Acute Morphine Research Articles

ВЛИЯНИЕ ОДНОКРАТНОГО КОМПЛЕКСНОГО ВВЕДЕНИЯ ЭТАНОЛА И МОРФИНА НА СОДЕРЖАНИЕ НЕЙРОАКТИВНЫХ АМИНОКИСЛОТ В ГОЛОВНОМ МОЗГЕ КРЫС

Background. Cases of combined consumption of surfactants (alcohol and opiates) in both the adult population and adolescents are quite common at present. An important role in the functional activity of the central nervous system is played by neuroactive amino acids, the level of which changes under the influence of psychotropic substances.Purpose. To study the content of neuroactive amino acids in the cerebral cortex, striatum, hypothalamus, midbrain and cerebellum in acute alcohol and morphine intoxication, as well as the complex administration of these substances.Material and methods. The experiments were carried out on white outbred male rats. Using the HPLC method in different parts of the brain, the levels of neurogenic amino acids were determined in acute alcohol and morphine intoxication, as well as their complex administration in different sections.Results. Acute complex morphine-alcohol intoxication is accompanied by manifestation of excitation processes in the striatum and hypothalamus, as well as inhibition in the midbrain. Alcohol-morphine intoxication leads to an increase in the content of GABA in all brain regions studied except the hypothalamus.Conclusion. Morphine-alcohol intoxication is accompanied by a decrease in the glycine content in the striatum, as well as an increase in its concentration in the midbrain and the level of glutamate in the hypothalamus. Alcohol-morphine intoxication leads to an increase in GABA levels in the cerebral cortex, striatum, midbrain and cerebellum.

Antioxidant activities of barringtonia racemosaleaf extract against acute morphine dependence rat model

Antioxidant activities of barringtonia racemosaleaf extract against acute morphine dependence rat model

Hemantane a Derivative of Aminoadamantane Alleviates Morphine-Induced Hyperlocomotion via Modulation of Activity of the Dopaminergic and Serotonergic Systems

Abstract—Morphine is known to induce a long-term hyperlocomotor response due to increased dopamine release in the nucleus accumbens via the activation of dopaminergic neurons in the ventral tegmental area. It has been demonstrated that the low-affinity antagonist of NMDA receptors hemantane can alleviate ethanol-induced stimulation of behavior due to its effect on the dopamine- and noradrenergic systems. In the present study, we studied the effects of the aminoadamantane derivative hemantane on the changes in the balance of monoamines and their metabolites in brain structures of C57Bl/6 mice after acute morphine administration. Single i.p. administration of hemantane at a dose of 20 mg/kg did not affect spontaneous locomotor activity per se but alleviated behavior stimulated by s.c. morphine injection at a dose of 20 mg/kg (p < 0.05). In the ex vivo experiments, hemantane prevented a morphine-induced significant increase in the DOPAC/DA and 5‑HIAA/5-HT ratios in the striatum (both p < 0.05) and HVA/DA in the nucleus accumbens (p < 0.01) and promoted the recovery of the DOPAC/DA ratio to the control level in the hypothalamus. These data demonstrate the capability of hemantane to inhibit morphine-induced behavioral stimulation, probably via modulation of the dopaminergic and serotonergic systems.

Acute naloxone-precipitated morphine withdrawal elicits nausea-like somatic behaviors in rats in a manner suppressed by N-oleoylglycine.

