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Eckard Weber - One of the best experts on this subject based on the ideXlab platform.
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acea 1328 a nmda receptor glycine site antagonist acutely potentiates Antinociception and chronically attenuates tolerance induced by morphine
Pharmacological Research, 1999Co-Authors: Kabirullah Lutfy, Peter Doan, Eckard WeberAbstract:Abstract The effect of ACEA-1328, a competitive and systemically bioavailable NMDA receptor/glycine site antagonist, was studied on Morphine-Induced Antinociception and tolerance in CD-1 mice using the tail flick test. To study the effect of acute administration of ACEA-1328 on Morphine-Induced Antinociception, mice were injected with either ACEA-1328 (1, 5, and 10 mg kg−1) or Bis–Tris (0.2 m ) immediately followed by an injection of morphine and tested for Antinociception 30 min later. ACEA-1328 significantly increased the antinociceptive potency of morphine. To study the effect of chronic administration of ACEA-1328 on Morphine-Induced Antinociception and tolerance, mice were treated, either once per day for 9 days or twice daily for 4 days, with ACEA-1328 or with the vehicle. Mice were then, within 1 min, injected daily with either morphine or saline. On the day of the test, mice were injected with only morphine and tested for Antinociception 30 min later. In comparison to the acute effect of ACEA-1328, chronic treatment with the NMDA receptor/glycine site antagonist did not affect the antinociceptive potency of morphine. Chronic treatment with morphine, by both methods, produced a significant degree of tolerance. Concurrent administration of ACEA-1328 with the opioid analgesic completely blocked morphine tolerance. Our results demonstrate that acute, but not chronic, treatment with ACEA-1328 increased the antinociceptive potency of morphine. Furthermore, co-admin- istration of the NMDA receptor antagonist with morphine abolished the development of tolerance. Overall, the data support a growing body of evidence showing that activation of the NMDA receptor plays a functional role in opioid-induced Antinociception and tolerance.
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blockade of morphine tolerance by acea 1328 a novel nmda receptor glycine site antagonist
European Journal of Pharmacology, 1995Co-Authors: Kabirullah Lutfy, Ke Zhong Shen, Ik Sung Kwon, Sui Xiong Cai, Richard M Woodward, John F W Keana, Eckard WeberAbstract:Recent studies indicate that competitive and non-competitive NMDA receptor antagonists can block the development of morphine tolerance. Since glycine is considered to be a co-agonist for activation of NMDA receptors we examined the effect of a novel bioavailable NMDA receptor/glycine site antagonist, 5-nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1328), on the development of morphine tolerance. Administration of ACEA-1328 (20 mg/kg) completely blocked tolerance to Morphine-Induced Antinociception in the tail flick test in CD-1 mice, without affecting the basal nociceptive response or potentiating Morphine-Induced antinociceptive effects. These data suggest that inhibition of NMDA receptor activity via blockade of the glycine co-agonist site is potentially viable as a therapeutic approach for preventing development of morphine tolerance.
Kabirullah Lutfy - One of the best experts on this subject based on the ideXlab platform.
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acea 1328 a nmda receptor glycine site antagonist acutely potentiates Antinociception and chronically attenuates tolerance induced by morphine
Pharmacological Research, 1999Co-Authors: Kabirullah Lutfy, Peter Doan, Eckard WeberAbstract:Abstract The effect of ACEA-1328, a competitive and systemically bioavailable NMDA receptor/glycine site antagonist, was studied on Morphine-Induced Antinociception and tolerance in CD-1 mice using the tail flick test. To study the effect of acute administration of ACEA-1328 on Morphine-Induced Antinociception, mice were injected with either ACEA-1328 (1, 5, and 10 mg kg−1) or Bis–Tris (0.2 m ) immediately followed by an injection of morphine and tested for Antinociception 30 min later. ACEA-1328 significantly increased the antinociceptive potency of morphine. To study the effect of chronic administration of ACEA-1328 on Morphine-Induced Antinociception and tolerance, mice were treated, either once per day for 9 days or twice daily for 4 days, with ACEA-1328 or with the vehicle. Mice were then, within 1 min, injected daily with either morphine or saline. On the day of the test, mice were injected with only morphine and tested for Antinociception 30 min later. In comparison to the acute effect of ACEA-1328, chronic treatment with the NMDA receptor/glycine site antagonist did not affect the antinociceptive potency of morphine. Chronic treatment with morphine, by both methods, produced a significant degree of tolerance. Concurrent administration of ACEA-1328 with the opioid analgesic completely blocked morphine tolerance. Our results demonstrate that acute, but not chronic, treatment with ACEA-1328 increased the antinociceptive potency of morphine. Furthermore, co-admin- istration of the NMDA receptor antagonist with morphine abolished the development of tolerance. Overall, the data support a growing body of evidence showing that activation of the NMDA receptor plays a functional role in opioid-induced Antinociception and tolerance.
