scholarly journals Behavioral Consequences of Delta-Opioid Receptor Activation in the Periaqueductal Gray of Morphine Tolerant Rats

2009 ◽  
Vol 2009 ◽  
pp. 1-7 ◽  
Author(s):  
Michael M. Morgan ◽  
Michelle D. Ashley ◽  
Susan L. Ingram ◽  
MacDonald J. Christie
Keyword(s):  
Plasma Membrane ◽  
Morphine Tolerance ◽  
Receptor Activation ◽  
Delta Opioid Receptor ◽  
Morphine Injection ◽  
Chronic Morphine ◽  
Delta Opioid Receptors ◽  
Morphine Administration ◽  
Consistent Manner ◽  
Deltorphin Ii

Chronic morphine administration shifts delta-opioid receptors (DORs) from the cytoplasm to the plasma membrane. Given that microinjection of morphine into the PAG produces antinociception, it is hypothesized that the movement of DORs to the membrane will allow antinociception to the DOR agonist deltorphin II as a way to compensate for morphine tolerance. Tolerance was induced by twice daily injections of morphine (5, 10, or 20 mg/kg, subcutaneous) for 3.5 days. Microinjection of deltorphin into the vPAG 6 hours after the last morphine injection produced a mild antinociception that did not vary in a consistent manner across morphine pretreatment doses or nociceptive tests. In contrast, deltorphin caused a decrease in activity in morphine tolerant rats that was associated with lying in the cage. The decrease in activity and change in behavior indicate that chronic morphine administration alters DORs in the vPAG. However, activation of these receptors does not appear to compensate for the decrease in antinociception caused by morphine tolerance.

Pharmacological blockade of neurokinin1 receptor restricts morphine-induced tolerance and hyperalgesia in the rat

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Mohammad Rahban ◽  
Samira Danyali ◽  
Jalal Zaringhalam ◽  
Homa Manaheji
Keyword(s):  
Side Effects ◽  
Morphine Tolerance ◽  
Laboratory Animals ◽  
Morphine Injection ◽  
Behavioral Tests ◽  
Chronic Morphine ◽  
Treatment Groups ◽  
Morphine Administration ◽  
Before And After ◽  
Induced Tolerance

Abstract Objectives The most notable adverse side effects of chronic morphine administration include tolerance and hyperalgesia. This study investigated the involvement of dorsal root ganglion (DRG) protein kinase Cɛ (PKCɛ) expression during chronic morphine administration and also considered the relationship between DRG PKCɛ expression and the substance P- neurokinin1 receptor (SP- NK1R) activity. Methods Thirty-six animals were divided into six groups (n=6) in this study. In the morphine and sham groups, rats received 10 µg intrathecal (i.t.) morphine or saline for eight consecutive days, respectively. Behavioral tests were performed on days 1 and 8 before and after the first injections and then 48 h after the last injection (day 10). In the treatment groups, rats received NK1R antagonist (L-732,138, 25 µg) daily, either alone or 10 min before a morphine injection, Sham groups received DMSO alone or 10 min before a morphine injection. Animals were sacrificed on days 8 and 10, and DRG PKCɛ and SP expression were analyzed by western blot and immunohistochemistry techniques, respectively. Results Behavioral tests indicated that tolerance developed following eight days of chronic morphine injection. Hyperalgesia was induced 48 h after the last morphine injection. Expression of SP and PKCɛ in DRG significantly increased in rats that developed morphine tolerance on day 8 and hyperalgesia on day 10, respectively. NK1R antagonist (L-732,138) not only blocked the development of hyperalgesia and the increase of PKCɛ expression but also alleviated morphine tolerance. Conclusions Our results provide evidence that DRG PKCɛ and SP-NK1R most likely participated in the generation of morphine tolerance and hyperalgesia. Pharmacological inhibition of SP-NK1R activity in the spinal cord suggests a role for NK1R and in restricting some side effects of chronic morphine. All experiments were performed by the National Institute of Health (NIH) Guidelines for the Care and Use of Laboratory Animals (NIH Publication No. 80-23, revised1996) and were approved by the Animal Ethics Committee of Shahid Beheshti University of Medical Sciences, Tehran, Iran (IR.SBMU.MSP.REC.1396.130).

scholarly journals Enhancement of Spinal N -Methyl-d-aspartate Receptor Function by Remifentanil Action at δ-Opioid Receptors as a Mechanism for Acute Opioid-induced Hyperalgesia or Tolerance