Acute naloxone-precipitated morphine withdrawal (MWD) produces a conditioned place aversion (CPA) in rats even after one or two exposures to high-dose (20 mg/kg, sc) morphine followed 24-h later by naloxone (1 mg/kg, sc). However, the somatic withdrawal reactions produced by acute naloxone-precipitated MWD inrats have not been investigated. A recently discovered fatty acid amide, N-oleoylglycine (OlGly), which has been suggested to act as a fatty acid amide hydrolase (FAAH) inhibitor and as a peroxisome proliferator-activated receptor alpha (PPARα) agonist, was previously shown to interfere with a naloxone-precipitated MWD-induced CPA in rats. The aims of these studies were to examine the somatic withdrawal responses produced by acute naloxone-precipitated MWD and determine whether OlGly can also interfere with these responses. Here, we report that following two exposures to morphine (20 mg/kg, sc) each followed by naloxone (1 mg/kg, sc) 24 h later, rats display nausea-like somatic reactions of lying flattened on belly, abdominal contractions and diarrhea, and display increased mouthing movements and loss of body weight. OlGly (5 mg/kg, ip) interfered with naloxone-precipitated MWD-induced abdominal contractions, lying on belly, diarrhea and mouthing movements in male Sprague-Dawley rats, by both a cannabinoid 1 (CB1) and a PPARα mechanism of action. Since these withdrawal reactions are symptomatic of nausea, we evaluated the potential of OlGly to interfere with lithium chloride (LiCl)-induced and MWD-induced conditioned gaping in rats, a selective measure of nausea; the suppression of MWD-induced gaping reactions by OlGly was both CB1 and PPARα mediated. These results suggest that the aversive effects of acute naloxone-precipitated MWD reflect nausea, which is suppressed by OlGly.

Prolonged ethanol administration prevents the development of tolerance to morphine-induced respiratory depression

BackgroundOpioid users regularly consume other drugs such as alcohol (ethanol). Acute administration of ethanol can rapidly reverse tolerance to morphine-induced respiratory depression. However, alcohol consumption by opioid users is likely to occur over prolonged time periods. We have therefore sought to determine the effect of prolonged alcohol consumption on the development of tolerance to opioid respiratory depression. MethodsMice were fed control or ethanol (5%) liquid diet for 16 days. On days 9–16 morphine tolerance was induced by administration of 3 priming injections of morphine followed by subcutaneous implantation of a morphine-filled osmotic mini-pump. Control mice received saline. Respiration was measured by plethysmography and the effect of an acute morphine challenge dose was measured on day 16 to assess the development of morphine tolerance. ResultsProlonged ethanol consumption for 14 days did not alter the respiratory depressant effect of an acute dose of morphine. Control mice treated with prolonged morphine developed tolerance to acute morphine respiratory depression whereas ethanol diet fed mice treated with prolonged morphine showed significant respiratory depression during morphine-pump treatment and remained sensitive to the respiratory depressant effect of the acute challenge dose of morphine. The ethanol consumption did not alter blood or brain levels of morphine, whilst conversely prolonged morphine treatment did not alter blood levels of ethanol. ConclusionsProlonged ethanol consumption prevents the development and maintenance of tolerance to the respiratory depressant effect of morphine. These data suggest that ethanol inhibition of tolerance will greatly increase the risk of fatal heroin overdose in humans.

Neuromodulatory effects of pudendal nerve stimulation on bladder hypersensitivity are present in opioid-pretreated rats

Background and objectivesBilateral electrical pudendal nerve stimulation (bPNS) reduces bladder hypersensitivity in rat models and anecdotally reduces pain in humans with pelvic pain of urologic origin. Concomitant opioids are known...

Divergent behavioral responses in protracted opioid withdrawal in male and female C57BL/6J mice.

Persons suffering from opioid use disorder (OUD) experience long-lasting dysphoric symptoms well into extended periods of withdrawal. This protracted withdrawal syndrome is notably characterized by heightened anxiety and hyperkatifeia. Here, we investigated if an exacerbated withdrawal model of acute morphine dependence results in lasting behavioral adaptation 6weeks into forced abstinence in C57BL/6J mice. We found that our exacerbated morphine withdrawal paradigm produced distinct alterations in behavior in elevated plus maze (EPM), open field, and social interaction tests in male and female mice. Following protracted withdrawal male mice showed enhanced exploration of the open arms of the EPM, reduced latency to enter the corner of the OF, and a social interaction deficit. In contrast, female mice showed enhanced thigmotaxis in the OF. Inboth sexes, protracted withdrawal enhanced locomotor behavior in response to subsequent morphine challenge, albeit at different doses. These findings will be relevant for future investigation examining the neural mechanisms underlying these behaviors and will aid in uncovering physiological sex differences in response to opioid withdrawal.

