Injection Of Morphine Research Articles

The Neuropeptide Receptor System, BigLEN‐GPR171, Interacts with the Opioid System to Relieve Pain

ProSAAS derived peptides, such as BigLEN, are abundantly expressed throughout the brain. We recently identified BigLEN as the endogenous peptide for the orphan receptor GPR171. Immunohistochemical analysis shows that both BigLEN and GPR171 are highly expressed in areas of the brain involved in pain modulation, including the periaqueductal gray (PAG). In addition, we find that GPR171 is co‐localized with mu opioid receptors (MOPr) in the ventrolateral PAG. Also, using immunohistochemistry we have identified that GPR171 is expressed in a portion of vGLut2 and GAD67 positive neurons. This brain region is especially known to contribute to opioid antinociception and tolerance. Given the expression pattern of GPR171, we hypothesized that GPR171 contributes to antinociception and tolerance. To test this, mice were injected with a GPR171 antagonist (MS21570; 5 mg/kg, i.p.) followed by the tail flick pain test which produced an increase in antinociception compared to controls. However, this compound is not as efficacious as morphine and pretreatment with MS21570 10 min prior to morphine (10 mg/kg, s.c.) did not alter morphine‐induced antinociception. To assess the role of GPR171 in morphine tolerance, mice were injected with morphine twice daily for 5 days. A subset of mice were pretreated with MS21570 10 min prior to each morphine injection. Those mice pretreated with MS21570 showed a decrease in the development of morphine tolerance. To understand how these systems may be working together, GPR171 was knocked down in Neuro2A cells which led to a decrease in MOPr‐mediated GTPγS signaling by DAMGO, but had no effect on GTPγS signaling by the delta opioid receptor agonist, deltorphin. This data suggests that the MOPr agonist, DAMGO, requires GPR171 expression in order to signal despite not directly binding to GPR171. Studies investigating GPR171 expression and signaling changes within the PAG following chronic morphine are ongoing. Taken together, this data shows that GPR171 and MOPr interact with one another and GPR171 antagonist may be a novel target to treat pain or opioid tolerance.Support or Funding InformationSupported by NIH grants, DA019521 and NS026880 (to LAD) and NIDA postdoctoral training grant DA007135 and a Young Investigator Grant from the Brain and Behavior Research Foundation (to ENB).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

SB-334867 (an Orexin-1 Receptor Antagonist) Effects on Morphine-Induced Sensitization in Mice\u2014a View on Receptor Mechanisms

The present study focused upon the role of SB-334867, an orexin-1 receptor antagonist, in the acquisition of morphine-induced sensitization to locomotor activity in mice. Behavioral sensitization is an enhanced systemic reaction to the same dose of an addictive substance, which assumingly increases both the desire for the drug and the risk of relapse to addiction. Morphine-induced sensitization in mice was achieved by sporadic doses (five injections every 3 days) of morphine (10 mg/kg, i.p.), while a challenge dose of morphine (10 mg/kg) was injected 7 days later. In order to assess the impact of orexin system blockade on the acquisition of sensitization, SB-334867 was administered before each morphine injection, except the morphine challenge dose. The locomotor activity test was performed on each day of morphine administration. Brain structures (striatum, hippocampus, and prefrontal cortex) were collected after behavioral tests for molecular experiments in which mRNA expression of orexin, dopamine, and adenosine receptors was explored by the qRT-PCR technique. Additionally, the mRNA expression of markers, such as GFAP and Iba-1, was also analyzed by the same technique. SB-334867 inhibited the acquisition of morphine-induced sensitization to locomotor activity of mice. Significant alterations were observed in mRNA expression of orexin, dopamine, and adenosine receptors and in the expression of GFAP and Iba-1, showing a broad range of interactions in the mesolimbic system among orexin, dopamine, adenosine, and glial cells during behavioral sensitization. Summing up, the orexin system may be an effective measure to inhibit morphine-induced behavioral sensitization.

