Morphine-induced Tolerance In Mice Research Articles

Effect of Electro-Acupuncture at ST36 and SP6 on the cAMP -CREB Pathway and mRNA Expression Profile in the Brainstem of Morphine Tolerant Mice.

Undoubtedly, opioid drugs have been the most popular treatment for refractory pain since found, such as morphine. However, tolerance to the analgesic effects caused by repeated use is inevitable, which greatly limits the clinical application of these drugs. Nowadays, it has become the focus of the world that further development of non-opioid-based treatment along with efficient strategies to circumvent opioid tolerance are urgently needed clinically. Fortunately, electro-acupuncture (EA) provides an alternative to pharmaceutic treatment, remaining its potential mechanisms unclear although. This study was aimed to observe the effects of EA on morphine-induced tolerance in mice and discover its underlying mechanism. Tail-flick assay and hot-plate test were conducted to assess the development of tolerance to morphine-induced analgesia effect. As a result of repeated administration scheme (10 mg/kg, twice per day, for 7 days), approximately a two-fold increase was observed in the effective dose of 50% (ED50) of morphine-induced antinociceptive effect. Interestingly, by EA treatment (2/100Hz, 0.5, 1.0, and 1.5 mA, 30 min/day for 7 days) at the acupoints Zusanli (ST36) and Sanyinjiao (SP6), morphine ED50 curves was remarkably leftward shifted on day 8. In addition, the RNA sequencing strategy was used to reveal the potential mechanisms. Due to the well described relevance of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), extracellular regulated protein kinases (ERK), and cAMP response element-binding (CREB) in brainstem (BS) to analgesia tolerance, the cAMP-PKA/ERK-CREB signaling was deeply concerned in this study. Based upon Enzyme-Linked Immunosorbent Assay, the up-regulation of the cAMP level was observed, whereas reversed with EA treatment. Similarly, western blot revealed the phosphorylation levels of PKA, ERK, and CREB were up-regulated in morphine tolerant mice, whereas the EA group showed a significantly reduced expression level instead. This study observed an attenuating effect of the EA at ST36 and SP6 on morphine tolerance in mice, and suggested several potential biological targets by RNA-seq, which include the cAMP-PKA/ERK-CREB signaling pathway, strongly supporting a useful treatment for combatting the opioid epidemic, and opioid-tolerant patients.

Antinociceptive and genotoxic assessments of the antagonist TRPV1 receptor SB-366791 on morphine-induced tolerance in mice.

Chronic pain is mainly treated with opioid analgesics such as morphine. However, the use of these substances can cause adverse effects, including dependence and tolerance, necessitating the discovery of a new approach to analgesic therapies. The transient receptor potential vanilloid 1 (TRPV1) is linked to thermal sensibility and has been considered as a new therapeutic option for pain treatment. This study aims to investigate the antinociceptive effect and toxicity of SB-366791, a TRPV1 antagonist. Morphine-tolerant and morphine non-tolerant Swiss mice were submitted to the hot plate and thermal tail flick tests. Toxicological evaluations of the genotoxic and mutagenic activities of SB-366791 were assessed using a comet assay and micronucleus test, and the Salmonella/microsome mutagenicity assay. In the hot plate test, intrathecal injection of SB-366791 or morphine resulted in significantly increased antinociception in non-tolerant mice. SB-366791 also led to an analgesic effect in the tail flick test. Tolerant mice that received SB-366791 demonstrated a central antinociceptive effect in both thermal tests. No genotoxic effects were observed in the comet assay and no mutagenic effects were detected in the micronucleus test or in the Salmonella/microsome assay. Behavioral results of the thermal nociception tests show that SB-366791 has antinociceptive potential in both morphine-tolerant and non-tolerant mice and does not cause genotoxic or mutagenic effects. Nevertheless, new studies should be performed to clarify the activity and participation of vanilloid channels in the antinociception of SB-366791.

Geraniin attenuates naloxone-precipitated morphine withdrawal and morphine-induced tolerance in mice.

