Injection Of Morphine Research Articles

Enhancement of morphine-induced antinociception after electroconvulsive shock in mice.

Electroconvulsive therapy (ECT) has been applied for chronic pain for decades. The amounts of opioids to treat pain are sometimes reduced after a series of ECT. The effect of ECT on morphine-induced analgesia and its mechanism underlying the reduction of morphine requirement has yet to be clarified. Therefore, we administered electroconvulsive shocks (ECS) to mice and investigated the antinociceptive effect of morphine in a hot plate test. We examined the expression level of µ-opioid receptor in the thalami of mice 25 h after administration of ECS compared to the thalami of mice without ECS administration using western blotting. ECS disturbed the development of a decrease in the percentage of maximal possible effect (%MPE), which was observed 24 h after a morphine injection, when ECS was applied 25, 23, 21, and 12 h before the second administration of morphine. We also examined the effect of ECS on the dose-response curve of %MPE to morphine-antinociception. Twenty-five hours after ECS, the dose-response curve was shifted to the left, and the EC50 of morphine given to ECS-pretreated mice decreased by 30.1% compared to the mice that were not pretreated with ECS. We also found that the expression level of µ-opioid receptors was significantly increased after ECS administration. These results confirm previous clinical reports showing that ECT decreased the required dose of opioids in neuropathic pain patients and suggest the hypothesis that this effect of ECT works through the thalamus.

Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain.

Research presented here sought to determine if opioid induced tolerance is linked to activity changes within the PI3Kγ-AKT-cGMP-JNK intracellular signaling pathway in spinal cord or peripheral nervous systems. Morphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl/6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance. Afterwards, spinal cord, dorsal root ganglia, and sciatic nerves were isolated for quantifying total and phosphorylated- JNK levels, cGMP, and gene expression analysis of Pik3cg, Akt1, Pten, and nNos1. This pathway was downregulated in the spinal cord with increased expression in the sciatic nerve of morphine tolerant and morphine tolerant mice after SNL. We also observed a significant increase in phosphorylated- JNK levels in the sciatic nerve of morphine tolerant mice with SNL. Pharmacological inhibition of PI3K or JNK, using thalidomide, quercetin, or SP600125, attenuated the development of morphine tolerance in mice with SNL as measured by thermal paw withdrawal. Overall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance in the peripheral nervous system. Continued research into this pathway will contribute to the development of new analgesic drug therapies.

モルヒネ誘導Straubの挙尾反応に対する選択的GSK-3阻害薬SB216763の抑制効果

Background: Straub’s tail reaction (STR) is a dorsiflexion of the tail that is often vertical to the orientation of the body or curling back over the animal. The phenomenon is thought to be mediated by activation of the opioid receptors because opioid receptor antagonists such as naloxone block the phenomenon. The endpoint of the STR can be identified easier than that of locomotor activity, but behavioral measures of STR can only be achieved by skilled observers. Methods: In this presentation, we investigated the measures of STR by using newly modified, infrared beam sensor-based automated apparatus. The positive tail response was considered as a persistent elevation of the tail at an angle more than 45°. Results: Mice treated with a single injection of morphine (30 mg/kg) showed a significant STR with a plateau level at a time point of 20 min after morphine challenge. Pretreatment of mice with a selective glycogen synthase kinase-3 inhibitor SB216763 (0.5 mg/kg) significantly inhibited morphine-induced STR and attenuated the time of STR duration. Horizontal locomotor activity was also attenuated by SB216763. It is of interest to note that mice showing the STR did not exhibit rearing, a search phase of exploratory behavior. Conclusions: Although the underlying mechanism is not clear, this data suggests that the inhibitory effect of SB216763 on morphine-induced STR may depend on the blockade of the glycogen synthase kinase-3 signaling pathway. Our measurement system is a useful tool for investigating the excitatory effects of morphine in experimental animals.

PMSF Attenuates Morphine Antinociceptive Tolerance and Dependence in Mice: Its Association with the Oxidative Stress Suppression.