The effects of morphine on gas exchange, ventilation pattern and ventilatory responses to hypercapnia and hypoxia in dwarf caiman (Paleosuchus palpebrosus)

Morphine and other opioids cause respiratory depression in high doses and lower the ventilatory responses to hypoxia and hypercapnia in mammals. Recent studies indicate that turtles respond similarly, but although they are used routinely for post-surgical analgesia, little is known about the physiological effects of opioids in reptiles. We therefore investigated the effects of morphine (10 and 20 mg kg−1) on gas exchange and ventilation in six dwarf caiman (Paleosuchus palpebrosus) using pneumotachography in a crossover design. Intraperitoneal injections of morphine changed the ventilation pattern from a typical intermittent/periodic pattern with a few or several breaths in ventilatory bouts to single breaths and prolonged the apnoea, such that respiratory frequency was depressed, while tidal volume was elevated. Furthermore, the duration of inspiration and especially expiration was prolonged. The resulting decrease in minute ventilation was attended by a lowering of the respiratory exchange ratio (RER) (especially for 20 mg kg−1 dose) indicating CO2 retention with a long time constant for approaching the new steady state. The changes in ventilation pattern and gas exchange reached a new stable level approximately 3 h after the morphine injection and did not significantly affect steady state O2 uptake, i.e. O2 consumption. As expected, the ventilatory response to 5% O2 was lower in morphine-treated caimans, but minute ventilation upon exposure to 2% CO2 did not differ significantly different from control animals.

Analgesic tolerance induced by repeated morphine injections induces cross-tolerance to the analgesic effect of orexin-A in rats.

Repeated administration of morphine or orexin-A produces tolerance to their antinociceptive effects. We investigated the possible incidence of cross-tolerance between orexin-A and morphine. Adult male Sprague-Dawley rats (200-250 g) were used. Under deep anesthesia, a stereotaxic apparatus was used to implant a 23 G cannula into the lateral ventricle for an intracerebroventricular (ICV) microinjection. The antinociceptive effect of three different doses of orexin-A (5, 20, and 40 µM; dissolved in 5 µl sterile saline; ICV) was examined using the hot-plate test at 15, 30, 60, and 90 min after infusion. To evaluate tolerance, orexin-A (20 µM; ICV) or morphine (10 mg/kg; intraperitoneal) was administered for 7 consecutive days (twice per day) and the analgesic response was assessed at days 1, 4, and 7. Cross-tolerance was investigated at day 8 with a single injection of morphine (10 mg/kg; intraperitoneal) to the repeated orexin-A group and a single microinjection of orexin-A (20 µM; ICV) to the repeated morphine group. Analgesic responses were then examined. Administration of both orexin-A and morphine produced significant antinociception at day 1 (P<0.001 compared with the saline group). However, a significant reduction in the analgesic effects of both morphine and orexin-A appeared at day 7, following repeated administration (P<0.01). Orexin-A microinjection at day 8 in the repeated morphine group did not result in significant antinociception (P>0.05), whereas morphine injection in the repeated orexin-A group at day 8 showed a significant analgesic effect (P<0.001). These results indicate cross-tolerance to the analgesic effect of orexin-A following morphine tolerance.

Midazolam as an antiemetic in patients receiving epidural morphine for postoperative pain relief

Epidural morphine has been associated with a significant incidence of postoperative nausea and vomiting (PONV). The authors have evaluated the prophylactic effects of midazolam in preventing nausea and vomiting following epidural morphine for postoperative pain control. The authors studied 80 women (n = 40 in each group) undergoing total abdominal hysterectomy under epidural anesthesia, in a randomized, double-blind, placebo-controlled study. At the end of the surgery, all patients received epidural morphine 3 mg for postoperative pain. Before morphine injection, the midazolam group received low-dose midazolam infusion (1 mg bolus followed by 1 mg h(-1)), while the placebo group received i.v. saline. Patients in the midazolam group reported a lower incidence of total PONV, and a lower frequency of rescue antiemetic request than those in the placebo group (p < 0.05). In addition, midazolam was associated with a reduced incidence of pruritus following epidural morphine (p < 0.05). The authors conclude that low-dose midazolam infusion is effective in the prevention of nausea, vomiting, and pruritus following epidural morphine for postoperative pain control.