Effect of Intracerebroventricular Morphine Withdrawal on Anxiety Behavior in Male Rats Reared in Social Isolation

Aims Narcotics prescription has controversial effects on the occurrence of anxiety processes; however, its acute and chronic effects on behavioral differences in social isolation are unclear in the processes of dependence and withdrawal. The present study aimed to investigate the effects of acute and chronic intracerebroventricular morphine sulfate withdrawal on the fear and anxiety behaviors of male rats reared in social isolation. Methods &amp; Materials The present experimental study investigated 32 male 21-day-old male weaned Wistar rats that were divided into two groups of saline (control) and morphine receivers (test). They were then divided into acute and chronic subgroups that were reared under social isolation conditions. The rats of the acute daily consumption group received 10 μg/kg of morphine sulfate solution via intracerebroventricular injection for 10 days, but the chronic rats received it for 60 days. After the end of dependence by its withdrawal, the rats were quitted for 5 days, and their anxiety levels were measured using the Elevated Plus Maze (EPM). The obtained data were analyzed in SPSS using one-way Analysis of Variance (ANOVA), Tukey’s posthoc test and Paired Samples t-test. Findings The research results indicated that the percentage of time and number of open arm entries in rats reared in social isolation significantly decreased during the dependence phase and 5 days after withdrawal in acute and chronic groups (P&lt;0.001). Furthermore, their anxiety rate increased compared to the control group. The findings also suggested a higher incidence of anxiety among chronic consumer groups than acute consumer groups after abstinence. Conclusion The study findings indicated that the discontinuation of morphine consumption in social isolation could increase the incidence of anxiety behaviors in rats. Therefore, negative emotional states associated with acute and chronic morphine withdrawal could lead to anxiety-like behaviors.Keywords: Anxiety, Morphine, Social isolation, Rats.

Deep sequencing analysis to identify novel and rare variants in pain-related genes in patients with acute postoperative pain and high morphine use.

PurposeMost of the genetic variants that are reported to be associated with common pain phenotypes and analgesic use are common polymorphisms. The objective of our study was to identify new variants and investigate less common genetic variants that are usually not included in either small single-gene studies or high-throughput genotyping arrays.Patients and methodsFrom a cohort of 1075 patients who underwent a scheduled total abdominal hysterectomy, 92 who had higher self-rated pain scores and used more morphine were selected for the re-sequencing of 105 genes.ResultsWe identified over 2400 variants in 104 genes. Most were intronic with frequencies >5%. There were 181 novel variants, of which 30 were located in exons: 17 nonsynonymous, 10 synonymous, 2 non-coding RNA, and 1 stop-gain. For known variants that are rare (population frequency <1%), the frequencies of 54 exonic variants and eight intronic variants for the sequenced samples were higher than the weighted frequencies in the Genome Aggregation Database for East and South Asians (P-values ranging from 0.000 to 0.046). Overall, patients who had novel and/or rare variants used more morphine than those who only had common variants.ConclusionOur study uncovered novel variants in patients who reported higher pain and used more morphine. Compared with the general population, rare variants were more common in this group.

NGF, BDNF and Arc mRNA Expression in the Hippocampus of Rats After Administration of Morphine.

