Long-term Morphine Administration Research Articles

Long-term administration of morphine specifically alters the level of protein expression in different brain regions and affects the redox state

Long-term administration of morphine specifically alters the level of protein expression in different brain regions and affects the redox state

Amiloride alleviates morphine tolerance by suppressing ASIC3-dependent neuroinflammation in the spinal cord

BackgroundThe use of morphine in clinical medicine is severely constrained by tolerance. Therefore, it is essential to examine pharmacological therapies that suppress the development of morphine tolerance. Amiloride suppressed the expression of inflammatory cytokines by inhibiting microglial activation. Microglia play a crucial role in the establishment of morphine tolerance. Thus, we anticipated that amiloride might suppress the development of morphine tolerance. During this investigation, we assessed the impact of amiloride on mouse morphine tolerance. MethodsMice received morphine (10 mg/kg, s.c.) twice daily with intrathecally injected amiloride (0.3 μg/5 μl, 1 μg/5 μl, and 3 μg/5 μl) for nine continuous days. To assess morphine tolerance, mice underwent the tail-flick and hot plate tests. BV-2 cells were used to investigate the mechanism of amiloride. By using Western blotting, real-time PCR, and immunofluorescence labeling methods, the levels of acid-sensing ion channels (ASICs), nuclear factor kappa B (NF-kB) p65, p38 mitogen-activated protein kinase (MAPK) proteins, and neuroinflammation-related cytokines were determined. ResultsThe levels of ASIC3 in the spinal cord were considerably increased after long-term morphine administration. Amiloride was found to delay the development of tolerance to chronic morphine assessed via tail-flick and hot plate tests. Amiloride reduced microglial activation and downregulated the cytokines IL-1β and TNF-a by inhibiting ASIC3 in response to morphine. Furthermore, amiloride reduced p38 MAPK phosphorylation and inhibited NF-κB expression. ConclusionsAmiloride effectively reduces chronic morphine tolerance by suppressing microglial activation caused by morphine by inhibiting ASIC3.

Overexpression of GDNF in Spinal Cord Attenuates Morphine Analgesic Tolerance in Rats with Bone Cancer Pain

Bone cancer pain (BCP) is one of the typical and distressing symptoms in cancer patients. Morphine is a widely used analgesic drug for BCP; however, long-term morphine administration will lead to analgesic tolerance. Our previous study indicated that spinal glial cell line-derived neurotrophic factor (GDNF) exerts analgesic effects in rats with BCP. In this study, BCP was established by inoculated Walker 256 carcinoma cells into rat tibias, while morphine tolerance (MT) was induced by intrathecally injecting morphine twice daily from the 9th to 15th postoperative day (POD) in BCP rats. The BCP rats developed mechanical and thermal hyperalgesia on POD 5 and it lasted to POD 15. The analgesic effect of morphine was decreased after repeat administration. Western blots and immunochemistry tests showed that GDNF was gradually decreased in the spinal cord after the development of MT in rats with BCP, and GDNF was colocalized with the μ opioid receptor (MOR) in the superficial laminate of the spinal cords. The overexpression of GDNF by lentivirus significantly attenuated MT, and restored the expression of MOR in the spinal cord. In summary, our results suggest that the reduction of GDNF expression participated in the development of MT in rats with BCP and could be a promising therapeutic option for BCP.

Regulation of body weight and food intake by AGRP neurons during opioid dependence and abstinence in mice.