Safety and effectiveness of coadministration of intrathecal sufentanil and morphine in hyperbaric bupivacaine-based spinal anesthesia for cesarean section

Subarachnoid block is a widely used technique for cesarean section. Opioids adding to the local anesthetics can improve its quality. In this prospective, randomized, double blind, controlled trial, we compared the effects of coadministration of intrathecal sufentanil and morphine with intrathecal sufentanil and a single administration of subcutaneous morphine. Sixty-four pregnant women scheduled for elective cesarean section under spinal anesthesia were assigned to two groups according to the way of administration of morphine: intrathecal sufentanil (5 microg) plus intrathecal morphine (150 microg) (ITM group), and intrathecal sufentanil (5 microg) plus single administration of 10 mg subcutaneous morphine (SCM group). In both groups, the local anesthetic used was hyperbaric bupivacaine 0.5 percent (10 mg). Both groups received 1 g acetaminophen every 6 hours. In the postoperative period, pain was recorded on a 0-100 visual analog scale (VAS) and intravenous tramadol (100 mg) was administered if VAS score was >40 mm. Collateral effects, such as nausea, itching, respiratory depression, and sedation were assessed. VAS scores at rest and on coughing were significantly higher in the SCM group than in the ITM group between 3 and 24 hours. The mean titrated dose of tramadol consumed was also significantly greater in the SCM group than in the ITM group (p < 0.05). The time to first administration of tramadol was lower in the SCM group versus the ITM group (p < 0.05). The incidence of nausea was significantly lower in the SCM group than in the ITM group (p < 0.05). There was no significant group difference in the incidence of pruritus (p > 0.05). In conclusion, coadministration of sufentanil and morphine into the subarachnoid space was effective and provided longer pain relief than intrathecal sufentanil plus a single injection of subcutaneous morphine, despite a higher incidence of side effects such as nausea and vomiting.

Honey potentially mitigates morphine analgesic tolerance and physical dependence in rats

Introduction:Honey has been used traditionally in medicine as well as food supplements. Honeybees are said to be able to cure many diseases. However, its influences on opioid tolerance and dependence have not yet been clarified.Materials and Methods:Adult male Sprague- Dawley rats were rendered tolerant to the analgesic effect of morphine by injection of morphine (10 mg/kg, i.p.) twice daily for 14 days. To develop morphine dependence rats given escalating doses of chronic morphine. To determine the effect of stingless bee honey on the development of morphine tolerance and dependence. The hotplate and naloxone precipitation tests were used to assess the degree of tolerance and dependence, respectively.The results: Our results showed that chronic morphine-injected rats displayed tolerance to the analgesic effect of morphine as well as morphine dependence. Methadone+morphine (MetM), methadone+morphine+ honey (MetMH) and morphine+Honey (MH) significantlylower the development of morphine tolerance with p-value p&lt;0.05. In addition, concomitant treatment of morphine with MH and MetMH attenuated almost all of the naloxone-induced withdrawal signs which include abdominal contraction, diarrhea, pertussis, teeth chattering, and jumping.Conclusion: The data indicate that honey has a potential to reduce tolerant and dependence property.Bangladesh Journal of Medical Science Vol.17(1) 2018 p.138-143

Genome-wide Association Study Identifies a Regulatory Variant of RGMA Associated With Opioid Dependence in European Americans

BackgroundOpioid dependence (OD) is at epidemic levels in the United States. Genetic studies can provide insight into its biology. MethodsWe completed an OD genome-wide association study in 3058 opioid-exposed European Americans, 1290 of whom met criteria for a DSM-IV diagnosis of OD. Analysis used DSM-IV criterion count. ResultsBy meta-analysis of four cohorts, Yale-Penn 1 (n = 1388), Yale-Penn 2 (n = 996), Yale-Penn 3 (n = 98), and SAGE (Study of Addiction: Genetics and Environment) (n = 576), we identified a variant on chromosome 15, rs12442183, near RGMA, associated with OD (p = 1.3 × 10−8). The association was also genome-wide significant in Yale-Penn 1 taken individually and nominally significant in two of the other three samples. The finding was further supported in a meta-analysis of all available opioid-exposed African Americans (n = 2014 [1106 meeting DSM-IV OD criteria]; p = 3.0 × 10−3) from three cohorts; there was nominal significance in two of these samples. Thus, of seven subsamples examined in two populations, one was genome-wide significant, and four of six were nominally (or nearly) significant. RGMA encodes repulsive guidance molecule A, which is a central nervous system axon guidance protein. Risk allele rs12442183*T was correlated with higher expression of a specific RGMA transcript variant in frontal cortex (p = 2 × 10−3). After chronic morphine injection, the homologous mouse gene (Rgma) was upregulated in C57BL/6J striatum. Coexpression analysis of 1301 brain samples revealed that RGMA messenger RNA expression was associated with that of four genes implicated in other psychiatric disorders, including GRIN1. ConclusionsThis is the first study to demonstrate an association of RGMA with OD. It provides a new lead into our understanding of OD pathophysiology.