Morphine can influence immediate early genes (IEG) of activity-regulated cytoskeletal-associated protein (Arc) and brain-derived neurotrophic factor (BDNF) which are activated in response to physiological stimuli during learning, as well as the nerve growth factor (NGF) gene which increases the expression of several IEGs for memory formation. The purpose of the current study was first to evaluate the effect of acute (1-day) and subchronic (15-days) morphine administration on memory retrieval of rats and second to determine the hippocampal expression of NGF, BDNF and Arc genes as potential contributors in the observed effects in each setting. The effects of morphine (intraperitoneal, 10, 15 and 20mg/kg) on memory function and gene expression were assessed using inhibitory avoidance test and real-time polymerase chain reaction, respectively. We found that a single dose of morphine at the highest dose of 20mg/kg decreases the post-training step-through-latency, while repeated administration of the same dose for 15 successive days increases this indicator of memory retrieval. We did not detect a significant change in the hippocampal expression of Arc, BDNF or NGF genes after a single episode of morphine treatment. However, subchronic morphine administration (15 and 20mg/kg) increased the expression of Arc and BDNF genes in a dose dependent manner. A higher mRNA expression for the NGF was observed at the higher dose of 20mg/kg. We hypothesize that the subchronic effects were morphine-induced behavioral sensitization which may have been enhanced through increased hippocampal Arc expression.

The Effect of Gabapentin on Postoperative Pain, Morphine Sparing Effect and Preoperative Anxiety in Patients Going for Sleeve Gastrectomy Surgical Procedure.

To determine the effectiveness of preoperative administration of gabapentin in reduction of acute postoperative pain, morphine consumption and preoperative anxiety and sedation in obese patients undergoing laparoscopic sleeve gastrectomy. Double-blinded randomised control trial. King Khalid University Hospital, King Saud University Riyadh, Saudi Arabia, from July 2014 to January 2017. Fifty patients undergoing sleeve gastrectomy were enrolled in the study. The subjects received either 1200 mg gabapentin or placebo 2 hours before surgery. The amount of morphine consumption and postoperative pain at 4, 8,12,16, 20 and 24 hours of surgery were measured. Preoperative anxiety and sedation were recorded at 2 hours interval after the drug administration. There was no significant difference in patient characteristics in both groups. 24 hours PCA morphine consumption was significantly lower in gabapentin group than in the placebo group, 15.08±4.55 vs. 27.80±2.51 (p=0.001). Preoperative VAS anxiety, pre- verses post-drug, was significantly lower in gabapentin group 5.80±1.11 vs. 3.52±1.00 (p=0.001) than in placebo group 6.08 1.28 vs. 6.28 1.24 (p=0.635). Preoperative sedation score was not different in both groups. Preoperative oral gabapentin was effective in reducing the postoperative pain, morphine consumption and preoperative anxiety in morbid obese patients undergone laparoscopic sleeve gastrectomy.

Covalent Poly(lactic acid) Nanoparticles for the Sustained Delivery of Naloxone.

The opioid epidemic currently plaguing the United States has been exacerbated by an alarming rise in fatal overdoses as a result of the proliferated abuse of synthetic mu opioid receptor (MOR) agonists, such as fentanyl and its related analogues. Attempts to manage this crisis have focused primarily on widespread distribution of the clinically approved opioid reversal agent naloxone (Narcan); however, due to the intrinsic metabolic lability of naloxone, these measures have demonstrated limited effectiveness against synthetic opioid toxicity. This work reports a novel polymer-based strategy to create a long-acting formulation of naloxone with the potential to address this critical issue by utilizing covalent nanoparticle (cNP) drug delivery technology. Covalently loaded naloxone nanoparticles (Nal-cNPs) were prepared via the naloxone-initiated, ring-opening polymerization (ROP) of l-lactide in the presence of a bifunctional thiourea organocatalyst with subsequent precipitation of the resulting naloxone-poly(l-lactic acid) polymer. This protocol afforded well-defined nanoparticles possessing a drug loading of approximately 7% w/w. The resulting Nal-cNPs demonstrated excellent biocompatibility, while exhibiting sustained linear release kinetics in vitro and blocking the effects of high dose (10 mg/kg) acute morphine for up to 98 h in an in vivo rodent model of neuropathic pain.

Roux Limb Motility in Gastric Bypass Patients with Chronic Abdominal Pain\u2014Is There an Association to Prescribed Opioids?

