention of relapse in opioid dependence, providing an alternative to agonist or partial agonist maintenance (ie, methadone and buprenorphine). The question remains, for whom is this unique treatment most efficacious and can patient-treatment matching factors be identified? METHODS: A moderator analysis was conducted on a previously reported 24-week, placebo-controlled, multisite, randomized controlled trial of XR-NTX (n = 126) versus placebo (n = 124) among recently detoxified opioid-dependent adults in Russia, which showed XR-NTX superior to placebo in proportion of opioid abstinent weeks. The moderator analysis examined a dichotomous indicator of good clinical response-achieving at least 90% of weeks abstinent over the 24-week trial. A series of logistic regression models were fit for this outcome as functions of treatment (XR-NTX vs placebo), each baseline moderator variable, and their interactions. The 25 baseline variables included demographics, clinical severity (Addiction Severity Index, SF-36, and Clinical Global Impression-Severity), functioning (EQ-5D), craving, and HIV serostatus (HIV+). RESULTS: More XR-NTX patients achieved 90% abstinence (64/126, 51%) versus placebo (39/124, 31%; P = 0.002). There were no significant interactions between baseline variables and treatment. There was a significant main effect of Clinical Global Impression-Severity score (P = 0.02), such that higher severity score was associated with a lower rate of Good Clinical Response. CONCLUSIONS: The absence of significant baseline by treatment interactions indicates that no patient-treatment matching variables could be identified. This suggests that XR-NTX was effective in promoting abstinence from opioids across a range of demographic and severity characteristics.

Delta opioid receptors: the link between exercise and cardioprotection.

This study investigated the role of opioid receptor (OR) subtypes as a mechanism by which endurance exercise promotes cardioprotection against myocardial ischemia-reperfusion (IR) injury. Wistar rats were randomly divided into one of seven experimental groups: 1) control; 2) exercise-trained; 3) exercise-trained plus a non-selective OR antagonist; 4) control sham; 5) exercise-trained plus a kappa OR antagonist; 6) exercise-trained plus a delta OR antagonist; and 7) exercise-trained plus a mu OR antagonist. The exercised animals underwent 4 consecutive days of treadmill training (60 min/day at ∼70% of maximal oxygen consumption). All groups except the sham group were exposed to an in vivo myocardial IR insult, and the myocardial infarct size (IS) was determined histologically. Myocardial capillary density, OR subtype expression, heat shock protein 72 (HSP72) expression, and antioxidant enzyme activity were measured in the hearts of both the exercised and control groups. Exercise training significantly reduced the myocardial IS by approximately 34%. Pharmacological blockade of the kappa or mu OR subtypes did not blunt exercise-induced cardioprotection against IR-mediated infarction, whereas treatment of animals with a non-selective OR antagonist or a delta OR antagonist abolished exercise-induced cardioprotection. Exercise training enhanced the activities of myocardial superoxide dismutase (SOD) and catalase but did not increase the left ventricular capillary density or the mRNA levels of HSP72, SOD, and catalase. In addition, exercise significantly reduced the protein expression of kappa and delta ORs in the heart by 44% and 37%, respectively. Together, these results indicate that ORs contribute to the cardioprotection conferred by endurance exercise, with the delta OR subtype playing a key role in this response.

Blockade of central delta-opioid receptors inhibits salt appetite in sodium-depleted rats.

Various studies have investigated the role of central opioid peptides in feeding behavior; however, only a few have addressed the participation of opioids in the control of salt appetite. The present study investigated the effect of intracerebroventricular injections of the δ-opioid antagonist, naltrindole (5, 10 and 20 nmol/rat) and the agonist, deltorphin II (2.5, 5, 10 and 20 nmol/rat) on salt intake. Two protocols for inducing salt intake were used: sodium-depletion and the central injection of angiotensin II. In addition, the effect of a central δ-opioid receptor blockade on locomotor activity, on palatable solution intake (0.1% saccharin) and on blood pressure was also studied. The blockade of central δ-opioid receptors inhibits salt intake in sodium-depleted rats, while the pharmacological stimulation of these receptors increases salt intake in sodium-replete animals. Furthermore, the blockade of central δ-opioid receptors inhibits salt intake induced by central angiotensinergic stimulation. These data suggest that during sodium-depletion activation of the δ-opioid receptors regulates salt appetite to correct the sodium imbalance and it is possible that an interaction between opioidergic and angiotensinergic brain system participates in this control. Under normonatremic conditions, δ-opioid receptors may be necessary to modulate sodium intake, a response that could be mediated by angiotensin II. The decrease in salt intake following central δ-opioid receptors blockade does not appear to be due to a general inhibition of locomotor activity, changes in palatability or in blood pressure.