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blockade of morphine tolerance by acea 1328 a novel nmda receptor glycine site antagonist
European Journal of Pharmacology, 1995Co-Authors: Kabirullah Lutfy, Ke Zhong Shen, Ik Sung Kwon, Sui Xiong Cai, Richard M Woodward, John F W Keana, Eckard WeberAbstract:Recent studies indicate that competitive and non-competitive NMDA receptor antagonists can block the development of morphine tolerance. Since glycine is considered to be a co-agonist for activation of NMDA receptors we examined the effect of a novel bioavailable NMDA receptor/glycine site antagonist, 5-nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1328), on the development of morphine tolerance. Administration of ACEA-1328 (20 mg/kg) completely blocked tolerance to Morphine-Induced Antinociception in the tail flick test in CD-1 mice, without affecting the basal nociceptive response or potentiating Morphine-Induced antinociceptive effects. These data suggest that inhibition of NMDA receptor activity via blockade of the glycine co-agonist site is potentially viable as a therapeutic approach for preventing development of morphine tolerance.
Jean M Bidlack - One of the best experts on this subject based on the ideXlab platform.
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mice with high fgf21 serum levels had a reduced preference for morphine and an attenuated development of acute antinociceptive tolerance and physical dependence
Neuropharmacology, 2022Co-Authors: Louben Dorval, Brian I Knapp, Olufolake A Majekodunmi, Sophia Eliseeva, Jean M BidlackAbstract:Abstract Because of increased opioid misuse, there is a need to identify new targets for minimizing opioid tolerance, and physical and psychological dependence. Previous studies showed that fibroblast growth factor 21 (FGF21) decreased alcohol and sweet preference in mice. In this study, FGF21-transgenic (FGF21-Tg) mice, expressing high FGF21 serum levels, and wildtype (WT) C57BL/6J littermates were treated with morphine and saline to determine if differences exist in their physiological and behavioral responses to opioids. FGF21-Tg mice displayed reduced preference for morphine in the conditioned place preference assay compared to WT littermates. Similarly, FGF21-Tg mice had an attenuation of the magnitude and rate of acute morphine antinociceptive tolerance development, and acute and chronic morphine physical dependence, but exhibited no change in chronic morphine antinociceptive tolerance. The ED50 values for Morphine-Induced Antinociception in the 55 °C hot plate and the 55 °C warm-water tail withdrawal assays were similar in both strains of mice. Likewise, FGF21-Tg and WT littermates had comparable responses to Morphine-Induced respiratory depression. Overall, FGF21-Tg mice had a decrease in the development of acute analgesic tolerance, and the development of physical dependence, and morphine preference. FGF21 and its receptor have therapeutic potential for reducing opioid withdrawal symptoms and craving, and augmenting opioid therapeutics for acute pain patients to minimize tolerance development.