Hyperbaric Oxygen Attenuates Withdrawal Symptoms by Regulating Monoaminergic Neurotransmitters and NO Signaling Pathway at Nucleus Accumbens in Morphine-Dependent Rats.

In this study, we examined whether hyperbaric oxygen (HBO2) plays a detoxification role in withdrawal symptoms in a morphine-dependent rat model. The model was established through injections of morphine at increasing doses for 7 days. Withdrawal symptoms were induced by naloxone injection on the 8th day. The detoxification effect of HBO2 was evaluated using the withdrawal symptom scores, biochemical indices and neurotransmitters. Compared with the model group, HBO2 therapy significantly attenuated the withdrawal symptom scores, body weight loss and the level of norepinephrine level, whereas it increased the dopamine level and tyrosine hydroxylase expression in the nucleus accumbens. Moreover, HBO2 therapy substantially alleviated the NO, NOS, cAMP, and cGMP levels. Our findings indicate that HBO2 can effectively alleviate withdrawal symptoms induced by morphine dependence, and these effects may be attributed to the modulation of monoaminergic neurotransmitters and the suppression of the NO-cGMP signaling pathway.

The Effect of Epidural Morphine-Bupivacaine Combined with a Low Dose of Naloxone on Respiratory Function and Analgesia in Patients with Chronic Low-Back Pain

Context: Hypoventilation and apnea after epidural morphine is a serious concern after surgery and an issue in chronic pain. A low dose of naloxone added to morphine can prevent this complication. Objective: To determine that the low dose of naloxone added to epidural morphine analgesic could change the effect of this opioid in chronic low back pain. In addition, we evaluate its effect on respiratory function and patient satisfaction. Patients: Twenty-seven adults suffering from chronic low back pain (LBP) who were candidates for epidural injection treatment. Intervention: This was a randomized double-blind, uniform crossover, controlled clinical trial. The patients were treated with mixture of morphine-bupivacaine and mixture of morphine-bupivacaine-naloxone. Main outcome measure: The primary goals were to evaluate pain intensity and respiratory function after epidural injection of morphine or morphine combined with naloxone. Secondary end-points were the incidence and the side effects (pruritus, nausea, vomiting, and urinary retention) of neuraxial injection of morphine or morphine combined with naloxone for 14 days after each epidural injection. Results: There was no significant difference between morphine and morphine combined with naloxone on mean peripheral capillary oxygen saturation (SpO2m), the lowest peripheral capillary oxygen saturation (SpO2), and the respiratory disturbance index (RDI). Morphine combined with naloxone seemed to decrease pain more than morphine alone, but the result was not significant (p=0.2116). In the group that received morphine and naloxone, pain decreased sooner by half from baseline pain (at day 2 versus at day 6) than the other group. Vomiting, pruritus, and urinary retention were seen with no significant difference in both groups. Conclusion: We conclude that epidural administration of naloxone can preserve the analgesic effect of morphine in treatment of chronic LBP. Naloxone does not have any effects on respiratory function. It reduces itching, nausea, and pruritus after epidural injection of morphine. We cannot be certain whether this is the ideal dose or whether any changes in the doses might produce fewer side effects without interfering with analgesia.

Hypothalamic KiSS1/GPR54 Gene Expressions and Luteinizing Hormone Plasma Secretion in Morphine Treated Male Rats.