Maternal isolation during the first two postnatal weeks affects novelty-induced responses and sensitivity to ethanol-induced locomotor activity during infancy.

Animals exposed to chronic maternal separation (MS) exhibit enhanced ethanol self-administration and greater hormonal and behavioral responsiveness to stress in adulthood. Whether the effects of MS are immediately evident in infancy or whether they appear only later on development is still an unanswered question This study tested sensitivity to ethanol's behavioral stimulating effects in infant rats that experienced MS from postnatal Day 1-14. MS infants exhibited significantly greater reactivity to the motor stimulating effects of 1.25 g/kg ethanol than control animals, yet greater motor suppression after 2.5 g/kg ethanol. Baseline level of response to novelty was altered in MS infants, in a nor-binaltorphimine insensitive manner, that is, despite modified activity of the kappa-opioid system. These results indicate that the consequences of chronic maternal isolation emerge early in ontogeny, affecting ethanol sensitivity in infancy.

ST36 laser acupuncture reduces pain-related behavior in rats: involvement of the opioidergic and serotonergic systems.

Laser acupuncture is a modality of low-level light therapy used as an alternative to needling for the past three decades. Although it has proved effective for the treatment of various conditions, the mechanisms underlying its effects are not fully understood. To contribute to this understanding, this study was designed to (1) evaluate the antinociceptive effect of ST36 laser acupuncture (830 nm, 3 J/cm(2)) in rat models of acute nociception and (2) to investigate the opioidergic and serotonergic systems involvement in this effect. Our results demonstrate that ST36 laser acupuncture inhibited (36 ± 2 %) acetic acid-induced abdominal constrictions and both neurogenic (48 ± 7 %) and inflammatory (phase IIA 42 ± 8 % and phase IIB 83 ± 6 %) phases of formalin-induced nociceptive behavior. Moreover, the antinociceptive activity of laser irradiation in the acetic acid test was significantly reversed by preadministration of naloxone (1 mg/kg, nonselective opioid receptor antagonist), pindolol (1 mg/kg, subcutaneous; nonselective 5-HT 1A/B receptor antagonist), and ketanserin (1 mg/kg; selective 5-HT2A receptor antagonist) but not by ondansetron (1 mg/kg, selective 5-HT3 receptor antagonist). Taken together, our data demonstrate, for the first time, that (1) ST36 laser acupuncture elicited significant antinociceptive effect against acetic acid- and formalin-induced behavior in rats and that (2) this effect is mediated by activation of the opioidergic and serotonergic (5-HT1 and 5-HT2A receptors) systems.

Early maternal separation affects ethanol-induced conditioning in a nor-BNI insensitive manner, but does not alter ethanol-induced locomotor activity.

Early environmental stress significantly affects the development of offspring. This stress has been modeled in rats through the maternal separation (MS) paradigm, which alters the functioning of the HPA axis and can enhance ethanol intake at adulthood. Infant rats are sensitive to ethanol's reinforcing effects, which modulate ethanol seeking and intake. Little is known about the impact of MS on sensitivity to ethanol's appetitive and aversive effects during infancy. The present study assessed ethanol-induced conditioned place preference established through second-order conditioning (SOC), spontaneous or ethanol-induced locomotor activity and ethanol intake in preweanling rats that experienced normal animal facility rearing (AFR) or daily episodes of maternal separation (MS) during postnatal days 1-13 (PDs 1-13). Low-ethanol dose (0.5 g/kg) induced appetitive conditioned place preference (via SOC) in control rats given conventional rearing but not in rats given maternal separation in early infancy, whereas 2.0 g/kg ethanol induced aversive conditioned place preference in the former but not the latter. The administration of a kappa antagonist at PD 1 or immediately before testing did not alter ethanol-induced reinforcement. High (i.e., 2.5 and 2.0 g/kg) but not low (i.e., 0.5 g/kg) ethanol dose induced reliable motor stimulation, which was independent of early maternal separation. Ethanol intake and blood alcohol levels during conditioning were unaffected by rearing conditions. Pups given early maternal separation had lower body weights than controls and showed an altered pattern of exploration when placed in an open field. These results indicate that, when assessed in infant rats, earlier maternal separation alters the balance between the appetitive and aversive motivational effects of ethanol but has no effect on the motor activating effects of the drug.