2008 ◽  
Vol 109 (2) ◽  
pp. 308-317 ◽  
Author(s):  
Min Zhao ◽  
Daisy T. Joo
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Activation ◽  
Delta Opioid Receptor ◽  
Receptor Subtype ◽  
Chronic Morphine ◽  
Nmda Current ◽  
Opioid Induced Hyperalgesia ◽  
Response Increase ◽  
Deltorphin Ii

Background Intraoperative remifentanil infusions have been associated with postoperative opioid-induced hyperalgesia and tolerance. Using a previously identified subpopulation of spinal neurons that displays an augmentation in N-methyl-D-aspartate (NMDA) receptor current after chronic morphine, investigations were undertaken to determine whether remifentanil induces acute increases in NMDA responses that are concentration dependent and receptor subtype dependent. Methods Electrophysiologic recordings of NMDA current were made from cultured rat dorsal horn neurons treated with remifentanil at various concentrations for 60 min. Selective mu- or delta-opioid receptor inhibitors and agonists were used to determine the site of action of remifentanil. Results Remifentanil at 4, 6, and 8 nM, but not higher or lower concentrations, caused significant mean increases in NMDA peak current amplitude of 37.30% (P < 0.001), 30.19% (P < 0.001), and 23.52% (P = 0.025), respectively, over control conditions. This occurred by 36 min of remifentanil perfusion and persisted throughout its washout. Inhibition by 100 nM naloxone or 1 nM naltrindole attenuated the remifentanil-induced NMDA response increase. Selective delta-opioid agonists [D-Pen(2), D-Pen(5)]enkephalin and deltorphin II displayed a similar bell-shaped concentration-response relation for the enhancement of NMDA responses, and 10 nM deltorphin II occluded the effects of 4 nM remifentanil on NMDA responses. Conclusions Clinically relevant concentrations of remifentanil induce rapid, persistent increases in NMDA responses that mirror the development of remifentanil-induced hyperalgesia and tolerance. NMDA enhancement by remifentanil is dependent on the activation of both mu- and delta-opioid receptors and is inducible solely by delta-opioid receptor activation. Therefore, selective delta-opioid inhibition may attenuate acute paradoxical increases in pain and tolerance to opioids.

scholarly journals Investigating the effect of Ultra-low dose naloxone on spinal BDNF and KCC2 cotransporter in morphine tolerant and hyperalgesia rats

2020 ◽  
Author(s):  
Mozhgan Baratzadeh ◽  
Samira Danialy ◽  
Jalal Zaringhalam ◽  
HOMA MANAHEJI
Keyword(s):  
Low Dose ◽  
Therapeutic Potential ◽  
Morphine Tolerance ◽  
Tolerance Test ◽  
Morphine Injection ◽  
Behavioral Tests ◽  
Morphine Group ◽  
Chronic Morphine ◽  
Before And After ◽  
Opioid Induced Hyperalgesia

Abstract Background: Chronic opioids administration could lead to several side effects including morphine tolerance and opioid induced hyperalgesia (OIH). Tolerance and hyperalgesia to opiates reduce their effectiveness in the treatment of severe pain. Although the mechanisms are unclear. Recently, we have shown that repeated morphine treatments induced increases in spinal PKCᵧ and GAT-1 expression. In this study we investigate the BDNF and KCC2 expression through ultra-low dose of naloxone coadministration of morphine.Results: In morphine group, rats received 10 mg i.p. morphine and in treatment group 15ng ultra-low dose of naloxone with morphine for consecutive 8 days. Behavioral tests were performed on day 1 before and after the morphine injection, day 5, 8 (tolerance test) and 10, 48h after last morphine injection (opioid induced hyperalgesia OIH test). A number of rats were sacrificed on day 8 and others on day 10, then expression of BDNF and KCC2 were analyzed by western blot and immunohistochemistry techniques, respectively. Behavioral tests suggested that following 8 days of chronic morphine injection tolerance developed. OIH was shown 48 hours after the last morphine injection. Expression of BDNF significantly was increased and KCC2 downregulated in rats that developed morphine tolerance and OIH respectively. Ultra-low dose of naloxone by decreasing BDNF and increasing KCC2 was able to suppress development of OIH and alleviated morphine tolerance.Conclusions: Our data suggest that BDNF and KCC2 maybe candidate molecules which are involved in tolerance and OIH. Ultra- low dose of naloxone along morphine might be a valuable therapeutic potential for controlling hypersensitivity following chronic morphine administration.

Melatonin Reduce Morphine-Induced Hyperalgesia and Tolerance of Rats via melatonin-MT1-PKCγ Pathway.

