Injection Of Morphine Sulfate Research Articles

Increases in Pro-inflammatory Cytokines in the Ventral Striatum Following Frequent Morphine Exposure Impose New Setpoints in the Expression of Biologically-Relevant Genes to Addiction and Neuroinflammation in Rats

Background: The ventral striatum is an integrated drug reward and addiction center. Objectives: We aimed to examine changes in pro-inflammatory cytokines and subsequent changes in the expression of biologically-relevant genes to addiction and neuroinflammation in the ventral striatum in response to frequent morphine exposure. Methods: Sixteen male Wistar rats were divided into two experimental groups, a control, and a morphine-treated group, receiving eight days of twice-daily injections of either saline or morphine sulfate (10 mg/kg). Results: The results revealed that frequent morphine treatment increased both gene and protein levels of pro-inflammatory cytokines, including tumor necrosis factor α, interleukin 1-β, and interleukin 6 in the ventral striatum. Frequent morphine treatment also induced significant upregulations in the mRNA levels of mu-opioid receptor, dopamine D1 receptor (Drd1), Fos, nuclear factor- kappa B, and pre-miRNAs expression including, mir-124, mir-133b, mir-339, mir-365, and Let-7c1 in the ventral striatum. On the contrary, frequent morphine injection significantly downregulated mRNA levels of toll-like receptor 4, cannabinoid CB1 and CB2 receptors, Drd2, Il1r, Il6r, tnfr, protein kinase Cγ, calcium/calmodulin-dependent protein kinase IIα, nitric oxide synthase, cAMP-response element-binding protein as well as p38 and Jnk3 MAP kinases in the ventral striatum. However, no group differences were detected in the expression of Erk1 and mir-219 in the ventral striatum. Conclusions: It can be concluded that dysregulations in pro-inflammatory cytokines and, subsequently, in the downstream signaling pathways impair physiological functions of the ventral striatum following chronic morphine exposure, affecting reward pathways and the expression of morphine tolerance and dependence.

The Expression and Function of Nitric Oxide Synthase Enzyme in Atorvastatin Effects on Morphine-Induced Dependence in Mice

Background: Atorvastatin exerts neuroprotective effects on the treatment of central nervous system disorders. Morphine analgesic tolerance and dependence remain as major concerns in medicine. Nitric oxide (NO) pathway mediates the development of opioid analgesic tolerance and dependence, as well as atorvastatin neuroprotection. Objectives: The present study aimed to assess the possible involvement of the NO/cGMP pathway in the process of the effects of atorvastatin on morphine physical dependence. Methods: Dependence was induced by repetitive injection of morphine sulfate. Naloxone was injected at the dose of 4 mg/kg on the last day of the experiment to assess withdrawal signs. Animals received atorvastatin (1, 5, 10, and 20 mg/kg, orally). Nitric oxide synthase (NOS) inhibitors and ODQ were injected before protective dose of atorvastatin. The gene expression of NOS isoforms was evaluated by real-time PCR. Thereafter, the hippocampal levels of cGMP and nitrite were measured. Results: Treatment with atorvastatin 10 mg/kg significantly attenuated naloxone-induced withdrawal behaviours. The administration of L-NAME, aminoguanidine, and ODQ before atorvastatin enhanced its effects. The treatment with atorvastatin significantly decreased the nitrite and cGMP levels as well as NOS gene expression in the hippocampus of dependent animals. Conclusions: It can be concluded that atorvastatin, possibly, through inducible NOS, could alleviate morphine dependence and withdrawal signs.

Oxycodone versus morphine for titration analgesia after laparoscopic gynecologic surgery in postanesthesia care unit: A prospective, randomized trial