Opioid µ-receptors in the rostral medullary raphe modulate hypoxia-induced hyperpnea in unanesthetized rats.

AIM: It has been suggested that the medullary raphe (MR) plays a key role in the physiological responses to hypoxia. As opioid µ-receptors have been found in the MR, we studied the putative role of opioid µ-receptors in the rostral MR (rMR) region on ventilation in normal and 7% hypoxic conditions. METHODS: We measured pulmonary ventilation (VE) and the body temperatures (Tb) of male Wistar rats before and after the selective opioid µ-receptor antagonist CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, cyclic, 0.1 µg per 0.1 µL) was microinjected into the rMR during normoxia or after 60 min of hypoxia. RESULTS: The animals treated with intra-rMR CTAP exhibited an attenuation of the ventilatory response to hypoxia (430 ± 86 mL kg(-1) min(-1)) compared with the control group (790 ± 82 mL kg(-1) min(-1) ) (P < 0.05). No differences in the Tb were observed between groups during hypoxia. CONCLUSION: These data suggest that opioids acting on µ-receptors in the rMR exert an excitatory modulation of hyperventilation induced by hypoxia.

Effect of a nanostructured dendrimer-naloxonazine complex on endogenous opioid peptides µ1 receptor-mediated post-ictal antinociception.

The aim of this study was to investigate the capacity of the host dendrimer DAB-Am-16 as a drug carrier to reduce the time required for the encapsulated naloxonaxine to establish an irreversible covalent bond with µ(1)-opioid receptor (resulting in a pharmacologically selective effect). The efficacy of dendrimer-naloxonazine nanocomplex (DNC) was studied in antinociception induced by convulsions elicited by intraperitoneal (IP) administration of pentylenetetrazole, and analgesia was measured by the tail-flick test. We found that animals showed increased tail-flick latencies following convulsions. Furthermore, acute pre-treatment (10 minutes) with DNC, but not with naloxonazine alone, antagonized post-ictal analgesia in comparison with control pre-treatment. However, naloxonazine treatment 24 hours before PTZ decreased post-ictal antinociception, but DNC failed to antagonize tonic-clonic seizure-induced analgesia. In addition, according to Racine's index of seizure severity, naloxonazine, DAB-Am-16 dendrimer or DNC did not influence seizure severity when administered either 10 minutes or 24 hours before PTZ. FROM THE CLINICAL EDITOR: This study characterizes the effect of a dendrimer-naloxonazine complex on µ1 receptor-mediated post-ictal antinociception in an animal model of seizure disorder.

Effect of naloxone and morphine on arcaine-induced state-dependent memory in rats.

RATIONALE: Arcaine is a competitive antagonist of the polyamine binding site at the N-methyl-D-aspartic acid receptor which induces state-dependent recall. However, no study has addressed the involvement of other neurotransmitter/neuromodulators in arcaine-induced state dependency. OBJECTIVES: The current study investigates whether the opioid system is involved in arcaine-induced state-dependent memory retrieval of the inhibitory avoidance task (IA) in rats. RESULTS: The systemic administration of arcaine (30 mg/kg, intraperitoneally (i.p.)) or morphine (5 mg/kg, i.p.) 0, 3, 6, or 9 h post-training, reduced step-down latencies at testing. Arcaine (30 mg/kg, i.p.) or morphine (5 mg/kg, i.p.) injection 30 min before testing reversed the performance deficit induced by administration of arcaine or morphine 0, 3 or 6, but not 9 h post-training. The reversal of arcaine-induced impairment of IA performance was completely transferred to morphine and vice versa. The association of low and ineffective doses of morphine and arcaine (10 and 1.5 mg/kg, respectively) were additive and caused state dependency. Naloxone (2 mg/kg, 3 min post-training, or 1 mg/kg, 1 h pre-test, i.p.) reversed the amnesia and the state dependency induced by morphine and arcaine. CONCLUSION: These results suggest that state dependency induced by arcaine involves the opioid system.

Differential effects of chronic naltrexone treatment on food intake patterns and body weight in rats depend on their food deprivation status.