Opioids use has been limited due to tolerance and dependence as major unwanted effects. Previous evidence has shown that targeting endocannabinoid signaling can prevent the development of opioid tolerance and dependence. This study was designed to evaluate the effect of phenylmethylsulfonyl fluoride (PMSF), an inhibitor of fatty acid amide hydrolase (FAAH), on morphine antinociceptive tolerance and physical dependence in mice. The antinociceptive effects of PMSF at the doses 60, 120, and 300 mg/kg were investigated. Results showed that PMSF has a notable antinociceptive effect at doses 120 and 300 mg/kg. The dose of (60 mg/kg, i.p.) PMSF was considered as a sub-antinociceptive dose. Morphine tolerance and dependence were induced by twice-daily injection of morphine (10 mg/kg, s.c.) for 10 consecutive days and the last dose on day 11. Tolerance was assessed by the hot-plate test and dependence by naloxone-precipitated morphine withdrawal signs. In the brain, oxidative stress markers include activities of glutathione peroxidase, catalase, superoxide dismutase, and levels of malondialdehyde and glutathione were determined. A sub-antinociceptive dose (60 mg/kg) of PMSF could reduce tolerance in both acute and chronic methods of administration. However, alleviation of dependence and suppression of oxidative stress markers occurred in the chronic administration of PMSF. In conclusion, it seems that PMSF can suppress morphine tolerance and dependence. However, more studies are needed to clarify its mechanism.

Central opioid receptors mediate morphine-induced itch and chronic itch via disinhibition.

Opioids such as morphine are mainstay treatments for clinical pain conditions. Itch is a common side effect of opioids, particularly as a result of epidural or intrathecal administration. Recent progress has advanced our understanding of itch circuits in the spinal cord. However, the mechanisms underlying opioid-induced itch are not fully understood, although an interaction between µ-opioid receptor (MOR) and gastrin-releasing peptide receptor (GRPR) in spinal GRPR-expressing neurons has been implicated. In this study we investigated the cellular mechanisms of intrathecal opioid-induced itch by conditional deletion of MOR-encoding Oprm1 in distinct populations of interneurons and sensory neurons. We found that intrathecal injection of the MOR agonists morphine or DAMGO elicited dose-dependent scratching as well as licking and biting, but this pruritus was totally abolished in mice with a specific Oprm1 deletion in Vgat+ neurons [Oprm1-Vgat (Slc32a1)]. Loss of MOR in somatostatin+ interneurons and TRPV1+ sensory neurons did not affect morphine-induced itch but impaired morphine-induced antinociception. In situ hybridization revealed Oprm1 expression in 30% of inhibitory and 20% of excitatory interneurons in the spinal dorsal horn. Whole-cell recordings from spinal cord slices showed that DAMGO induced outward currents in 9 of 19 Vgat+ interneurons examined. Morphine also inhibited action potentials in Vgat+ interneurons. Furthermore, morphine suppressed evoked inhibitory postsynaptic currents in postsynaptic Vgat- excitatory neurons, suggesting a mechanism of disinhibition by MOR agonists. Notably, morphine-elicited itch was suppressed by intrathecal administration of NPY and abolished by spinal ablation of GRPR+ neurons with intrathecal injection of bombesin-saporin, whereas intrathecal GRP-induced itch response remained intact in mice lacking Oprm1-Vgat. Intrathecal bombesin-saporin treatment reduced the number of GRPR+ neurons by 97% in the lumber spinal cord and 91% in the cervical spinal cord, without changing the number of Oprm1+ neurons. Additionally, chronic itch from DNFB-induced allergic contact dermatitis was decreased by Oprm1-Vgat deletion. Finally, naloxone, but not peripherally restricted naloxone methiodide, inhibited chronic itch in the DNFB model and the CTCL model, indicating a contribution of central MOR signalling to chronic itch. Our findings demonstrate that intrathecal morphine elicits itch via acting on MOR on spinal inhibitory interneurons, leading to disinhibition of the spinal itch circuit. Our data also provide mechanistic insights into the current treatment of chronic itch with opioid receptor antagonist such as naloxone.

Morphine Antinociception Restored by Use of Methadone in the Morphine-Resistant Inflammatory Pain State.