Background/AimA number of patients continue to suffer from chronic abdominal pain of unknown origin, which may also lead to a prolonged use of opioid analgesics. Symptoms of abdominal pain, nausea and vomiting in this patient group resemble the characteristics of the Roux stasis Syndrome. The aim was to elucidate relationships between chronic abdominal pain, Roux limb motor activity and opioid analgesics.MethodsRoux limb high-resolution manometry and ratings of abdominal pain and quality of life were analysed in 15 gastric bypass patients reporting abdominal pain of unknown origin. Effect of acute opiate administration (morphine i.v.) on fasting Roux limb motor activity was assessed in asymptomatic and morphine-naïve gastric bypass patients (n = 9) and compared with an untreated control group (n = 11).ResultsIn the symptomatic patient group, we found disturbed Roux limb motor patterns in 10 out of 15 examinations, but no signs of Roux stasis syndrome. A high prevalence of prescribed opioid analgesics as well as a high number of reoperations in this group. The worst quality of life and the highest number of pain-killing medications were observed among the patients with distal pacemaker activity in Roux limb. In the morphine-naïve and asymptomatic patients, morphine increased the muscular tone in the Roux limb during phase III-like motor activity.Summary and ConclusionsA majority of the RYGBP patients with chronic abdominal pain had a disturbed Roux limb fasting motility, and there was a high prevalence of prescribed opioid analgesics. In opiate-naïve RYGBP patients, acute morphine intravenously increased the muscular tone of the Roux limb.

Cell-type and region-specific nucleus accumbens AMPAR plasticity associated with morphine reward, reinstatement, and spontaneous withdrawal.

Despite evidence that morphine-related pathologies reflect adaptations in NAc glutamate signaling, substantial gaps in basic information remain. The current study examines the impact of non-contingent acute, repeated, and withdrawal-inducing morphine dosing regimens on glutamate transmission in D1- or D2-MSNs in the nucleus accumbens shell (NAcSh) and core (NAcC) sub-regions in hopes of identifying excitatory plasticity that may contribute tounique facets of opioid addiction-related behavior. Following an acute morphine injection (10mg/kg), average miniature excitatory postsynaptic current (mEPSC) amplitude mediated by AMPA-type glutamate receptors was increased at D1-MSNs in the both the NAcShl and NAcC, whereas only the frequency of events was elevated at D2-MSNs in the NAcSh. In contrast, spontaneoussomatic withdrawal induced by escalating dose of repeated morphine twice per day (20, 40, 60, 80, 100mg/kg) enhanced mEPSC frequency specifically atD2-MSNs in the NAcSh. Similar to previous findings, excitatory drive was elevated at NAcSh D1-MSNs after10-14dayshome cage abstinence. Following abstinence, an acute drug re-exposureproduced a rapid and enduring endocytosis of GluA2-containing AMPARs at D1-MSNs in the shell, that when blocked by an intra-NAc shell infusion of the Tat-GluA23Y peptide, increased reinstatement of morphine place preference-a phenomenon distinctly different than effects previously found with cocaine. The present study is the first to directly identify unique circuit specific adaptations in NAc glutamate synaptic transmission associated with morphine-related acute reward and somatic withdrawal as well as post-abstinence short-term plasticity. Moreover,while differing classes of abused drugs (i.e., psychostimulants and opioids) produce seemingly similar bidirectional plasticity in the NAc following drug re-exposure, our findings indicate this plasticity has distinct behavioral consequences.

Gabapentin Completely Neutralized the Acute Morphine Activation in the Rat Hypothalamus: a c-Fos Study

Aim: The molecular mechanism of gabapentin (GBP)–morphine combinational function and its neuro-anatomical sites of action to prevent, to neutralize morphine side effects and also the enhancement its analgesic effect of morphine is unknown. Methods: Morphine (10 mg/kg), saline, co-injection: GBP (150 mg/kg) with morphine (10 mg/kg) were injected by intraperitoneal injection in rats under deep anaesthesia. C-Fos immunohistochemistry technique was used to locate c-Fos expression in rat hypothalamus. Results: Gabapentin in combination with morphine significantly (p &lt; 0.01) attenuated the acute morphine induced c-Fos immunoreactive neuron in hypothalamus. Conclusion: GBP neutralized the morphine sensitization in rat hypothalamus. GBP might neuromodulate and or antagonize the receptor regulatory machinery of morphine sensitization circuit which might work for drug discovery of morphine abuse.