We want to compare the efficacy and side effects of oxycodone and morphine in the management of postoperative pain by titration in patients who underwent laparoscopic gynecologic surgery because of neglect of postoperative analgesia and rare literature of intravenous oxycodone used in PACU, China. Thirty adult female patients were scheduled for elective laparoscopic gynecologic surgery under general anesthesia. The patients were randomly assigned to either morphine sulfate injection group (Group M, n = 15 cases) or oxycodone hydrochloride injection group (Group O, n = 15 cases). All the patients were given an intravenous PEG nanometer drug delivery system. Furthermore, when they arrived at the postanesthesia care unit (PACU), a visual analog scale (VAS) was used to evaluate postoperative pain. Also, the patients were given 3 mg oxycodone or morphine for titration when the pain VAS score was more than 30 mm, and the pain and sedation scores were re-evaluated after 5 minutes. The titration stopped if the VAS score was ≤ 30 mm otherwise the titration continued as per the above method until the VAS score was less than 30 mm. The required titration dosage, times, and time of oxycodone titration were noted and they were all remarkably lower than those of morphine titration group (P < 0.05). The incidence of side effects in Group M was statistically significantly higher in Group O (P < 0.05). More so, oxycodone titration showed faster analgesic effects, less analgesic drug consumption, and lower incidence of adverse complications during postoperative pain management when compared to morphine titration. The reliability and effectiveness of the PEG nanometer drug delivery system were simultaneously proved.

Alteration of Hematologic Parameters in Morphine-Dependent Rats by Long-Term Administration of Orexin Type 1 Receptor Antagonist

Background: Orexin peptides that are produced in the hypothalamic nuclei are involved in opioid dependence. Objectives: In the current study, we aimed to figure out the effect of orexin type 1 receptor (OXR1) antagonist on hematologic factors in morphine-dependent rats. Patients and Methods: Male Wistar rats were rendered morphine-dependent by subcutaneous injection of morphine sulfate (10 mg/Kg) at an interval of 12 hours twice a day for seven days. In the control and treatment groups, SB-334867 vehicle and SB-334867 were injected during postnatal days 1 to 30 (P1-P30) daily and then before each morphine injection during for days. Data were analyzed using unpaired two-tailed Student t-test and one-way analysis of variance (ANOVA). The defined level of statistical significance was P < 0.05. Results: Morphine increased white blood cell count (WBC), platelet cell count, and hematocrit. Application of SB-334867 reduced several hematologic factors in morphine-dependent rats, including mean corpuscular hemoglobin concentration (MCHC), WBC, and platelet count compared to morphine-dependent rats. Conclusions: Inhibition of OXR1 may improve morphine-induced changes in hematologic factors in morphine-dependent rats.

Glial cells modulate hippocampal synaptic plasticity in morphine dependent rats

Drugs of abuse mediate adaptive mechanisms leading to alterations in the synaptic plasticity that has been shown to underlie addictive behaviors. Glial cells play a critical role in modulation of synaptic strength and are potentially involved in drug addiction. Chronic administration of morphine has been shown to increase glial cell activation; therefore, it is possible that altered neuroplasticity induced by drugs of abuse is in part mediated by the activity of glial cells. We investigated the effect of hippocampal glial inhibition on synaptic plasticity in morphine treated rats. The fluorocitrate (an inhibitor of glial cells) was microinjected into the CA1 area before morphine injection. The rats received subcutaneous (s.c.) injections of morphine sulfate (10 mg/kg) every 12 h for 9 days. Field excitatory postsynaptic potentials (fEPSP) were recorded from the stratum radiatum of the CA1 area following Schaffer collateral stimulation. Our results indicated that morphine treatment increases long-term potentiation (LTP) and inhibition of glial cells prevents morphine-induced LTP enhancement. Morphine exposed rats exhibited a resistance to LTD induction, whereas, pretreatment with fluorocitrate reduced this resistance. Glial inhibition did not affect LTP and LTD in the untreated animals. The paired pulse ratio (PPR) in inter stimulus intervals (ISI) of 80 ms in the morphine treated group was significantly higher than the control group, while glial inhibition significantly decreased the PPR in morphine treated rats. Our results suggest that morphine exposure modulates hippocampal short- and long-term synaptic plasticity and these alterations in neuronal activity are in part due to glial activity.

Sophora alopecuroides L. var. alopecuroides alleviates morphine withdrawal syndrome in mice: involvement of alkaloid fraction and matrine.