The antinociceptive effect of methadone in the morphine-resistant inflammatory pain state was described in the paw-withdrawal test using the complete Freund’s adjuvant (CFA)-induced mouse inflammatory pain model. After intraplantar (i.pl.) injection of CFA, thermal hyperalgesia was observed in the ipsilateral paw. The antinociceptive effects of subcutaneous (s.c.) injection of morphine, fentanyl, and oxycodone against thermal hyperalgesia in the inflammatory pain state were reduced in the ipsilateral paw 7 days after CFA pretreatment. On the contrary, the antinociceptive effect of s.c. injection of methadone was maintained in the ipsilateral paw 7 days after CFA pretreatment. The suppressed morphine antinociception in the CFA model mice was bilaterally restored following s.c. treatment with methadone 20 min prior to or 3 days after CFA pretreatment. The suppressed morphine antinociception was also bilaterally restored by intraperitoneal treatment with MK-801 30 min prior to CFA pretreatment; however, the s.c. injection of morphine 30 min prior to CFA pretreatment failed to restore the suppressed morphine antinociception in the CFA model mice. The expression level of mRNA for µ-opioid receptors 7 days after i.pl. pretreatment was not significantly changed by i.pl. pretreatment with CFA or s.c. pretreatment with methadone. In conclusion, methadone is extremely effective against thermal hyperalgesia in the morphine-resistant inflammatory pain state, and restores suppressed morphine antinociception in the inflammatory pain state without altering the expression level of mRNA for µ-opioid receptors.

Possible mechanism and potential application of anti-opioid effect of diazepam-binding inhibitor

AimsOur previous study has demonstrated that porcine diazepam-binding inhibitor (pDBI) and its active fragments, pDBI-16 and pDBI-19, have inhibition effect on morphine analgesia in mice. The present study aimed to investigate the underlying mechanism and potential application of this anti-opioid effect. Materials and methodsEffect of DBI on morphine analgesia was examined by the tail electric stimulation vocalization test. Complementary peptides and antiserum were used to further confirm the effect of DBI in morphine tolerance and dependence. Pharmacological and microinjection methods were used to investigate the underlying mechanism. Key findingsFirstly, pDBI administered either intracerebroventricularly or intravenously dose-dependently inhibited morphine analgesia, while blocking DBI-16 or DBI-19 by the complementary peptides for DBI-16 (CP-DBI-16) or DBI-19 (CP-DBI-19) potentiated it in mice. Secondly, explicit immunoexpression of DBI in the lateral habenular (LHb) was observed in naive rats, and intra-LHb injection of pDBI dose-dependently abolished analgesic effect produced by intra-periaqueductal gray (PAG) injection of morphine in rats. Thirdly, pretreatment with N-Methyl-d-Aspartate receptor (NMDAR) antagonist MK-801 or nitric oxide (NO) synthase inhibitor L-NAME abolished the inhibition effect of pDBI, pDBI-16 or pDBI-19 on morphine analgesia in mice. Finally, antiserum against DBI dose-dependently reversed analgesic tolerance induced by increasing doses of morphine twice daily for 13 days in mice, while CP-DBI-16 or CP-DBI-19 significantly inhibited naloxone-precipitated morphine withdrawal jumping in mice. SignificanceTaken together, our results demonstrated that NMDAR/NO signaling and LHb-PAG pathway are crucially involved in the anti-opioid effect of DBI, which could provide a potential biological target for opioid tolerance and dependence.