Potentially life-threatening and unpleasant side effects associated with some analgesics have fueled the drive for the search for more analgesics with better side effect profiles. Geraniin, the most dominant secondary metabolite in the aqueous extract of the aerial parts of Phyllanthus muellerianus, has been shown to possess antinociceptive properties mediated partly by opioidergic mechanisms. The purpose of this study is to determine whether geraniin exhibits tolerance and if it is able to ameliorate withdrawal signs in naloxone-precipitated morphine withdrawal. After chronic treatment of mice with geraniin orally, the formalin test was used to ascertain whether tolerance will develop to its antinociceptive effects and if there is morphine-induced tolerance cross-generalization with geraniin. The effect of geraniin on naloxone-precipitated morphine withdrawal signs in morphine-dependent mice was also investigated. Geraniin (3-30 mg/kg) did not produce any tolerant effects after chronic administration and there was also no cross-generalization with the tolerant effects of morphine. Geraniin did not induce withdrawal signs but significantly reduced the number of jumps in morphine-dependent mice. Geraniin does not produce any tolerant effects like morphine and also reduced the signs associated with naloxone-precipitated morphine withdrawal in mice.

Effects of Magnesium sulfate and Bupropion on Morphine Induced tolerance in mice

Introduction: Chronic opiate exposure induces tolerance to opiate analgesic effects. Glutamate system is believed to play a major role in morphine induced tolerance. The inhibitory effects of magnesium sulfate and bupropion on this system are well-studied. The aim of this study was to evaluate the effects of magnesium sulfate and bupropion on the prevention of morphine induced tolerance in mice. Materials and Methods: Animals were divided into the nine groups which received drugs intraperitoneally for four consecutive days according to the following protocol: saline (10 ml/kg) + saline (10 ml/kg), morphine (50 mg/kg) + saline (10 ml/kg), morphine (50 mg/kg) + magnesium sulfate (20, 40 and 60 mg/kg), morphine (50 mg/kg) + bupropion (2, 4 and 8 mg/kg) and morphine (50 mg/kg) + magnesium sulfate (20 mg/kg) + bupropion (2 mg/kg). To evaluate the effects of mentioned drugs on morphine tolerance, a test dose of morphine (9 mg/kg) was administered on the fifth day in all groups. In the hot-plate test, thermal stimulation was measured at time intervals of 0, 15, 30, 45 and 60 minutes. Results: Administration of magnesium sulfate, bupropion and their combination before daily injection of morphine, significantly attenuated tolerance to morphine. Also, the highest tolerance reduction was observed at the 30th minute of the study (P<0.001). Conclusion: Magnesium sulfate and bupropion can be used to attenuate morphine induced tolerance. The possible mechanisms are antagonist behavior on N-methyl-D-aspartate (NMDA) receptor and inhibition of glutamate release, respectively. Key words: Bupropion; Hot plate; Magnesium sulfate; Morphine; Tolerance

Effect of roots aqueous extract of Delphinium denudatum on morphine-induced tolerance in mice

The aqueous extract of Delphinium denudatum (Dd) roots showed a significant effect against morphine- (10 mg/kg) induced tolerance and dependence in mice. Oral administration of the extract (200–1600 mg/kg) showed a significant dose-dependent inhibition of naloxone- (1 mg/kg) induced withdrawal.

Effects of 5-HT receptor antagonists on morphine-induced tolerance in mice

The effect of 5-HT receptor antagonists on tolerance to morphine antinociception was studied in mice. Slow release morphine suspension was injected subcutaneously (s.c.) in order to produce tolerance. When different doses of morphine (3, 6 and 9 mg/kg) were administered on the 4th day after injection of slow-release morphine suspension, tolerance to the test doses of morphine was observed. The tolerance obtained was decreased by pretreatment with the non-selective 5-HT receptor antagonist methysergide (1 and 2 mg/kg) or the 5-HT 2 receptor antagonist ritanserin (1 and 2 mg/kg). When the 5-HT receptor antagonists were used on the 2nd and 3rd day after injection of slow-release morphine suspension or on the 4th day (60 min before last dose of morphine), a maximum reduction in morphine tolerance was observed on the 3rd day. Pretreatment of animals with metergoline (1 and 2 mg/kg) or mianserin (1 and 2 mg/kg) also decreased the tolerance to morphine. It may be concluded that at least a 5-HT 2 receptor mechanism is involved in tolerance to morphine antinociception.

O-283 - Involvement of A1 adenosine receptor in the brain on morphine-induced tolerance in mice.

O-283 - Involvement of A1 adenosine receptor in the brain on morphine-induced tolerance in mice.