Evaluation of the Sophora alopecuroides var. alopecuroides seed effects on morphine withdrawal syndrome in mice and determination of the alkaloid composition of the seed total extract. The effects of the seed total extract, alkaloid fraction and major compound matrine on the mice morphine withdrawal syndrome were compared to saline and methadone. Mice were made dependent on morphine by morphine sulfate injection 3 times a day for 3 days. The withdrawal jumping and diarrhea were induced by administration of naloxone 2 hr after the 10th injection of morphine sulfate on the day 4. The total extract (100, 200, 300 mg/kg), alkaloid fraction (5, 10, 20 mg/kg), matrine (5, 15, 30 mg/kg), methadone (10 mg/kg) or saline were injected 30 min before naloxone. All drugs were administered by subcutaneous injection. The total extract alkaloid composition was also determined by gas chromatography (GC) and GC-MS analysis. All doses of the total extract, alkaloid fraction and matrine as well as methadone decreased jumping and diarrhea significantly compared to the saline. The effects of the total extract and alkaloid fraction were not significantly different from methadone. But, there were significant differences between the effects of matrine and methadone. Matrine, cytisine, sophoridine, n-methyl cytisine, sophocarpine and sophoramine were the major alkaloids. There was no nicotine in the total extract. S. alopecuroides var. alopecuroides suppresses opioid withdrawal with efficacy comparable to methadone. Matrine may be one of the alkaloids responsible for the effect of the plant.

Hyperbaric oxygen treatment suppresses withdrawal signs in opioid‐dependent mice (659.12)

HBO2 therapy has been approved by the Food and Drug Administration for limited clinical conditions (Gesell, The Hyperbaric Oxygen Therapy Committee Report: Indications and Results, 12th Ed, 2008). It has been reported that HBO2 treatments reduce opioid withdrawal in human subjects (Epifanova, Anesteziol Reanimatol, May‐June 1995 issue, 34‐39). However, no further research has been conducted to investigate the mechanism of HBO2 in reducing opioid withdrawal. The purpose of this research was to determine whether HBO2 treatment could suppress signs of withdrawal in opioid‐dependent mice. Male NIH Swiss mice received repeated s.c. injections of morphine sulfate or saline twice a day for 4 days. The daily dose of morphine sulfate was increased progressively from 50 mg/kg on day 1 to 125 mg/kg on day 4. On day 5, opioid withdrawal was precipitated by intraperitoneal injection of 5.0 mg/kg naloxone. Withdrawal signs in mice, including jumping, forepaw tremor and wet dog shakes, were recorded for 30 min and scored. Sixty min prior to the naloxone injection, different groups of mice received a 30‐min or 60‐min HBO2 treatment at 3.5 atmospheres absolute. The results show that HBO2 treatment caused a dose‐dependent reduction in withdrawal jumping, forepaw tremor and wet dog shakes in opioid‐dependent mice.Grant Funding Source: Supported by NIH Grant AT‐007222 and the Allen I. White Distinguished Professorship.

Switching from morphine to fentanyl attenuates the decline of μ-opioid receptor expression in periaqueductal gray of rats with morphine tolerance

Background Opioid switching is a therapeutic maneuver to improve analgesic response and/or reduce adverse side effects although the underlying mechanisms remain unknown. The μ-opioid receptor (MOR) has an important role in mediating the actions of morphine and other analgesic agents. This study is aimed at exploring the changes of MOR in the periaqueductal gray (PAG) in rats when morphine is substituted for equianalgesic fentanyl. Methods Forty rats were randomly assigned to five treatment groups: 7 days normal saline group (N group), 7 days fentanyl group (F group), 7 days morphine group (M group), 7 days morphine and 7 days fentanyl-switching group (MF group), and 14 days morphine group (MM group). Rats repeatedly received subcutaneous injections of morphine sulfate (10 mg/kg) or equianalgesic fentanyl sulfate (0.1 mg/kg) twice daily. Rats' antinociceptive response to thermal pain was evaluated by the tail flick latency assay. MOR mRNA and protein expression in the PAG were measured using RT-PCR and Western blotting analyses respectively. Results This study showed that after morphine was substituted with fentanyl on day 8, the tail flick latency (TFL) increased from (3.9±0.4) seconds to (11.4±0.4) seconds. The results also demonstrated that both MOR mRNA and protein expression in the PAG of rats in the MF group were less than that in the M group (P<0.05) but more than that in MM group (P<0.05). Conclusions Equianalgesic fentanyl was still antinociceptive effective in rats with morphine tolerance, which may be due to the switching from morphine to fentanyl attenuating the decline of MOR expression in the PAG of rats.