Cross-reinstatement of mitragynine and morphine place preference in rats

Kratom is a medicinal plant that exhibits promising results as an opiate substitute. However, there is little information regarding the abuse profile of its main psychoactive constituent, mitragynine (MG), particularly in relapse to drug abuse. Using the place conditioning procedure as a model of relapse, this study aims to evaluate the ability of MG to induce conditioned place preference (CPP) reinstatement in rats. To evaluate the cross-reinstatement effects, MG and morphine were injected to rats that previously extinguished a morphine- or MG-induced CPP. Following a CPP acquisition induced by either MG (10 and 30 mg/kg, i.p.) or morphine (10 mg/kg, i.p.), rats were subjected to repeated CPP extinction sessions. A low dose priming injection of MG or morphine produced a reinstatement of the previously extinguished CPP. In the second experiment of this study, a priming injection of morphine (1, 3 and 10 mg/kg, i.p.) dose-dependently reinstated an MG-induced CPP. Likewise, a priming injection of MG (3, 10 and 30 mg/kg, i.p.) was able to dose-dependently reinstate a morphine-induced CPP. The present study demonstrates a cross-reinstatement effect between MG and morphine, thereby suggesting a similar interaction in their rewarding motivational properties. The findings from this study also suggesting that a priming exposure to kratom and an opioid may cause relapse for a previously abused drug.

The Role of Hydrogen Sulfide in the Development of Tolerance and Dependence to Morphine in Mice

Objective: Hydrogen sulfide is an endogenous gaseous mediator that has been indicated to have a role in pain mechanisms. In this study, we aimed to detect brain and spinal cord hydrogen sulfide levels during different phases of tolerance and dependence to morphine and to determine the effects of inhibition of endogenous hydrogen sulfide production on the development of tolerance and dependence. Methods: Morphine tolerance and dependence was developed by subcutaneous injection of morphine (10 mg/kg) twice daily for 12 days. Physical dependence was determined by counting the jumps for 20 min, which is a withdrawal symptom occurring after a single dose of naloxone (5 mg/kg) administered intraperitoneally (i.p.). Propargylglycine (30 mg/kg, i.p.), a cystathionine-γ-lyase inhibitor, and hydroxylamine (12.5 mg/kg, i.p.), a cystathionine-β-synthase inhibitor, were used as hydrogen sulfide synthase inhibitors. The tail-flick and hot-plate tests were used to determine the loss of antinociceptive effects of morphine and development of tolerance. Results: It was found that chronic and acute uses of both propargylglycine and hydroxylamine prevented the development of tolerance to morphine, whereas they had no effect on morphine dependence. Chronic and acute administrations of hydrogen sulfide synthase inhibitors did not exert any difference in hydrogen sulfide levels in brain and spinal cords of both morphine-tolerant and -dependent animals. Conclusion: It has been concluded that hydrogen sulfide synthase inhibitors may have utility in preventing morphine tolerance.

Feasibility study of morphine-induced rat pica model by tail vein injection to replace vomiting model

Objective： To explore the feasibility of the morphine-induced rat pica model by tail vein injection to replace the vomiting model，and the effective dose of morphine with less severe complications when the model was developed.Methods： Fifty SD rats were randomly divided into the blank control group and the M1，M2，M3 and M4 groups，each consisting of 10 animals. The rats in the blank control group were injected with 10 ml/kg normal saline（NS） via tail vein，while the animals in the M1，M2，M3 and M4 groups were injected with morphine hydrochloride injection at a dosage of 5，10，20 and 30 mg/kg via tail vein.Heart rate，blood oxygen saturation and activities of the animals were closely observed and recorded at 5，10 and 15 minutes after medication.Then，changes in the intake of kaolin，feed and water of the rats in each group were recorded and compared between the groups for 4 successive days after medication.Results： The blood oxygen saturation in the morphine treatment groups all reduced significantly，and statistical significance could be seen，when it was compared with that of the blank control group（P<0.05）.On the first day after medication，the intake of kaolin in the M3 and M4 groups increased significantly，as compared with that of the blank control group（P<0.05）.On the third day after medication，the intake of kaolin in the M1 group significantly increased，as compared with that of the blank control group（P<0.05）.Conclusion： The rat pica model was established by tail vein injection of morphine，which could be used to replace the vomiting model.The effective dose of morphine was 20 mg/kg with less severe complications.

Chronic opioid exposure differentially modulates oxycodone self-administration in male and female rats.