Dysregulation of body weight maintenance and opioid dependence are often treated as independent disorders. Here, we assessed the effects of both acute and long-term administration of morphine with and without chemogenetic activation of agouti-related peptide (AGRP)-expressing neurons in the arcuate nucleus (ARCAGRP neurons) to elucidate whether morphine and neuronal activation affect feeding behavior and body weight. First, we characterized interactions of opioids and energy deficit in wild-type mice. We observed that opioid administration attenuated both fasting-induced refeeding and ghrelin-stimulated feeding. Moreover, antagonism of opioid receptors blocked fasting-induced refeeding behavior. Next, we interfaced chemogenetics with opioid dependence. For chemogenetic experiments of ARCAGRP neurons, we conducted a priori behavioral qualification and post-mortem FOS immunostaining verification of arcuate activation following ARCAGRP chemogenetic activation. We administered clozapine during short-term and long-term morphine administration paradigms to determine the effects of dependence on food intake and body weight. We found that morphine occluded feeding behavior characteristic of chemogenetic activation of ARCAGRP neurons. Notably, activation of ARCAGRP neurons attenuated opioid-induced weight loss but did not evoke weight gain during opioid dependence. Consistent with these findings, we observed that morphine administration did not block fasting-induced activation of the ARC. Together, these results highlight the strength of opioidergic effects on body weight maintenance and demonstrate the utility of ARCAGRP neuron manipulations as a lever to influence energy balance throughout the development of opioid dependence.

Mesoporous Polydopamine Nanoparticles Attenuate Morphine Tolerance in Neuropathic Pain Rats by Inhibition of Oxidative Stress and Restoration of the Endogenous Antioxidant System.

Oxidative stress resulting from reactive oxygen species (ROS) is known to play a key role in numerous neurological disorders, including neuropathic pain. Morphine is one of the commonly used opioids for pain management. However, long-term administration of morphine results in morphine antinociceptive tolerance (MAT) through elevation of ROS and suppression of natural antioxidant defense mechanisms. Recently, mesoporous polydopamine (MPDA) nanoparticles (NPS) have been known to possess strong antioxidant properties. We speculated that morphine delivery through an antioxidant nanocarrier might be a reasonable strategy to alleviate MAT. MPDAs showed a high drug loading efficiency of ∼50%, which was much higher than conventional NPS. Spectral and in vitro studies suggest a superior ROS scavenging ability of NPS. Results from a rat neuropathic pain model demonstrate that MPDA-loaded morphine (MPDA@Mor) is efficient in minimizing MAT with prolonged analgesic effect and suppression of pro-inflammatory cytokines. Additionally, serum levels of liver enzymes and levels of endogenous antioxidants were measured in the liver. Treatment with free morphine resulted in elevated levels of liver enzymes and significantly lowered the activities of endogenous antioxidant enzymes in comparison with the control and MPDA@Mor-treated group. Histopathological examination of the liver revealed that MPDA@Mor can significantly reduce the hepatotoxic effects of morphine. Taken together, our current work will provide an important insight into the development of safe and effective nano-antioxidant platforms for neuropathic pain management.

Morphine Addiction and Oxidative Stress: The Potential Effects of Thioredoxin-1.

Long-term administration of morphine for the management of chronic pain will result in tolerance to its analgesic effect and could even cause drug dependence. Numerous studies have demonstrated significant redox alteration in morphine dependence and addiction. Thioredoxin-1 (Trx-1) play important roles in controlling the cellular redox balance. In recent years, several recent studies have demonstrated that Trx-1 may be a promising novel therapeutic target for morphine addiction. In this article, we firstly review the redox alteration in morphine addiction. We also summarize the expression and the protective roles of Trx-1 in morphine dependence. We further highlight the protection of geranylgeranylacetone (GGA), a noncytotoxic pharmacological inducer of Trx-1, in morphine-induced conditioned place preference. In conclusion, Trx-1 may be very promising for clinical therapy of morphine addiction in the future.

NEUROPEPTIDES EFFECTS ON RAT ESTROUS CYCLE DISORDERS CAUSED BY MORPHINE

The aim of the study was to evaluate the influence of the Delta sleep-inducing peptide (DSIP) or the analogue of the adrenocorticotropin4-10 fragment (FACTH) on changes in the estrous cycle of rats caused by long-term administration of morphine. It has been found that the intranasal administration of DSIP or FACTH for 14 days did not lead to significant changes in the estrous cycle in mature female inbred rats. The introduction of morphine at a dose of 60 mg/kg for 60 days was accompanied by a statistically significant change in the duration and structure of the estrous cycle in experimental animals: a decrease in the duration of the estrus period to 1,50 ± 0,17 days and an increase in interintegration to 8,30 ± 0,80 days, as well as the total duration of the estrous cycle up to 9,60 ± 0,65 days. In turn, the use of DSIP and FACTH for 14 days after the administration of morphine at a dose of 60 mg/kg for 60 days led to the normalization of the structure and duration of the estrous cycle in mature female inbred rats.