Background:The inhibitory effects of morphine and the stimulatory influence of kisspeptin signaling have been demonstrated on gonadotropin releasing hormone (GnRH)/luteinizing hormone (LH) release. Hypothalamic kisspeptin is involved in relaying the environmental and metabolic information to reproductive axis. In the present study, the role of kisspeptin/ GPR54 signaling system was investigated on relaying the inhibitory influences of morphine on LH hormone secretion.Materials and Methods:In this experimental study, 55 wistar male rats weighing 230-250 g were sub-grouped in 11 groups (in each group n=5) receiving saline, kisspeptin (1 nmol), peptide234 (P234, 1 nmol), morphine (5 mg/kg), naloxone (2 mg/kg), kisspeptin/P234, morphine/naloxone, kisspeptin/morphine, kisspeptin/naloxone, P234/morphine or P234/naloxone respectively. Blood samples were collected via tail vein. Mean plasma (LH) concentrations and mean relative KiSS1 or GPR54 mRNA levels were determined by radioimmunoassay (RIA) and real time reverse transcriptase-polymerase chain reaction (RT-PCR), respectivwely.Results:Morphine significantly decreased mean plasma LH concentration and mean relative KiSS1 gene expression compared to saline; while it did not significantly decrease mean relative GPR54 gene expression compared to saline. Naloxone significant increased mean LH level and mean relative KiSS1 gene expression compared to saline; while it did not significantly increase mean relative GPR54 gene expression compared to saline. Injections of kisspeptin plus morphine significantly increased mean LH concentration compared to saline or morphine, while simultaneous infusions of them significantly declined mean plasma LH level compared to kisspeptin. In kisspeptin/naloxone group mean plasma LH level was significantly increased compared to saline or naloxone. Co-administration of P234/morphine significantly decreased mean LH concentration compared to saline.Conclusion:Down regulation of KiSS1 gene expression may be partly involved in the mediating the inhibitory effects of morphine on reproductive axis.

Sublingual buprenorphine versus intravenous morphine as a premedicant and postoperative analgesic in laparoscopic appendectomy under general anesthesia—A randomized control trial

Background: Minimally invasive surgery aims to minimize trauma, cause rapid mobilization, and thus achieve a satisfactory therapeutic result. But the challenging fact with the laparoscopic surgery is its hemodynamic changes because of pneumoperitoneum and the complex visceral pain in the postoperative period. Aim: To find a safe, reliable, and highly effective drug as a premedicant in laparoscopic appendectomies under general anesthesia. Materials and Methods: A total of 110 patients undergoing laparoscopic appendectomies were randomized into two groups: group M (morphine) and group B (buprenorphine) with 55 patients in each group. Group B patients received 0.4 μg of buprenorphine tablet sublingually 1 h before surgery and group M patients received 0.1 mg/kg of intravenous morphine 10 min before anesthesia induction. Intraoperative hemodynamics, postoperative pain score, rescue analgesic requirement, and complications were recorded. Results: Intraoperative vitals that is heart rate and mean arterial pressure were significantly stable in group B compared to group M. Only 11 % patients in group B required dexmedetomidine infusion compared to 37% in group M, to control intraoperative hypertension. Visual analog scale (VAS) values in group B at 2nd (1.30 ± 0.46), 4th (1.31 ± 0.54), and 6th hour (1.33 ± 0.63) were significantly less than group M at 2nd (4.56 ± 0.65), 4th (5.68 ± 0.72), and 6th h (4.45 ± 1.15). Duration of analgesia in postoperative period in group B (260.0 ± 28.52 min) was significantly longer than group M (124.10 ± 20.832 min). Conclusion: Sublingual buprenorphine premedication is an alternative to intravenous injection of morphine with perioperative hemodynamic stability and better postoperative analgesia.