Oleoyl glycine: interference with the aversive effects of acute naloxone-precipitated MWD, but not morphine reward, in male Sprague-Dawley rats.

Oleoyl glycine (OlGly), a recently discovered fatty acid amide that is structurally similar to N- acylethanolamines, which include the endocannabinoid, anandamide (AEA), as well as endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonists oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), has been shown to interfere with nicotine reward and dependence in mice. Behavioral and molecular techniques were used to investigate the ability of OlGly to interfere with the affective properties of morphine and morphine withdrawal (MWD) in male Sprague-Dawley rats. Synthetic OlGly (1-30 mg/kg, intraperitoneal [ip]) produced neither a place preference nor aversion on its own; however, at doses of 1 and 5 mg/kg, ip, it blocked the aversive effects of MWD in a place aversion paradigm. This effect was reversed by the cannabinoid 1 (CB1) receptor antagonist, AM251 (1 mg/kg, ip), but not the PPARα antagonist, MK886 (1 mg/kg, ip). OlGly (5 or 30 mg/kg, ip) did not interfere with a morphine-induced place preference or reinstatement of a previously extinguished morphine-induced place preference. Ex vivo analysis of tissue (nucleus accumbens, amygdala, prefrontal cortex, and interoceptive insular cortex) collected from rats experiencing naloxone-precipitated MWD revealed that OlGly was selectively elevated in the nucleus accumbens. MWD did not modify levels of the endocannabinoids 2-AG and AEA, nor those of the PPARα ligands, OEA and PEA, in any region evaluated. Here, we show that OlGly interferes with the aversive properties of acute naloxone-precipitated morphine withdrawal in rats. These results suggest that OlGly may reduce the impact of MWD and may possess efficacy in treating opiate withdrawal.

Evaluation of intravenous lidocaine in head and neck cancer surgery: study protocol for a randomized controlled trial

BackgroundPain after major head and neck cancer surgery is underestimated and has both nociceptive and neuropathic characteristics. Extended resection, flap coverage, nerve lesions, inflammation, and high-dose opioid administration can also lead to hyperalgesia and chronic postoperative pain. Opioids are frequently associated with adverse events such as dizziness, drowsiness, nausea and vomiting, or constipation disturbing postoperative recovery and extending the length of hospital stay. Patients eligible for major head and neck cancer surgery cannot benefit from full multimodal pain management with locoregional anesthesia. Intravenous lidocaine, investigated in several studies, has been found to decrease acute pain and morphine consumption. Some data suggest also that it can prevent chronic postsurgical pain. Evidence supporting its use varies between surgical procedures, and there is no published study regarding systemic lidocaine administration in major head and neck cancer surgery. We hypothesized that intravenous lidocaine infused in the perioperative period would lead to opioid sparing and chronic postsurgical pain reduction.Methods/designA total of 128 patients undergoing major head and neck surgery will be included in this prospective two-center, double-blind, randomized controlled trial. Patients will be randomly assigned to lidocaine or placebo treatment. After induction of general anesthesia, an intravenous lidocaine bolus will be administered (1.5 mg.kg− 1), followed by a continuous infusion (2 mg.kg− 1.h− 1) which will be reduced in the postanesthesia care unit (1 mg.kg− 1.h− 1). The primary outcome measure is morphine consumption 48 h after surgery. The secondary outcomes include intraoperative remifentanil consumption, morphine consumption 24 h after surgery, and chronic postsurgical pain that will be assessed 3–6 months after surgery.DiscussionRecent evidence suggests that intravenous lidocaine can lead to opioid sparing and chronic postsurgical pain reduction for certain types of surgery. This is the first trial to prospectively investigate the efficacy and safety of intravenous lidocaine in major head and neck cancer surgery.Trial registrationClinicalTrials.gov, NCT02894710. Registered on 11 August 2016.