Behavioral, histopathological, and biochemical evaluations on the effects of cinnamaldehyde, naloxone, and their combination in morphine-induced cerebellar toxicity

Long-term morphine use for therapeutic approaches may lead to serious side effects. Several studies have suggested opioid antagonist and antioxidant therapy for reducing adverse effects of morphine. Cinnamaldehyde has a potent anti-oxidant property. In this study, separate and combined effects of cinnamaldehyde and naloxone (an opioid receptor antagonist) on behavioral changes and cerebellar histological and biochemical outcomes were investigated after long-term morphine administration. Seventy-eight rats were divided into two major morphine-treated and morphine-untreated groups. Morphine-treated group was subdivided into seven subgroups for receiving vehicle, normal saline, cinnamaldehyde (1.25, 5, and 20 mg/kg), naloxone, and cinnamaldehyde plus naloxone before morphine. Morphine-untreated group was subdivided into six subgroups and treated with vehicle, cinnamaldehyde (1.25, 5, and 20 mg/kg), naloxone, and their combination. Chemical compounds were administered for 28 consecutive days. Behavioral tests including footprint, rotarod, and beam balance tests were employed. Histopathological and biochemical alterations of cerebellum were determined. Body and cerebellum weights, stride width, time spent on the rotarod, Purkinje cell number, thickness of molecular and granular layers, superoxide dismutase (SOD), and total antioxidant capacity (TAC) decreased as a result of administrating morphine. Morphine increased beam transverse time, malondealdehyde (MDA), tumor necrosis factor-α (TNF-α), and caspase-3 levels. Histopathological changes such as cellular vacuolation and loss were also produced as a result of treatment with morphine. Cinnamaldehyde, naloxone, and their combination treatments improved all the above-mentioned alterations induced by morphine. We concluded that cinnamaldehyde produced a neuroprotective effect through anti-oxidant, anti-inflammatory, apoptotic, and probably naloxone-sensitive opioid receptor interaction mechanisms.

MiR-873a-5p Targets A20 to Facilitate Morphine Tolerance in Mice.

Long-term morphine administration leads to tolerance and a gradual reduction in analgesic potency. Noncoding microRNAs (miRNAs) modulate gene expression in a posttranscriptional manner, and their dysregulation causes various diseases. Emerging evidence suggests that miRNAs play a regulatory role in the development of morphine tolerance. In the present study, we hypothesized that miR-873a-5p is a key functional small RNA that participates in the development and maintenance of morphine tolerance through the regulation of A20 (tumor necrosis factor α-induced protein 3, TNFAIP3) in mice. We measured the percentage of maximum possible effect (MPE %) to evaluate the analgesic effect of morphine. The expression of miR-873a-5p and its target gene A20 were determined after the morphine-tolerant model was successfully established. Intrathecal injection with lentivirus to intervene in the expression of A20 and the miR-873a-5p antagomir was used to explore the role of miR-873a-5p in the development of morphine tolerance. Chronic morphine administration significantly increased the expression of miR-873a-5p, which was inversely correlated with decreased A20 expression in the spinal cord of morphine-tolerant mice. Downregulation of miR-873a-5p in the spinal cord attenuated and partly reversed the development of morphine tolerance accompanied by overexpression of A20. Similarly, A20 was upregulated by a recombinant lentivirus vector, which attenuated and reversed the pathology of morphine tolerance by inhibiting the activation of nuclear factor (NF)-κB. Collectively, our results indicated that miR-873a-5p targets A20 in the spinal cord to facilitate the development of morphine tolerance in mice. Downregulating the expression of miR-873a-5p may be a potential strategy to ameliorate morphine tolerance.