Efficacy and safety of oxycodone hydrochloride injection for postoperative analgesia in patients undergoing operation under general anesthesia: a prospective, randomized, blind, multicenter, positive-controlled,clinical trial

Objective To evaluate the efficacy and safety of oxycodone hydrochloride injection for postoperative analgesia in patients undergoing the operation under general anesthesia in a prospective,randomized,blind,multicenter,positive-controlled,clinical trial.Methods Two hundred and forty ASA Ⅰ or Ⅱ patients of both sexes,aged 18-64 yr,weighing 40-95 kg,scheduled for elective abdominal operation or orthopedic surgeries under general anesthesia,were randomly divided into 2 groups (n =120 each):morphine sulfate injection group (group M) and oxycodone hydrochloride injection group (group O).Morphine or oxycodone 1 mg was injected intravenously when the patients complained of pain after tracheal extubation or removal of the laryngeal mask,and administration was repeated if necessary until VAS≤40 mm.Then patient-controlled intravenous analgesia (PCIA) (100 ml,0.5 mg/ml) with morphine or oxycodone was used for postoperative analgesia (lasting for 48 h).The PCIA pump was set up with a 1 ml bolus dose,a 5 min lockout interval and background infusion at a rate of 0.5 mg/h.Pain at rest and during movement was assessed using VAS score at 3,24 and 48 h after administration,and non-inferiority test was performed.Total morphine or oxycodone consumption,requirement for rescue analgesic,the number of unsuccessfully delivered dose,the number of attempts,and the level of patient' s satisfaction were recorded within 48 h after operation.The adverse events were recorded and laboratory examinations (blood and urine routine test,blood biochemical examination) were performed within 72 h after administration.Results There was no significant difference in the VAS scores at rest and during movement at different time points,requirement for rescue analgesic,the number of unsuccessfully delivered doses and attempts,level of patient' s satisfaction,total morphine or oxycodone consumption,and adverse events between the two groups (P ＞ 0.05).No serious adverse event occurred in the two groups.The most common adverse event was nausea,followed by vomiting.There was no significant difference in the incidences and degree of nausea and vomiting between the two groups (P ＞ 0.05).The incidences of nausea and vomiting in patients underwent orthopedic surgeries were significantly lower in group O than in group M (P ＜ 0.05).The other adverse events were fewer and abnormal laboratory examinations were rare in the two groups.95％ confidence interval of the difference between the mean VAS scores at rest and during movement at each time point was within 15 mm (boundary values of non-inferiority testing) in the two groups.Conclusion PCIA with oxycodone hydrochloride injection is safe and effective in reducing pain after moderate or major operation,and the analgesic efficacy is similar to that of morphine sulfate injection,however,the development of nausea and vomiting is reduced when PCIA with oxycodone hydrochloride injection is used for orthopedic surgeries as compared with that when morphine sulfate injection is used and the ratio between the analgesic efficacy of the two drugs is close to 1∶1. Key words: Oxycodone ; Analgesia, patient-controlled ; Pain, postoperative

Morphine deteriorates spatial memory in sodium salicylate treated rats

Tolerance and cross-tolerance for the effects of morphine (M) and sodium salicylate on nociception and learning were examined. The anti-nociceptive effects were measured by using the classic tail flick (TF) and hot plate (HP) tests and learning was measured with the Morris water maze (MWM). Tolerance or cross-tolerance was induced by daily injection (i.p.) of morphine sulfate (10mg/kg for 7 days) or sodium salicylate (300mg/kg for 6 days). The injection of sodium salicylate increased both TF and HP latencies. This anti-nociceptive effect was progressively decreased across six injections and tolerance to sodium salicylate was developed. When M was injected to sodium salicylate-tolerant rats, a weakened anti-nociceptive effect was seen, indicating cross-tolerance to M. Acute treatment with M also increased TF latency. This anti-nociceptive effect was successively decreased across seven injections and tolerance to M was developed. When sodium salicylate was injected to M-tolerant rats, a diminished anti-nociceptive effect was seen, indicating cross-tolerance to sodium salicylate. Acute M impaired water maze performance, while chronic M and sodium salicylate had no effects on MWM performance. However, when M was injected to rats that had received sodium salicylate after each training trial for 7 days, these rats spent less time in target quadrant as compared to M and saline groups. It is concluded that chronic sodium salicylate induces tolerance to anti-nociceptive effects of M and vice versa. Also chronic salicylate may produce lasting metaplastic changes in brain mechanisms behind spatial learning and memory, which can be visualized in cross-sensitization to morphine.