Unidirectional opioid-cannabinoid cross-tolerance in the modulation of social play behavior in rats.

The endocannabinoid and the endogenous opioid systems interact in the modulation of social play behavior, a highly rewarding social activity abundantly expressed in young mammals. Prolonged exposure to opioid or cannabinoid receptor agonists induces cross-tolerance or cross-sensitization to their acute behavioral effects. Behavioral and biochemical experiments were performed to investigate whether cross-tolerance or cross-sensitization occurs to the play-enhancing effects of cannabinoid and opioid drugs on social play behavior, and the possible brain substrate involved. The play-enhancing effects induced by systemic administration of JZL184, which inhibits the hydrolysis of the endocannabinoid 2-AG, were suppressed in animals repeatedly pretreated with the opioid receptor agonist morphine. Conversely, acute morphine administration increased social play in rats pretreated with vehicle or with either JZL184 or the cannabinoid agonist WIN55,212-2. Acute administration of JZL184 increased the activation of both CB1 receptors and their effector Akt in the nucleus accumbens and prefrontal cortex, brain regions important for the expression of social play. These effects were absent in animals pretreated with morphine. Furthermore, only animals repeatedly treated with morphine and acutely administered with JZL184 showed reduced activation of CB1 receptors and Akt in the amygdala. The present study demonstrates a dynamic opioid-cannabinoid interaction in the modulation of social play behavior, occurring in limbic brain areas strongly implicated in social play behavior. A better understanding of opioid-cannabinoid interactions in social play contributes to clarify neurobiological aspects of social behavior at young age, which may provide new therapeutic targets for social dysfunctions.

(283) Adjuvant Treatment with Dopamine Receptor Modulators Prevents the Development of Morphine Tolerance in a Rodent Model

Opioids have a prominent role in managing acute pain. However, long-term management of pain with opioids is complicated, as tolerance for the drug develops, increasing the risk for misuse and abuse. The need exists for chronically effective treatments that minimize the rewarding component. Our data shows that, in animal models, combining low-dose morphine with a dopamine 3 receptor (DR3) agonist or dopamine 1 receptor (D1R) antagonist provides superior analgesia against acute painful stimuli compared to morphine alone. The current study examined if adjuvant treatment with D3R agonists or D1R antagonists can also prevent the development of tolerance to and reduce the addictive potential of morphine. Thermal and mechanical thresholds were tested in 16, female Long-Evans rats before and after a single subcutaneous dose of morphine (2mg/kg). Rats were then randomized to 1 of 4 chronic drug conditions: saline; morphine (5mg/kg/day); morphine + pramipexole (D3R agonist, 0.1mg/kg/day); morphine + SCH39166 (D1R antagonist, 0.1mg/kg/day). Drugs were delivered for 14 days via subcutaneous osmotic pump. Analgesia provided by an acute dose of morphine was re-assessed at 7 and 14 days after initiation of drug delivery. Addictive potential of each drug combination was determined using conditioned place preference (CPP). Prior to drug delivery, acute morphine injection increased thermal and mechanical thresholds in all animals. Fourteen days after chronic administration of morphine, sensory thresholds did not change in response to acute morphine (i.e. animals were tolerant). In contrast, sensory thresholds were increased in animals that had received morphine in combination with either dopamine receptor modulator. The addition of either dopamine receptor modulator to morphine also reduced the preference for the drug compared to morphine alone. Adjuvant therapy with clinically-available dopamine receptor agonists or antagonists can prevent the development of morphine tolerance and reduce the rewarding effect of morphine alone.

3447 Effects of intranasal ketamine on uncontrolled cancer related pain

3447 Effects of intranasal ketamine on uncontrolled cancer related pain