Overexpression of Thioredoxin-1 Blocks Morphine-Induced Conditioned Place Preference Through Regulating the Interaction of γ-Aminobutyric Acid and Dopamine Systems.

Morphine is one kind of opioid, which is currently the most effective widely utilized pain relieving pharmaceutical. Long-term administration of morphine leads to dependence and addiction. Thioredoxin-1 (Trx-1) is an important redox regulating protein and works as a neurotrophic cofactor. Our previous study showed that geranylgeranylaceton, an inducer of Trx-1 protected mice from rewarding effects induced by morphine. However, whether overexpression of Trx-1 can block morphine-induced conditioned place preference (CPP) in mice is still unknown. In this study, we first examined whether overexpression of Trx-1 affects the CPP after morphine training and further examined the dopamine (DA) and γ-aminobutyric acid (GABA) systems involved in rewarding effects. Our results showed that morphine-induced CPP was blocked in Trx-1 overexpression transgenic (TG) mice. Trx-1 expression was induced by morphine in the ventral tegmental area (VTA) and nucleus accumbens (NAc) in wild-type (WT) mice, which was not induced in Trx-1 TG mice. The DA level and expressions of tyrosine hydroxylase (TH) and D1 were induced by morphine in WT mice, which were not induced in Trx-1 TG mice. The GABA level and expression of GABABR were decreased by morphine, which were restored in Trx-1 TG mice. Therefore, Trx-1 may play a role in blocking CPP induced by morphine through regulating the expressions of D1, TH, and GABABR in the VTA and NAc.

N‐Methyl‐d‐aspartate receptor antagonist MK‐801 attenuates morphine tolerance and associated glial fibrillary acid protein up‐regulation: a proteomic approach

It is well known that long-term morphine administration results in tolerance, which limits the clinical use of this drug in pain management. Male Wistar rats were randomly assigned to receive one of four different infusions: morphine [15 microg/h, intrathecal (i.t.)], saline, MK-801 (5 microg/h, i.t.) plus morphine (15 microg/h, i.t.), or MK-801 (5 microg/h, i.t.) alone. Morphine infusion induced a maximal antinociceptive effect on day 1 and tolerance on day 3, and the maximal anti-receptive tolerance was observed on day 5. Co-infusing MK-801 with morphine attenuated morphine's anti-receptive tolerance. Two-dimensional gel electrophoretic analysis of spinal proteins revealed that eight protein spots were up-regulated in morphine-tolerant rats, and that they were significantly inhibited by MK-801 co-infusion. Among the up-regulated proteins, glial fibrillary acid protein (GFAP), a glial-specific maker, was identified by mass spectrometry. This finding was also confirmed by Western blot analysis. Using proteomic analysis, we identified eight GFAP protein spots that were up-regulated in the dorsal horn of morphine-tolerant rat spinal cords. This up-regulation was partly inhibited by N-methyl-D-aspartate receptor antagonist MK-801 co-infusion, which suggests that GFAP protein can be considered to be a pathogenesis marker of morphine tolerance.

Endothelin ET A receptor blockade potentiates morphine analgesia but does not affect gastrointestinal transit in mice