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mice with high fgf21 serum levels had a reduced preference for morphine and an attenuated development of acute antinociceptive tolerance and physical dependence
bioRxiv, 2021Co-Authors: Louben Dorval, Brian I Knapp, Olufolake A Majekodunmi, Sophia Eliseeva, Jean M BidlackAbstract:As a result of the opioid epidemic, there is a desire to identify new targets for treating opioid use disorder. Previous studies showed that fibroblast growth factor 21 (FGF21) decreased alcohol and sweet preference in mice. In this study, FGF21-transgenic (FGF21-Tg) mice, expressing high FGF21 serum levels, and wildtype (WT) C57BL/6J littermates were treated with morphine and saline to determine if differences exist in their physiological and behavioral responses to opioids. FGF21-Tg mice displayed reduced preference for morphine in the conditioned place preference assay compared to WT littermates. Similarly, FGF21-Tg mice had an attenuation of the magnitude and rate of acute morphine antinociceptive tolerance development, and acute and chronic morphine physical dependence, but exhibited no change in chronic morphine antinociceptive tolerance. The ED50 values for Morphine-Induced Antinociception in the 55-degree C hot plate and the 55-degree C warm-water tail withdrawal assays were similar in both strains of mice. Likewise, FGF21-Tg and WT littermates had comparable responses to Morphine-Induced respiratory depression. Overall, FGF21-Tg mice had an attenuated preference for morphine, a reduced development of Morphine-Induced dependence, and a reduction in the development of acute morphine antinociceptive tolerance. FGF21 and its receptor have therapeutic potential for reducing opioid withdrawal symptoms and craving, and augmenting opioid therapeutics for acute pain treatment.
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characterization of a novel bivalent morphinan possessing κ agonist and μ agonist antagonist properties
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Jennifer L. Mathews, John L. Neumeyer, Ao Zhang, Wennan Xiong, Xuemei Peng, Stevens S Negus, Jean M BidlackAbstract:Previous research has shown that compounds with mixed κ and μ activity may have utility for the treatment of cocaine abuse and dependence. The present study characterizes the pharmacological profile of a bivalent morphinan that was shown to be a κ opioid receptor agonist and a μ opioid receptor agonist/antagonist. MCL-145 [bis( N -cyclobutylmethylmorphinan) fumarate] is related to the morphinan cyclorphan and its N -cyclobutylmethyl derivative MCL-101 [3-hydroxy- N -cyclobutylmethyl morphinan S -(+)-mandelate]. MCL-145 consists of two morphinans connected by a spacer at the 3-hydroxy position. This compound had K i values of 0.078 and 0.20 nM for the κ and μ opioid receptors, respectively, using radioligand binding assays as shown by [Neumeyer et al. in 2003][1]. In the guanosine 5′- O -(3-[35 S]thiotriphosphate) binding assay, MCL-145 produced an E max value of 80% for the κ opioid receptor and 42% for the μ opioid receptor. The EC50 values obtained for this compound were 4.3 and 3.1 nM for the κ and μ opioid receptors, respectively. In vivo MCL-145 produced a full dose-response curve in the 55°C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the μ-selective antagonist β-funaltrexamine and the κ-selective antagonist nor-binaltorphimine. MCL-145 also acted as a μ antagonist, as measured by the inhibition of Morphine-Induced Antinociception. [1]: #ref-20
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8-Carboxamidocyclazocine: A Long-Acting, Novel Benzomorphan
The Journal of pharmacology and experimental therapeutics, 2002Co-Authors: Jean M Bidlack, Dana J. Cohen, Jay P. Mclaughlin, Rongliang Lou, Mark P. WentlandAbstract:To obtain benzomorphans with a longer duration of action that may be potential therapeutics for treating cocaine abuse, 8-carboxamidocyclazocine was synthesized. The pharmacological properties of 8-carboxamidocyclazocine were compared with the parent compound cyclazocine. Changing the 8-hydroxyl group on cyclazocine to an 8-carboxamido group resulted in only a 2-fold decrease in the affinity of the compound for the κ-receptor, and no change in the affinity for the μ-opioid receptor, with both compounds having K i values of less than 1 nM, based on radioligand binding assays. In the guanosine 5′- O -(3-[35S]thio)triphosphate ([35S]GTPγS) binding assay, the two compounds produced moderate stimulation of GTP binding to the human κ- and μ-receptors. When given by i.c.v. injection, the compounds produced less than 60% Antinociception in the mouse 55°C warm-water tail-flick test. However, in the mouse writhing test, the compounds had high potency in producing Antinociception. Antinociception induced by either 8-carboxamidocyclazocine or cyclazocine was mediated by both κ- and μ-opioid receptors. Cyclazocine acted as a μ-antagonist in addition to its agonist properties at the μ-receptor, as measured by the inhibition of Morphine-Induced Antinociception. In contrast, 8-carboxamidocyclazocine did not inhibit Morphine-Induced Antinociception, demonstrating that it was not a μ-opioid receptor antagonist in this assay. An i.p. injection of an ED70 dose of 8-carboxamidocyclazocine produced Antinociception that lasted for 15 h in contrast to cyclazocine, which produced Antinociception, lasting 2 h. 8-Carboxamidocyclazocine is a novel, long-acting benzomorphan, which possesses pharmacological properties that are distinct from the properties of cyclazocine.