The aim of the present study was to assess the effect of chronic naltrexone treatment on daily patterns of food intake in food-deprived and free-feeding rats. In experiment 1, Wistar male rats had continuous access to food and water, while in experiment 2 they were deprived of food for 12h/day. Animals in both experiments were studied as follows: a baseline period (7days), followed by a treatment period (14days) with either saline or naltrexone at 10mg/kg/day. Finally, a post-treatment period (7days) was assessed. Food and water consumption were measured every 2h after the naltrexone or saline injection for 12h and once more 12h later. Experiment 1: Food intake was higher in the naltrexone group 10h after injection. Total food intake and body weight gain were higher in the naltrexone group than in the saline group in the second week of treatment and in the post-treatment period. Experiment 2: The overeating observed in the saline group in the hours following the 12h of the food deprivation period was suppressed by naltrexone, though total daily food intake was not affected. Body weight gain was initially reduced by naltrexone, but a rebound effect was observed during the post-treatment period in the naltrexone group. Naltrexone produced a differential effect on food intake and body weight that depended on the rats' food deprivation status. These results could be explained in terms of opioid receptor up-regulation that enhances the rewarding effects of food or by naltrexone-produced changes in palatability.

Is the sulphonamide radical in the celecoxib molecule essential for its analgesic activity?

In a model of peripherally induced inflammatory pain in rats, selective inhibitors of cyclooxygenase (COX)-2 raised nociceptive thresholds above basal values, an effect referred to as "hypoalgesia". However other, non-selective, inhibitors of COX (indomethacin, piroxicam) or a selective inhibitor of COX-1 did not induce hypoalgesia in this model, implying that COX inhibition was not causally related to the hypoalgesic effect. Here, we have assessed whether other COX-2 inhibitors or other sulphonamides, apart from celecoxib could exhibit hypoalgesia in our model of inflammatory pain. Inflammation was induced in one hind paw of rats by intraplantar injection of carrageenan (250 µg). Nociceptive thresholds to mechanical stimulation were measured in the inflamed and contralateral paws for 6 h after carrageenan. Three sulphonamides, celecoxib itself, furosemide (a loop diuretic), acetazolamide (a carbonic anhydrase inhibitor), or a selective COX-2 inhibitor lacking the sulphonamide group, lumiracoxib, were injected s.c., 30 min before the pro-inflammatory stimulus. Naltrexone, a non-selective opioid antagonist was also administered s.c., 30 min before test drugs. Furosemide and acetazolamide dose-dependently induced hypoalgesia in the inflamed paw, as did celecoxib. However, lumiracoxib only produced anti-hyperalgesia. Pre-treatment with naltrexone completely prevented the hypoalgesia induced by the sulphonamides, but only partially prevented the anti-hyperalgesic effect of lumiracoxib. Taken together, our results suggest that the sulphonamide group in the structure of celecoxib is more critical for the development of hypoalgesia in our model than its ability to inhibit COX-2. Further, other sulphonamides lacking significant COX inhibition were also able to exhibit hypoalgesic effects, mediated by the endogenous opioid system.

Participation of the endogenous opioid system in the acquisition of a prenatal ethanol-related memory: effects on neonatal and preweanling responsiveness to ethanol.

The present study tested the involvement of the opioid system in the acquisition and expression of prenatal ethanol-related memories. We evaluated how this prenatal experience modulates ethanol self-administration in newborn rats, and preweanling's ingestion of the drug. During Gestational Days (GDs) 17-20, four groups of dams were treated with ethanol (2 g/kg) or water, followed immediately by naloxone (10 mg/kg) or saline administration. A fifth group received a similar dose of naloxone 20min before ethanol administration. On PD 1, pups were tested on an operant learning procedure to obtain milk or 3% ethanol. One hour later, an extinction session was performed. At Postnatal Days (PDs) 14 and 15, preweanlings representing each prenatal treatment were evaluated in an intake test with infusions of 5% ethanol or water. Prior to the intake test on PD14, preweanlings were administered naloxone (1 mg/kg), saline or remained untreated. In both tests, animals representative of both genders were utilized. One-day-old pups rapidly learned the operant behavior to gain access to milk. In contrast, only pups prenatally treated with ethanol (administered immediately before naloxone or saline injection) increased operant responding to gain access to ethanol. On an intake test at PDs 14 and 15, those animals prenatally exposed to naloxone 20 min before ethanol administration consumed significantly lower ethanol levels than the remaining prenatal ethanol groups. Postnatal treatment with naloxone diminished intake of all solutions at PD14. These results suggest that prenatal ethanol exposure facilitates neonatal operant learning reinforced by intraoral administration of ethanol and increases ethanol consumption during PDs 14-15. The endogenous opioid system apparently is involved in the acquisition of prenatal ethanol memories, which can modulate the reinforcing attributes of the drug in neonatal and preweanling rats.