2020 ◽  
Author(s):  
Yuchao Fan ◽  
Xiao Liang ◽  
Bixin Zheng ◽  
Li Song
Keyword(s):  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Morphine Tolerance ◽  
Melatonin Level ◽  
Chronic Morphine ◽  
Lower Serum ◽  
Regulation Of Expression ◽  
Spinal Dorsal ◽  
Sd Rats ◽  
Morphine Administration

Abstract Background: Morphine is commonly used for treating acute and chronic pain. However, its using is complicated with tolerance and hyperalgesia. Endogenous melatoninergic system is involved in development of tolerance and hyperalgesia induced by chronic morphine administration, but the precise mechanism remains unknown. Methods: 18 male SD rats were randomly divided into Saline(Sal), Morphine(Mor) and Morphine+Chelerythrine (Mor+Che) group (n = 6, respectively). Each group were received twice-daily intrathecal injections of saline (10μl), morphine (15μg/10μl) or morphine (15μg/5μl)+ chelerythrine (5μg/5μl) for consecutive 9 days, respectively. MWT and TWL of all animals were recorded on day 1, 3, 5, 7, 9. The morphine tolerance was depicted as MPAE on day 1, 3, 5, 7, 9 and on day 10 which can be used to calculate for ED50 of each group. Then we determined the serum level of melatonin by ELISA and expression of MOR , MT1, MT2 and PKCγ by RT-qPCR and WB in spinal dorsal horn of three group rats.Results: Comparing with Sal group, the Mor group exhibited a significant lower serum melatonin level and up-regulation of expression of the MT1, MT2 and PKCγ in the spinal dorsal horn. Co-administration of chelerythrine with morphine not only attenuates morphine-induced hyperalgesia and tolerance, but also increases the down-regulation of serum melatonin level) and reduces the up-regulation of expression of MT1 and PKCγ in spinal dorsal horn compared with Mor group. Conclusion：Melatonin can reduce morphine-induced hyperalgesia and tolerance of rats via melatonin-MT1-PKCγ pathway.

scholarly journals Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/β-catenin pathway

2018 ◽  
Vol 115 (9) ◽  
pp. E2085-E2094 ◽  
Author(s):  
Sevasti Gaspari ◽  
Immanuel Purushothaman ◽  
Valeria Cogliani ◽  
Farhana Sakloth ◽  
Rachael L. Neve ◽  
...  
Keyword(s):  
Analgesic Efficacy ◽  
Opioid Analgesics ◽  
Morphine Tolerance ◽  
Protein Signaling ◽  
Chronic Morphine ◽  
Analgesic Tolerance ◽  
Biochemical Assays ◽  
Morphine Administration ◽  
Promising Target

Regulator of G protein signaling z1 (RGSz1), a member of the RGS family of proteins, is present in several networks expressing mu opioid receptors (MOPRs). By using genetic mouse models for global or brain region-targeted manipulations of RGSz1 expression, we demonstrated that the suppression of RGSz1 function increases the analgesic efficacy of MOPR agonists in male and female mice and delays the development of morphine tolerance while decreasing the sensitivity to rewarding and locomotor activating effects. Using biochemical assays and next-generation RNA sequencing, we identified a key role of RGSz1 in the periaqueductal gray (PAG) in morphine tolerance. Chronic morphine administration promotes RGSz1 activity in the PAG, which in turn modulates transcription mediated by the Wnt/β-catenin signaling pathway to promote analgesic tolerance to morphine. Conversely, the suppression of RGSz1 function stabilizes Axin2–Gαz complexes near the membrane and promotes β-catenin activation, thereby delaying the development of analgesic tolerance. These data show that the regulation of RGS complexes, particularly those involving RGSz1-Gαz, represents a promising target for optimizing the analgesic actions of opioids without increasing the risk of dependence or addiction.

Chronic morphine administration results in tolerance to delta opioid receptor-mediated antinociception

Neuroscience ◽  
2006 ◽  
Vol 141 (2) ◽  
pp. 947-954 ◽  
Author(s):  
A.A.A. Pradhan ◽  
C. Siau ◽  
A. Constantin ◽  
P.B.S. Clarke
Keyword(s):  
Opioid Receptor ◽  
Delta Opioid Receptor ◽  
Chronic Morphine ◽  
Morphine Administration

scholarly journals Morphine tolerance is attenuated in germfree mice and reversed by probiotics, implicating the role of gut microbiome