Blockade of orexin receptor 1 attenuates the development of morphine tolerance and physical dependence in rats

The goals of this study were to evaluate the effects of pretreatment by orexin receptor-1 antagonist on the development of morphine tolerance and physical dependence in rat. Animals were rendered dependent on morphine by subcutaneous (SC) injection of morphine sulfate (10mg/kg) at set intervals of 12h for 10days. Just before the morphine administration, the animals received SB-334867, a selective orexin receptor 1 (OXR1) antagonist. To assess morphine tolerance, the antinociceptive responses of morphine were measured using the warm-water tail immersion test before and after its administration. On day 11, naloxone was injected 2h after morphine administration and the physical dependence evaluated by quantifying/scoring naloxone-precipitated withdrawal signs for 30min. The effect of chronic SB-334867 on locomotion was carried out by calculating the number of grid crossings as a measure of locomotor activity. Our findings demonstrated that although morphine-tolerance tended to develop in response to repeated injections of morphine, pre-treatment of OXR1 antagonist prevented this effect, causing a delay in the development of morphine-tolerance. Moreover, co-administration of orexin receptor 1 antagonist with morphine significantly decreased the somatic signs of withdrawal including diarrhea, teeth chattering, jumping, and defecation. Administration of SB-334867 alone or in a chronic co-administration with morphine failed to change locomotor activity. These results suggest that the activation of OXR1 might be involved in the development of morphine tolerance and dependence.

Height-dependent difference in the expression of naloxone-induced withdrawal jumping behavior in morphine dependent rats

Opiate withdrawal syndrome may motivate opiate seeking and taking. Thus, development of an effective medical treatment for these symptoms is a primary research goal and strongly relies on improved experimental models. Opiate withdrawal syndrome is characterized by several behavioral signs such as wet dog shake, teeth chattering, sniffing, scratching, chewing, diarrhea, rearing, ptosis and jumping. The goal of present study was to evaluate the impact of the cylindrical chamber height on the expression of jumping behavior in morphine dependent rats. Adult male Wistar rats were rendered dependent on morphine by subcutaneous (s.c.) injection of morphine sulfate (10mg/kg) with an interval of 12h for 9 days. On day 10, 2h after morphine injection, rats were injected with naloxone (1mg/kg, i.p.). Naloxone-induced jumping was monitored during a period of 30min in a clear cylindrical Plexiglas test chamber with the floor covered by woodchip. The chambers had the same diameter (35cm), but the heights of chambers were different (30, 40, 50, 60, 70 and 80cm). Incidence and frequency of jumping decreased with increasing the height of the test chambers (P<0.05). Altogether, these findings highlight the possibility of detecting height-dependent difference in the expression of naloxone-induced jumping behavior in morphine dependent rats.

Social influences on morphine-conditioned place preference in adolescent BALB/cJ and C57BL/6J mice

Among human adolescents, drug use is substantially influenced by the attitudes and behaviors of peers. Social factors also affect the drug-seeking behaviors of laboratory animals. Conditioned place preference (CPP) experiments indicate that social context can influence the degree to which rodents derive a rewarding experience from drugs of abuse. However, the precise manner by which social factors alter drug reward in adolescent rodents remains unknown. We employed the relatively asocial BALB/cJ (BALB) mouse strain and the more prosocial C57BL/6J (B6) strain to explore whether "low" or "high" motivation to be with peers influences the effects of social context on morphine CPP (MCPP). Adolescent mice were conditioned by subcutaneous injections of morphine sulfate (0.25, 1.0, or 5.0 mg/kg). During the MCPP procedure, mice were housed in either isolation (Ih) or within a social group (Sh). Similarly, following injection, mice were conditioned either alone (Ic) or within a social group (Sc). Adolescent B6 mice expressed a robust MCPP response except when subjected to Ih-Sc, which indicates that, following isolation, mice with high levels of social motivation are less susceptible to the rewarding properties of morphine when they are conditioned in a social group. By contrast, MCPP responses of BALB mice were most sensitive to morphine conditioning when subjects experienced a change in their social environment between housing and conditioning (Ih-Sc or Sh-Ic). Our findings demonstrate that susceptibility to morphine-induced reward in adolescent mice is moderated by a complex interaction between social context and heritable differences in social motivation.

The stability of injection of morphine sulphate.

The stability of injection of morphine sulphate.

Comparing of the effects of hypericin and synthetic antidepressants on the expression of morphine-induced conditioned place preference.