Withdrawal from opioid painkillers can produce short‐lived physical symptoms and protracted psychological symptoms including anxiety and depressive‐like states that often lead to opioid misuse and opioid use disorder (OUD). Studies testing the hypothesis that opioid withdrawal potentiates the reinforcing effects of opioid self‐administration (SA) are largely inconclusive and have focused on males. Although some clinical evidence indicates that women are more likely than men to misuse opioids to self‐medicate, preclinical studies in both sexes are lacking. Based on clinical reports, we hypothesized that withdrawal from escalating‐dose morphine injections that approximates a prescription painkiller regimen would lead to increased oxycodone SA to a greater extent in female compared to male rats. After escalating‐dose morphine (5–30 mg/kg or vehicle, twice/day for 12 days), rats underwent a 2‐week abstinence period during which withdrawal signs were measured. The impact of this treatment was assessed on oxycodone SA acquisition, maintenance, dose response, and progressive ratio responding, with additional analyses to compare sexes. We found that both sexes expressed somatic withdrawal, whereas only males demonstrated hyperalgesia in the warm water tail flick assay. During SA acquisition, males with prior morphine exposure took significantly more oxycodone than females. Finally, females with prior morphine exposure demonstrated the lowest motivation to SA oxycodone in the progressive ratio test. Contrary to our initial hypothesis, our findings suggest that prior opioid exposure increases vulnerability to initiate misuse more in males and decreases the reinforcing efficacy of oxycodone in females.

Effect of Intravenous Morphine Injection on Neurological Examination of Dogs With Thoracolumbar Intervertebral Disk Extrusion.

Objectives: We aimed to determine the effect of intravenous morphine injection on the modified Frankel scores of dogs with thoracolumbar intervertebral disk extrusion (IVDE).Methods: This was a prospective, blinded, randomized, and placebo-controlled study. We included dogs with a presumptive diagnosis of thoracolumbar IVDE that did not undergo analgesic, anti-inflammatory, or sedative treatment within the last 12 h. A neurological examination was performed and the deficits were graded using the modified Frankel score (MFS). Subsequently, each dog was randomly allocated to receive an intravenous injection of either morphine or placebo. After 30 min, the dogs were re-evaluated by the same veterinary officer who was blinded to the contents of the injections. Dogs were included in the study if IVDE was ultimately confirmed by surgery within one week of initial presentation.Results: Among the 79 dogs initially enrolled, 62 dogs met the inclusion criteria. Among them, thirty-two dogs received intravenous morphine injections and there was no difference between the pre- and post-injection modified Frankel scores. Thirty dogs received an intravenous placebo injection. One dog had a worsening of the MFS by one grade in the post-injection examination.Clinical Significance: In dogs with thoracolumbar intervertebral disk extrusion, an intravenous injection of morphine does not affect the modified Frankel score after 30 min compared with the pre-injection value. These findings support the use of an analgesic morphine dose if the neurological examination can be performed 30 min or later after the injection.

Repeated Administration of Baclofen Modulates TRPV-1 Channel Expression by PKC Pathway in Dorsal Root Ganglia of Spinal Cord in Morphine Tolerance Model of Rats

Background:Tolerance and dependence to anti-nociceptive effect of morphine restricted its use. Nowadays co-administration of morphine and other drugs suggests diminishing this tolerance. Baclofen is one of the drugs that may be beneficial in the attenuation of tolerance to morphine. Studies have shown that changes in TRPV-1 expression during administration of morphine have a pivotal role in developing morphine tolerance. Therefore, the effect of baclofen on TRPV-1 expression during chronic administration of morphine was investigated in this study. Methods:A total of 48 rats were divided into four groups of control, morphine single injection, morphine tolerance, and morphine tolerance + baclofen. To induce morphine tolerance in rats, animals received 10 mg/kg of i.p. morphine sulfate once a day for 10 days. In the treatment group, baclofen (0.5 mg/kg) was injected for 10 days, before morphine injection. Finally, to evaluate baclofen treatment on morphine analgesia and hyperalgesia, thermal hyperalgesia and formalin test were used. TRPV-1 and PKC expression and protein production in DRG of spinal cord were then evaluated by real-time PCR and Western blot. Results:In baclofen treatment group, thermal hyperalgesia and formalin test improved in comparison with morphine tolerance group. In morphine tolerance group, both TRPV-1/PKC gene expression and protein levels increased in comparison with the control group. However, following the baclofen treatment, the TRPV-1 and PKC levels decreased. Conclusion:Baclofen can enhance anti-nociceptive effect of morphine by modulating TRPV-1 channel and PKC activity.