Rapid titration of opiate doses via patient-controlled intravenous analgesia for patients with severe cancer pain

This study was to investigate the feasibility and safety of patient-controlled intravenous analgesia for opiate titration in patients with severe cancer. Eligible patients with cancer pain were randomly divided into two groups, which were titrated with a subcutaneous injection of morphine and patient-controlled intravenous analgesia, respectively. The time required for patients to begin titration to reach visual analog scale score ⩽ 3, the adverse reactions during titration, the time spent by nurses in titrating each patient, and the time to complete the titration with a delayed-release dosage form analgesic effect and adverse reaction. The mean titration time of patient-controlled intravenous analgesia group (1.09 ± 0.82 vs 2.97 ± 1.98) and morphine dosage (18.78 ± 12.32 vs 13.23 ± 8.07) were significantly lower than those in the subcutaneous group ( P &lt; 0.05). The incidences of nausea, vomiting, pruritus, urinary retention, and sedation in the subcutaneous injection group were significantly lower than those in the subcutaneous injection group ( P &lt; 0.05). The assessment times of the two groups (10.19 ± 3.72 vs 10.25 ± 4.88) were similar ( P &gt; 0.05). However, the time required for subcutaneous injection in patients under patient-controlled intravenous analgesia was significantly lower than that in the subcutaneous injection group (36.36 ± 12.15 vs 132.36 ± 32.79), which was statistically significant ( P &lt; 0.05). After the titration, the controlled release opioid was used to treat cancer pain. The visual analog scale score of the patient-controlled intravenous analgesia group was significantly lower than that of the subcutaneous group (2.44 ± 1.37 vs 2.73 ± 0.91) at 7 days after treatment in the subcutaneous group (1.05 ± 0.30 vs 2.45 ± 1.29; P &lt; 0.05). Patient-controlled intravenous analgesia technique can effectively and quickly complete the titration of cancer pain treatment with less occupational care resources and is better than the subcutaneous injection titration.

Effects of BDNF receptor antagonist on the severity of physical and psychological dependence, morphine-induced locomotor sensitization and the ventral tegmental area-nucleus accumbens BDNF levels in morphine- dependent and withdrawn rats

This study examined the effects of systemic administration of the TrkB receptor antagonist (ANA-12) on the severity of physical and psychological dependence and morphine-induced locomotor sensitization, the ventral tegmental area (VTA)-nucleus accumbens (NAc) BDNF levels in morphine-dependent and withdrawn rats. Rats were injected with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine for 10 days. Then, rats were tested for naloxone-precipitated morphine withdrawal signs, the anxiety (the elevated plus maze-EPM) after the last morphine injection and injection of ANA12 (ip). Also, morphine-induced locomotor sensitization was evaluated after morphine challenge followed by an injection of ANA-12 in morphine-withdrawn rats. The VTA-NAc BDNF levels were assessed in morphine-dependent and withdrawn rats. The overall Gellert–Holtzman score was significantly higher in morphine-dependent rats receiving ANA-12 than in those receiving saline. Also, the percentage of time spent in the open arms in control and morphine-dependent rats receiving ANA-12 were higher compared to the Cont/Sal and D/Sal rats, respectively. There was no significant difference in the locomotor activity and the VTA-NAc BDNF levels between D/Sal/morphine and D/ANA-12/morphine groups after morphine withdrawal. We conclude that the systemic administration of ANA-12 exacerbates the severity of physical dependence on morphine and partially attenuates the anxiety-like behavior in morphine-dependent rats. However, ANA-12 did not affect morphine-induced locomotor sensitization and the VTA-NAc BDNF levels in morphine-dependent and withdrawn rats.

Comparison of Single-Shot Intrathecal Morphine Injection and Continuous Epidural Bupivacaine for Post-Operative Analgaesia after Elective Abdominal Hysterectomy.

Abdominal hysterectomy (AH) is painful. The aim of this study was to compare intrathecal morphine (ITM) and epidural bupivacaine (EB) for their analgaesia effectiveness after this surgery. Thirty-two patients undergoing elective AH were randomised into Group ITM (ITM 0.2 mg + 2.5 mL 0.5% bupivacaine) (n = 16) and Group EB (0.25% bupivacaine bolus + continuous infusion of 0.1% bupivacaine-fentanyl 2 μg/mL) (n = 16).The procedure was performed before induction, and all patients subsequently received standard general anaesthesia. Both groups were provided patient-controlled analgaesia morphine (PCAM) as a backup. Visual analogue scale (VAS) scores, total morphine consumption, hospital stay duration, early mobilisation time and first PCAM demand time were recorded. The median VAS score was lower for ITM than for EB after the 1st hour [1.0 (IqR 1.0) versus 3.0 (IqR 3.0), P < 0.001], 8th hour [1.0 (IqR 1.0) versus 2.0 (IqR 1.0), P = 0.018] and 16th hour [1.0 (IqR1.0) versus (1.0 (IqR 1.0), P = 0.006]. The mean VAS score at the 4th hour was also lower for ITM [1.8 (SD 1.2) versus 2.9 (SD 1.4), P = 0.027]. Total morphine consumption [11.3 (SD 6.6) versus 16.5 (SD 4.8) mg, P = 0.016] and early mobilisation time [2.1 (SD 0.3) versus 2.6 (SD 0.9) days, P = 0.025] were also less for ITM. No significant differences were noted for other assessments. The VAS score was better for ITM than for EB at earlier hours after surgery. However, in terms of acceptable analgaesia (VAS ≤ 3), both techniques were comparable over 24 hours.