The effect of hypericin on the expression of morphine-induced conditioned place preference (CPP) was investigated and compared with the effect of the synthetic antidepressants. The CPP paradigms took place over six days using an unbiased procedure. The results demonstrate that intra-peritoneal (IP) injection of morphine sulfate (2.5, 5 and 10 mg/Kg) significantly induce the CPP in rat. Intra-peritoneal and intracerebroventricular (ICV) injection of hypericin and/or synthetic antidepressants augmented morphine-induced CPP. It has been suggested that the adrenergic, serotonergic and dopaminergic neurotransmissions play an important role in mediating the antidepressant effect of hypericin and this effect may be due to its inhibitory effect on the reuptake of neurotransmitters. Morphine produces a reinforcement (reward) effect by activating. The μ-receptors that facilitate dopaminergic transmission. Serotonin is also a potent stimulator of dopamine release in such a way that an increase in brain serotonin could possibly stimulate the dopaminergic system. In conclusion, it may suggest that the augmentation of morphine-induced CPP by hypericin and synthetic antidepressants may be related to the increasing dopamine and serotonin concentrations in synaptic clefts.

Antagonism of orexin type 1 receptors in the locus coeruleus attenuates signs of naloxone-precipitated morphine withdrawal in rats

It has been shown that orexin neuropeptides contribute to morphine-induced physical dependence. The locus coeruleus (LC), which receives a dense extra-hypothalamic orexinergic projection, is a key brain region implicated in the expression of somatic signs of morphine withdrawal syndrome. The aim of the present study is to investigate the role of LC orexin type 1 receptors (OXR1) on naloxone-precipitated morphine withdrawal signs in rats. Adult male Wistar rats were rendered dependent on morphine by subcutaneous (s.c.) injection of morphine sulfate (10 mg/kg) at an interval of 12 h for 9 days. On day 10, naloxone (1 mg/kg i.p.) was injected 2 h after morphine administration. Somatic signs of withdrawal were then evaluated in a clear Plexiglas test chamber (30 cm diameter, 50 cm height) for 25 min. One group of animals received intra-LC SB-334867-A, a selective OXR1 antagonist, (100 μM, 0.2 μl) immediately before naloxone. In the control group, SB-334867-A vehicle was microinjected into the LC in the same manner. The results showed that intra-LC OXR1 receptor blockade significantly decreased the somatic signs of withdrawal including chewing, diarrhea, scratching, teeth chattering, wet-dog shake and ptosis. These results suggest that activation of OXR1 in the LC might be involved in the expression of withdrawal signs in morphine dependent rats.

Effect of Complete Maternal and Littermate Deprivation on Morphine-Induced Fos-Immunoreactivity in the Adult Male Rat Brain

Previous research has demonstrated that rats reared in isolation from their dam and littermates show altered behavioral responsiveness to both natural and drug-mediated rewards. This study examined the effects of complete maternal deprivation through the use of artificial rearing on neural activation after acute morphine exposure in adulthood. Male rats were either artificially reared (AR) or maternally reared (MR) from postnatal day 5 to 21. In adulthood (4 mo old), rats received a single injection of morphine sulfate (10 mg/kg) or equivolume saline 2 h before perfusion and brain extraction. Neural activation was quantified using Fos immunohistochemistry. Analyses of several brain regions revealed a consistent pattern of differences between AR and MR rats. Specifically, relative to MR rats, AR rats showed significantly greater morphine-induced Fos-immunoreactivity in brain regions associated with the mesocorticolimbic "reward" pathway. These results support the hypothesis that functional activity in reward neurocircuitry can be altered by early life experience.

Ingestion of amniotic fluid enhances the facilitative effect of VTA morphine on the onset of maternal behavior in virgin rats