Effects of dopamine D1- and D2-like receptors in the CA1 region of the hippocampus on expression and extinction of morphine-induced conditioned place preference in rats

Considering the extent of drug use and its relapse rate worldwide, in the present study, we explored the role of intra-CA1 administration of D1-like and D2-like receptor antagonists on the expression and extinction of morphine-induced CPP. To induce morphine CPP, adult male Wistar rats received a daily subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. Different doses of SCH23390 (0.25, 1 or 4 μg/0.5 μl saline), as a selective D1-like receptor antagonist, and sulpiride (0.25, 1, or 4 μg/0.5 μl DMSO), as a selective D2-like receptor antagonist, were bilaterally microinjected into the CA1 region in the expression and extinction phases 1 h before CPP evaluation. Conditioning scores and locomotor activities were recorded during the tests. Results indicated that the injection of the antagonists into the CA1 region dose-dependently attenuated the expression of the morphine-induced CPP and sulpiride revealed prominent behavioral results compared to SCH23390 in the expression phases. Furthermore, microinjections of SCH23390 and sulpiride shortened the extinction phase of the morphine-induced CPP without changing the locomotor activity. The results indicated the involvement of D1- and D2-like receptors within the CA1 region in the expression and extinction of rewarding properties of morphine.

Loss of mu and delta opioid receptors on neurons expressing dopamine receptor D1 has no effect on reward sensitivity

Opioid signaling controls the activity of the brain's reward system. It is involved in signaling the hedonic effects of rewards and has essential roles in reinforcement and motivational processes. Here, we focused on opioid signaling through mu and delta receptors on dopaminoceptive neurons and evaluated the role these receptors play in reward-driven behaviors. We generated a genetically modified mouse with selective double knockdown of mu and delta opioid receptors in neurons expressing dopamine receptor D1. Selective expression of the transgene was confirmed using immunostaining. Knockdown was validated by measuring the effects of selective opioid receptor agonists on neuronal membrane currents using whole-cell patch clamp recordings. We found that in the nucleus accumbens of control mice, the majority of dopamine receptor D1-expressing neurons were sensitive to a mu or delta opioid agonist. In mutant mice, the response to the delta receptor agonist was blocked, while the effects of the mu agonist were strongly attenuated. Behaviorally, the mice had no obvious impairments. The mutation did not affect the sensitivity to the rewarding effects of morphine injections or social contact and had no effect on preference for sweet taste. Knockdown had a moderate effect on motor activity in some of the tests performed, but this effect did not reach statistical significance. Thus, we found that knocking down mu and delta receptors on dopamine receptor D1-expressing cells does not appreciably affect some of the reward-driven behaviors previously attributed to opioid signaling.

Morphine and Fentanyl Repeated Administration Induces Different Levels of NLRP3-Dependent Pyroptosis in the Dorsal Raphe Nucleus of Male Rats via Cell-Specific Activation of TLR4 and Opioid Receptors.