Development of analgesic tolerance and constipation remain a major clinical concern during long-term administration of morphine in pain management. Central endothelin mechanisms are involved in morphine analgesia and tolerance. The present study was conducted to investigate the effect of intracerebroventricular (i.c.v.) and peripheral administration of endothelin ET A receptor antagonist, BMS182874, and endothelin ET B receptor agonist, IRL1620, on morphine analgesia and changes in gastrointestinal transit in male Swiss Webster mice. Results indicate that morphine (6 mg/kg, s.c.) produced a significant increase in tail flick latency compared to control group. Pretreatment with BMS182874 (50 μg, i.c.v.) significantly enhanced morphine-induced analgesia, while IRL1620 (30 μg, i.c.v.) pretreatment did not affect tail-flick latency values. Changes in gastrointestinal transit were measured by percent of distance traveled by charcoal in the small intestine of gastrointestinal tract. Percent distance traveled in morphine (6 mg/kg, s.c.) treated mice (48.45 ± 5.65%) was significantly lower ( P < 0.05) compared to control group (85.07 ± 1.82%). Administration of BMS182874 centrally (50 μg, i.c.v.) or peripherally (10 mg/kg, i.p.) did not affect morphine-induced inhibition of gastrointestinal transit. Pretreatment with IRL1620 (30 μg, i.c.v., or 10 mg/kg, i.v.) also did not affect morphine-induced inhibition of gastrointestinal transit. This study demonstrates that endothelin ET A receptor antagonists delivered to the CNS enhance morphine analgesia without affecting gastrointestinal transit.

Spinal L-Type Calcium Channel Blockade Abolishes Opioid-Induced Sensory Hypersensitivity and Antinociceptive Tolerance

Recent studies have suggested that prolonged exposure to morphine results in the development of paradoxical, abnormal enhanced pain. It has also been suggested that this enhanced pain state may be interpreted as antinociceptive tolerance. Although the precise mechanisms that drive opioid-induced abnormal pain are not well known, considerable evidence suggests that this state may be supported by enhanced, stimulus-evoked excitatory transmission. We hypothesized that blockade of L-type calcium channels, which are critical for excitatory neurotransmitter release, would alter the development of opioid-induced hyperalgesia and antinociceptive tolerance. Male, Swiss-Webster mice received twice-daily intrathecal injections of morphine (10 microg) alone or in combination with amlodipine (10 microg) for 8 days. Mice receiving repeated morphine injections developed enhanced responses to tactile and thermal stimuli. These hypersensitivities were prevented by the coadministration of the putative selective L-type calcium channel blocker amlodipine. Moreover, mice receiving morphine for 8 days demonstrated a significant rightward shift of the morphine antinociceptive dose-response curve, indicative of antinociceptive tolerance, whereas those that also received amlodipine along with morphine did not demonstrate tolerance. These results suggest that blockade of the L-type calcium channels with amlodipine prevented opioid-induced hyperalgesia and the expression of antinociceptive tolerance to spinal morphine, presumably by reducing stimulus-induced excitatory neurotransmitter release.

Clinical pharmacology of morphine and morphine-6-glucuronide. A PK/PD modeling approach

The clinical pharmacology of morphine is complicated by its active metabolite, morphine-6-β-glucuronide (M6G). M6G is a potent μ-opioid agonist that has been recognized to play an important role in the clinical effects of morphine. However, M6G probably crosses the blood brain barrier with difficulties, and is of importance for the effects of morphine only during long-term morphine administration because only then M6G may reach high enough CNS concentrations. Since M6G is eliminated from the body via the kidney, it may cause severe opioid side effects with insidious onset and long persistence when renal function is impaired. This time dependent participation of M6G at the clinical effects of morphine makes it difficult to predict the effect of morphine in an individual patient. The problem may be solved using a PK/PD modeling approach to the clinical pharmacology of morphine that takes the delayed action of M6G into consideration.

From pressure–volume loops and magnetic resonance imaging to mathematical models for cardiac surgery simulation

The clinical pharmacology of morphine is complicated by its active metabolite, morphine-6-β-glucuronide (M6G). M6G is a potent μ-opioid agonist that has been recognized to play an important role in the clinical effects of morphine. However, M6G probably crosses the blood brain barrier with difficulties, and is of importance for the effects of morphine only during long-term morphine administration because only then M6G may reach high enough CNS concentrations. Since M6G is eliminated from the body via the kidney, it may cause severe opioid side effects with insidious onset and long persistence when renal function is impaired. This time dependent participation of M6G at the clinical effects of morphine makes it difficult to predict the effect of morphine in an individual patient. The problem may be solved using a PK/PD modeling approach to the clinical pharmacology of morphine that takes the delayed action of M6G into consideration.