The impact of OxyContin reformulation at the Sydney Medically Supervised Injecting Centre: Pros and cons

Abstract Background Oxycodone is implicated in a large number of overdose deaths, many involving intravenous administration of preparations designed for oral administration. International responses have included education strategies, regulatory changes, and tamper-resistant preparations to discourage injecting. Reformulated OxyContin ® was introduced in Australia in April 2014 and this study examines its impact on service utilisation, defined as visits to inject drugs at the Sydney Medically Supervised Injecting Centre (MSIC) and opioid overdoses at the MSIC. Methods Data from February 2007 to February 2016 are presented for drug type injected and onsite opioid overdose. The reformulated OxyContin ® effect was modelled using an interrupted time series approach. Results Client visits declined >1000 per month, or 18%, following reformulation, largely explained by a reduction in visits to inject oxycodone, partially offset by increased morphine or fentanyl injections. Despite this significant reduction in visits, there was no corresponding decrease in the number of overdoses managed, explained somewhat by a partial displacement from oxycodone to other opioids. Stable overdose numbers within the context of decreased visit numbers were consistent with increases in heroin and morphine overdose, with an extra 22 heroin and 12 morphine overdoses on average per month. This increase was offset by the decrease of 17 OxyContin ® , overdoses per month. Conclusions This study replicates the trend towards substitution of OxyContin ® with other opioids following the introduction of reformulated OxyContin ® in Australia and extends initial findings by showing the rate of overdose per MSIC visit increased following reformulation. These unintended consequences need to be considered when evaluating the success or otherwise of these kinds of changes in product formulation.

Role of orexin-1 receptors in the dorsal hippocampus (CA1 region) in expression and extinction of the morphine-induced conditioned place preference in the rats

Orexinergic system is involved in reward processing and drug addiction. Objectives here, we investigated the effect of intra-hippocampal CA1 administration of orexin-1 receptor (OX1r) antagonist on the expression, and extinction of morphine-induced place preference in rats. Conditioned place preference (CPP) was induced by subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. Two experimental plots were designed; SB334867 as a selective OX1r antagonist was dissolved in 12% DMSO, prepared in solutions with different concentrations (3, 30, and 300 nM), and microinjected into the CA1 and some neighboring regions (0.5 μl/side), bilaterally. CPP score and locomotor activity were recorded during the CPP test. Results demonstrated that intra-CA1 administration of the OX1r antagonist attenuates the expression of morphine-induced CPP. Furthermore, higher concentrations of SB334867 facilitated the extinction period of morphine-induced CPP and reduced its latency. Nevertheless, solely administration of DMSO did not have any influence on the CPP scores and locomotion in both phases. Our findings suggest that OX1rs in the CA1 region of the hippocampus are involved in the expression of morphine CPP. Moreover, blockade of OX1rs could facilitate extinction and may extinguish the ability of drug-related cues. It seems that the antagonist might be considered as a propitious therapeutic agent in suppressing drug-seeking behaviors.

Suppressive effects of morphine injected into the ventral bed nucleus of the stria terminalis on the affective, but not sensory, component of pain in rats.