Morphine promotes neuroinflammation after NOD-like receptorprotein 3 (NLRP3) oligomerization in glial cells, but the capacity of other opioids to induce neuroinflammation and its relationship to the development of analgesic tolerance is unknown. We studied the effects of morphine and fentanyl on NLRP3 inflammasome activation in glial and neuronal cells in the dorsal raphe nucleus (DRN), a region involved in pain regulation. Male Wistar rats received i.p. injections of morphine (10mg/kg) or fentanyl (0.1mg/kg) 3 × daily for 7days and were tested for nociception. Two hours after the last (19th) administration, we analyzed NLRP3 oligomerization, caspase-1 activation and gasdermin D-N (GSDMD-N) expression in microglia (CD11b positive cells), astrocytes (GFAP-positive cells) and neurons (NeuN-positive cells). Tolerance developed to both opioids, but only fentanyl produced hyperalgesia. Morphine and fentanyl activated NLRP3 inflammasome in astrocytes and serotonergic (TPH-2-positive) neurons, but fentanyl effects were more pronounced. Both opioids increased GFAP and CD11b immunoreactivity, caspase-1 and GSDMD activation, indicating pyroptotic cell death. The opioid receptor antagonist (-)-naloxone, but not the TLR4 receptor antagonist (+)-naloxone, prevented microglia activation and NLRP3 oligomerization. Only (+)-naloxone prevented astrocytes' activation. The anti-inflammatory agent minocycline and the NLRP3 inhibitor MCC950 delayed tolerance to morphine and fentanyl antinociception and prevented fentanyl-induced hyperalgesia. MCC950 also prevented opioid-induced NLRP3 oligomerization. In conclusion, morphine and fentanyl differentially induce cell-specific activation of NLRP3 inflammasome and pyroptosis in the DRN through TLR4 receptors in astrocytes and through opioid receptors in neurons, indicating that neuroinflammation is involved in opioid-induced analgesia and fentanyl-induced hyperalgesia after repeated administrations.

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.

Disparity in the effect of morphine on eupnea and gasping in anesthetized spontaneously breathing adult rats.

The goal of this study was to examine the effects of systemic morphine on the pattern and morphology of gasping breathing during respiratory autoresuscitation from transient anoxia. We hypothesized that systemic morphine levels sufficient to cause significant depression of eupnea would also cause depression of gasping breathing. Respiratory and cardiovascular variables were studied in 20 spontaneously breathing pentobarbital-anaesthetized adult male rats. Sham (saline) injections caused no significant change in resting respiratory or cardiovascular variables (n = 10 rats). Morphine, on the other hand, caused significant depression of eupneic breathing, with ventilation and peak inspiratory flow decreased by ∼30-60%, depending on the background condition (n = 10 rats). In contrast, morphine did not depress gasping breathing. Duration of primary apnea, time to restore eupnea, the number and amplitude of gasping breaths, average and maximum peak flows, and volume of gasping breaths were not significantly different postinjection in either condition. Blood pressures were all significantly lower following morphine injection at key time points in the process of autoresuscitation. Last, rate of successful recovery from anoxia was 80% in the morphine group (8/10 rats) compared with 100% (10/10 rats) in the sham group, postinjection. We conclude that the mechanisms and/or anatomic correlates underlying generation of gasping rhythm are distinct from those underlying eupnea, allowing gasping to remain robust to systemic morphine levels causing significant depression of eupnea. Morphine nevertheless decreases likelihood of recovery from transient anoxia, possibly as a result of decreased tissue perfusion pressures at critical time points during the process of respiratory autoresuscitation.

A case of indomitable vomiting in an ectopic pregnancy. Injection of morphine into the fetal sac. Recovery

A patient, tall and strong, about 30 years old, a woman was always healthy and only a month before that she began to feel sometimes cramp-like pains in the lower abdomen and notice leucorrhoea, which either intensified or weakened. Menstruation is correct from the age of 13, but the last meager regulations on April 30 were caused artificially, and on the third day there were pains with contractions, bringing the patient to fainting.

Multimodal perioperative pain management in a horse undergoing partial phallectomy

A well-balanced multimodal pain management including local anaesthetic techniques was used to provide perioperative analgesia in a horse undergoing partial phallectomy. This surgical intervention has been associated with moderate to severe pain and may present additional challenges to the veterinarian when providing pain relief postoperatively.In the present case, preoperative analgesia included morphine and flunixin meglumine, both intravenously. Throughout surgery, adaptable constant rate infusions (CRIs) with ketamine and xylazine were supplemented to address different receptors of the pain pathway. Additionally, a pudendal nerve block with ropivacaine was added intraoperatively to reduce nociception and decrease sensitisation of the central nervous system. An epidural injection of morphine and dexmedetomidine was performed after recovery from general anaesthesia. Postoperative pain treatment included morphine and flunixin meglumine that resulted in adequate pain relief, based on pain assessment every 6–12 hours. Neither side effects nor complications were observed during the hospital stay.