Intraoperative accuracy of non-invasive registration in computer assisted cranio–maxillofacial surgery

The clinical pharmacology of morphine is complicated by its active metabolite, morphine-6-β-glucuronide (M6G). M6G is a potent μ-opioid agonist that has been recognized to play an important role in the clinical effects of morphine. However, M6G probably crosses the blood brain barrier with difficulties, and is of importance for the effects of morphine only during long-term morphine administration because only then M6G may reach high enough CNS concentrations. Since M6G is eliminated from the body via the kidney, it may cause severe opioid side effects with insidious onset and long persistence when renal function is impaired. This time dependent participation of M6G at the clinical effects of morphine makes it difficult to predict the effect of morphine in an individual patient. The problem may be solved using a PK/PD modeling approach to the clinical pharmacology of morphine that takes the delayed action of M6G into consideration.

A computerized training neuronavigator for functional neurosurgery

The clinical pharmacology of morphine is complicated by its active metabolite, morphine-6-β-glucuronide (M6G). M6G is a potent μ-opioid agonist that has been recognized to play an important role in the clinical effects of morphine. However, M6G probably crosses the blood brain barrier with difficulties, and is of importance for the effects of morphine only during long-term morphine administration because only then M6G may reach high enough CNS concentrations. Since M6G is eliminated from the body via the kidney, it may cause severe opioid side effects with insidious onset and long persistence when renal function is impaired. This time dependent participation of M6G at the clinical effects of morphine makes it difficult to predict the effect of morphine in an individual patient. The problem may be solved using a PK/PD modeling approach to the clinical pharmacology of morphine that takes the delayed action of M6G into consideration.

Surgical cockpit system and effectiveness of its immersive environment

The clinical pharmacology of morphine is complicated by its active metabolite, morphine-6-β-glucuronide (M6G). M6G is a potent μ-opioid agonist that has been recognized to play an important role in the clinical effects of morphine. However, M6G probably crosses the blood brain barrier with difficulties, and is of importance for the effects of morphine only during long-term morphine administration because only then M6G may reach high enough CNS concentrations. Since M6G is eliminated from the body via the kidney, it may cause severe opioid side effects with insidious onset and long persistence when renal function is impaired. This time dependent participation of M6G at the clinical effects of morphine makes it difficult to predict the effect of morphine in an individual patient. The problem may be solved using a PK/PD modeling approach to the clinical pharmacology of morphine that takes the delayed action of M6G into consideration.

Combining low- and high-resolution volume data for use in MR tracking

The clinical pharmacology of morphine is complicated by its active metabolite, morphine-6-β-glucuronide (M6G). M6G is a potent μ-opioid agonist that has been recognized to play an important role in the clinical effects of morphine. However, M6G probably crosses the blood brain barrier with difficulties, and is of importance for the effects of morphine only during long-term morphine administration because only then M6G may reach high enough CNS concentrations. Since M6G is eliminated from the body via the kidney, it may cause severe opioid side effects with insidious onset and long persistence when renal function is impaired. This time dependent participation of M6G at the clinical effects of morphine makes it difficult to predict the effect of morphine in an individual patient. The problem may be solved using a PK/PD modeling approach to the clinical pharmacology of morphine that takes the delayed action of M6G into consideration.

Navigation system for pedicle screw insertion

The clinical pharmacology of morphine is complicated by its active metabolite, morphine-6-β-glucuronide (M6G). M6G is a potent μ-opioid agonist that has been recognized to play an important role in the clinical effects of morphine. However, M6G probably crosses the blood brain barrier with difficulties, and is of importance for the effects of morphine only during long-term morphine administration because only then M6G may reach high enough CNS concentrations. Since M6G is eliminated from the body via the kidney, it may cause severe opioid side effects with insidious onset and long persistence when renal function is impaired. This time dependent participation of M6G at the clinical effects of morphine makes it difficult to predict the effect of morphine in an individual patient. The problem may be solved using a PK/PD modeling approach to the clinical pharmacology of morphine that takes the delayed action of M6G into consideration.