Pain is a complex experience with both sensory and affective components. Clinical and preclinical studies have shown that the affective component of pain can be reduced by doses of morphine lower than those necessary to reduce the sensory component. Although the neural mechanisms underlying the effects of morphine on the sensory component of pain have been investigated extensively, those influencing the affective component remain to be elucidated. The bed nucleus of the stria terminalis (BNST) has been implicated in the regulation of various negative emotional states, including aversion, anxiety and fear. Thus, this study aimed to clarify the role of the ventral part of the BNST (vBNST) in the actions of morphine on the affective and sensory components of pain. First, the effects of intra-vBNST injections of morphine on intraplantar formalin-induced conditioned place aversion (CPA) and nociceptive behaviors were investigated. Intra-vBNST injections of morphine reduced CPA without affecting nociceptive behaviors, which suggests that intra-vBNST morphine alters the affective, but not sensory, component of pain. Next, to examine the effects of morphine on neuronal excitability in type II vBNST neurons, whole-cell patch-clamp recordings were performed in brain slices. Bath application of morphine hyperpolarized type II vBNST neurons. Thus, the suppressive effects of intra-vBNST morphine on pain-induced aversion may be due to its inhibitory effects on neuronal excitability in type II vBNST neurons. These results suggest that the vBNST is a key brain region involved in the suppressive effects of morphine on the affective component of pain.

Cupping: a reasonable choice for attenuating morphine withdrawal symptoms in Wistar rats

Background: Nowadays, the sedative drugs are the main treatments to attenuate the opioid withdrawal symptoms. However, physical therapies are found a safe alternative treatment without any serious adverse effects. This study aimed to evaluate the effects of cupping treatment on the morphine withdrawal symptoms in rats.Methods: Eighty rats were divided into two main groups; treated with morphine or saline, and each group was also divided to cupping and sham cupping subgroups (with single or daily treatment). Injection of morphine and saline were done in the morphine and saline groups twice a day for nine days. On the ninth day, the naloxone was administered and the withdrawal symptoms including jumping, rearing, body grooming, abdominal writing, and wet-dog shaking were recorded for 60 minutes. Cupping or sham cupping was applied on the GV14 once before or daily after withdrawal induction in each group.Results: The results revealed that a single cupping before the withdrawal induction significantly attenuated the withdrawal symptoms in the morphine group (p&lt;0.01).But, the daily cupping failed to decrease the withdrawal symptoms in this group. The results also indicated that the daily cupping in the saline group increased the naloxone-induced withdrawal symptoms significantly (p&lt;0.01).Conclusions: Single session cupping before the withdrawal induction could decreased the withdrawal symptoms. This finding might be related to the modulation of GABAergic system.

Brain-derived neurotrophic factor-mediated projection-specific regulation of depressive-like and nociceptive behaviors in the mesolimbic reward circuitry.

Increasing evidence suggests that the mesolimbic reward system plays critical roles in the regulation of depression and nociception; however, its circuitry and cellular mechanisms remain unclear. In this study, we investigated the output-specific regulatory roles of dopaminergic (DA) neurons within the ventral tegmental area (VTA) in depressive-like and nociceptive behaviors in mice subjected to unpredictable chronic mild stress (CMS), using the projection-specific electrophysiological recording, pharmacological manipulation, behavioral test, and molecular biology technologies. We demonstrated that CMS decreased the firing activity in VTA projecting to medial prefrontal cortex (VTA → mPFC), but not in VTA to nucleus accumbens (VTA → NAc), DA neurons. However, both VTA → mPFC and VTA → NAc DA neurons showed increased firing activity in response to morphine perfusion in CMS mice. Behavioral results showed that intra-VTA microinjection of morphine (25.5 ng/0.15 μL) relieved depressive-like behaviors, intriguingly, accompanied by a thermal hyperalgesia. Furthermore, the relief of depressive-like behaviors induced by intra-VTA injection of morphine in CMS mice could be prevented by blocking brain-derived neurotrophic factor (BDNF) signaling and mimicked by the administration of exogenous BDNF in mPFC rather than in NAc shell. Nociceptive responses induced by the activation of VTA DA neurons with morphine in CMS mice could be prevented by blocking BDNF signaling or mimicked by administration of exogenous BDNF in NAc shell, but not in mPFC. These results reveal projection-specific regulatory mechanisms of depression and nociception in the mesolimbic reward circuitry and provide new insights into the neural circuits involved in the processing of depressive and nociceptive information.