Previous research has shown that injection of morphine into the ventral tegmental area (VTA) facilitates the onset of maternal behavior in virgin female rats, and injection of the opioid antagonist naltrexone into the VTA disrupts the onset of maternal behavior in parturient rats. Placentophagia – ingestion of placenta and amniotic fluid, usually at parturition – modifies central opioid processes. Ingestion of the active substance in placenta and amniotic fluid, Placental Opioid-Enhancing Factor (POEF), enhances the hypoalgesic effect of centrally administered morphine, and more specifically, enhances δ- and κ-opioid-receptor-mediated hypoalgesia and attenuates μ-opioid-receptor-mediated hypoalgesia. POEF (in placenta or amniotic fluid) ingestion does not, by itself, produce hypoalgesia. In the present study, we tested the hypothesis that ingestion of amniotic fluid enhances the facilitative effect of opioid activity (unilateral morphine injection) in the VTA on the rate of onset of maternal behavior. Virgin female Long-Evans rats were given one intra-VTA injection of morphine sulfate (0.0, 0.01, or 0.03 μg, in saline) and an orogastric infusion of 0.25 ml amniotic fluid or saline once each day of the first three days of the 10-day testing period. Subjects were continuously exposed to foster pups that were replaced every 12 h; replacement of pups was followed by a 15-min observation period. Maternal behavior latency was determined by the first of two consecutive tests wherein the subject displayed pup retrieval, pup licking in the nest, and crouching over all foster pups, during the 15-min observation. We confirmed the previous finding that the VTA injection, alone, of 0.03 μg morphine shortened the latency to show maternal behavior and that 0.0 μg and 0.01 μg morphine did not. Ingestion of amniotic fluid (and therefore POEF) facilitated the onset of maternal behavior in rats receiving an intra-VTA microinjection of an otherwise subthreshold dose of morphine (0.01 μg).

Preemptive Morphine Analgesia Attenuates the Long-Term Consequences of Neonatal Inflammation in Male and Female Rats

Despite mounting evidence on the importance of pain management in preterm infants, clinical use of analgesics in this population is limited. Our previous studies have shown that neonatal inflammation results in long-term alterations in adult somatosensory thresholds, characterized by decreased baseline nociceptive sensitivity, and enhanced hyperalgesia after a subsequent inflammatory insult. The present studies were conducted to determine whether preemptive morphine attenuates these negative consequences. At P0, pups received an injection of morphine sulfate before an intraplantar injection of 1% carrageenan. Control pups received either saline (SAL) followed by intraplantar carrageenan, morphine sulfate followed by intraplantar SAL, or SAL followed by intraplantar SAL. Preemptive morphine significantly attenuated neonatal injury-induced hypoalgesia in adolescence and adulthood. Similarly, morphine pretreated animals displayed significantly less hyperalgesia and recovered faster from a subsequent inflammatory insult compared with controls. Neonatal morphine had no significant effect on morphine analgesia in adulthood. Interestingly, neonatally injured animals that did not receive morphine displayed a significant rightward shift in the morphine dose-response curve in the absence of peripheral inflammation. Together, these results demonstrate that preemptive morphine significantly attenuates the long-term behavioral impact of neonatal inflammatory injury.

Potentiation of morphine-induced conditioned place preference with concurrent use of amantadine and fluvoxamine by the intraperitoneal and intracerebroventricular injection in rat

In this study, the effect of concurrent use of fluvoxamine and amantadine on morphine-induced conditioned place preference (CPP) was investigated by the intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) injection in rat. The CPP paradigms took place on 6 consecutive days by using an unbiased procedure. Our results showed that i.p. injection of morphine sulfate (2.5–10 mg/kg) induced CPP in rat. On day 6, fluvoxamine (5 and 10 mg/kg, i.p.), and amantadine (5 and 10 mg/kg, i.p.) both increased morphine-induced conditioned place preference. Intracerebroventricular injection of fluvoxamine (10 μg/rat) and amantadine (10 μg/rat) were also increased morphine-induced conditioned preference significantly. Concurrent use of fluvoxamine (5 mg/kg, i.p.; 10 μg/rat i.c.v.) and amantadine (10 mg/kg, i.p.; 10 μg/rat, i.c.v.) potentiated morphine-induced conditioned preference significantly. Release of dopamine from neurons cause reinforcing behavior. Morphine produces reinforcement (reward) effect by activation of μ receptors which facilitated dopaminergic transmission through dopamine release. Fluvoxamine, a serotonin reuptake inhibitor, increase serotonin concentration in synaptic clefts, which is a potent stimulator of dopamine release. Amantadine also appears to work by increasing dopamine release from neuron. In conclusion, our results show that concurrent use of fluvoxamine and amantadine potentiate morphine-like effect on CPP through increasing dopaminergic transmission and this combination may simulate the rewarding effect of morphine and can be candidate for controlling the drug compulsive seeking in morphine dependent subjects.