2019 ◽  
Vol 116 (27) ◽  
pp. 13523-13532 ◽  
Author(s):  
Li Zhang ◽  
Jingjing Meng ◽  
Yuguang Ban ◽  
Richa Jalodia ◽  
Irina Chupikova ◽  
...  
Keyword(s):  
Bacterial Communities ◽  
Prolonged Exposure ◽  
Morphine Tolerance ◽  
Fecal Microbiota ◽  
Chronic Morphine ◽  
Analgesic Tolerance ◽  
Microbial Dysbiosis ◽  
Morphine Administration ◽  
Selective Depletion

Prolonged exposure to opioids results in analgesic tolerance, drug overdose, and death. The mechanism underlying morphine analgesic tolerance still remains unresolved. We show that morphine analgesic tolerance was significantly attenuated in germfree (GF) and in pan-antibiotic−treated mice. Reconstitution of GF mice with naïve fecal microbiota reinstated morphine analgesic tolerance. We further demonstrated that tolerance was associated with microbial dysbiosis with selective depletion in Bifidobacteria and Lactobacillaeae. Probiotics, enriched with these bacterial communities, attenuated analgesic tolerance in morphine-treated mice. These results suggest that probiotic therapy during morphine administration may be a promising, safe, and inexpensive treatment to prolong morphine’s efficacy and attenuate analgesic tolerance. We hypothesize a vicious cycle of chronic morphine tolerance: morphine-induced gut dysbiosis leads to gut barrier disruption and bacterial translocation, initiating local gut inflammation through TLR2/4 activation, resulting in the activation of proinflammatory cytokines, which drives morphine tolerance.

scholarly journals An Emerging Role for the Delta Opioid Receptor in the Regulation of Mu Opioid Receptor Function

2007 ◽  
Vol 7 ◽  
pp. 64-73 ◽  
Author(s):  
Raphael Rozenfeld ◽  
Noura S. Abul-Husn ◽  
Ivone Gomez ◽  
Lakshmi A. Devi
Keyword(s):  
Opioid Receptor ◽  
Critical Role ◽  
Site Occupancy ◽  
Morphine Tolerance ◽  
Delta Opioid Receptor ◽  
Receptor Binding Site ◽  
Delta Opioid Receptors ◽  
Physiological Adaptations ◽  
Opiate Tolerance ◽  
The Impact

Morphine and related opiates are commonly used in the clinical management of various types of pain. However, the antinociceptive properties of morphine are often overshadowed by the development of tolerance and dependence following its chronic use. The mechanisms underlying opiate tolerance are not fully understood, but appear to involve numerous and complex physiological adaptations. Recently, a role for the heterodimerization of mu and delta opioid receptors in the development of morphine tolerance has been proposed. This novel mechanism could help us to understand several observations, such as the critical role of delta opioid receptor regulation, the impact of delta opioid receptor binding site occupancy, and the participation of beta-arrestin2, in the development of morphine tolerance.

Morphine Tolerance in Mice Changes Response of Heroin from mu to delta Opioid Receptors

2000 ◽  
Vol 224 (2) ◽  
pp. 93-101 ◽  
Author(s):  
Jodie J. Rady ◽  
Blythe B. Holmes ◽  
Philip S. Portoghese ◽  
James M. Fujimoto
Keyword(s):  
Opioid Receptors ◽  
Morphine Tolerance ◽  
Delta Opioid Receptors

scholarly journals Revising Endosomal Trafficking under Insulin Receptor Activation

2021 ◽  
Vol 22 (13) ◽  
pp. 6978
Author(s):  
Maria J. Iraburu ◽  
Tommy Garner ◽  
Cristina Montiel-Duarte
Keyword(s):  
Plasma Membrane ◽  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
Small Gtpases ◽  
Early Endosome ◽  
Tyrosine Kinase Receptors ◽  
Endosomal Trafficking ◽  
Cell Functions

The endocytosis of ligand-bound receptors and their eventual recycling to the plasma membrane (PM) are processes that have an influence on signalling activity and therefore on many cell functions, including migration and proliferation. Like other tyrosine kinase receptors (TKR), the insulin receptor (INSR) has been shown to be endocytosed by clathrin-dependent and -independent mechanisms. Once at the early endosome (EE), the sorting of the receptor, either to the late endosome (LE) for degradation or back to the PM through slow or fast recycling pathways, will determine the intensity and duration of insulin effects. Both the endocytic and the endosomic pathways are regulated by many proteins, the Arf and Rab families of small GTPases being some of the most relevant. Here, we argue for a specific role for the slow recycling route, whilst we review the main molecular mechanisms involved in INSR endocytosis, sorting and recycling, as well as their possible role in cell functions.

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