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n cyclobutylmethyl analog of normorphinone n cbm tamo a short term opioid agonist and long term mu selective irreversible opioid antagonist
Journal of Pharmacology and Experimental Therapeutics, 1996Co-Authors: Ahmad Seyedmozaffari, Sydney Archer, Jean M BidlackAbstract:The antinociceptive and opioid binding properties of the N-cyclobutylmethyl analog of normorphinone, 14 alpha, 149 beta-[dithiobis[(2-oxo-2, 1-ethanediyl)imino]]bis[7,8-dihydro-N-(cyclobutylmethyl)-normor phinone] (N-CBM-TAMO) were investigated. This compound is a dimer, containing a disulfide capable of binding to thiol groups on the opioid receptor. Competition radioligand binding assays with bovine striatal membranes demonstrated that N-CBM-TAMO displayed a higher affinity for mu opioid receptors than for kappa and delta receptors. Incubation of membranes with N-CBM-TAMO resulted in wash-resistant inhibition of the binding of the mu-selective peptide [3H][D-Ala2,(Me)Phe4, Gly(ol)5]-enkephalin, the kappa-selective opioid [3H]U69,593 ((trans)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide+ ++ methanesulfonate hydrate)) and, to a lesser extent, the delta-selective peptide [D-Pen2, p-Cl-phenylalanine4, D-Pen5]enkephalin. Scatchard analysis of saturation binding data showed that N-CBM-TAMO decreased the Bmax value without affecting the Kd value for [3H][D-Ala2,(Me)Phe4, Gly(ol)5]enkephalin binding, whereas, N-CBM-TAMO increased the Kd value without altering the Bmax value for [3H]U69,593, which suggests that N-CBM-TAMO interacted covalently with the mu but not the kappa receptor. In the mouse 55 degrees C warm-water tail-flick test, N-CBM-TAMO given supraspinally acted as an agonist with low efficacy because only submaximal Antinociception was observed at doses up to 100 nmol. The Antinociception induced by N-CBM-TAMO in the tail-flick test was partially blocked by both the mu-selective antagonist beta-funaltrexamine and the kappa-selective antagonist nor-binaltorphimine. In the mouse acetic acid writhing test, N-CBM-TAMO acted as a full agonist with a D50 value of 0.08 (0.04-0.14) nmol, and the Antinociception was blocked by coadministration of the kappa-selective antagonist nor-binaltorphimine. Pretreatment of mice with an i.c.v. dose of N-CBM-TAMO of 10 nmol, a dose that exhibited modest short-term Antinociception in the tail-flick test, produced a time- and dose-dependent long-term antagonism of Morphine-Induced Antinociception in an irreversible manner in this assay. Pretreatment of mice with i.c.v. N-CBM-TAMO at doses of 3 nmol and higher, which produced supermaximal short-term Antinociception in the writhing test, produced a time- and dose-dependent long-term antagonism of U50,488 (trans)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate hydrate)-induced Antinociception in a reversible manner, probably because of the development of tolerance. These in vivo data, together with the in vitro binding data, demonstrate that N-CBM-TAMO is a potent kappa agonist and at higher doses produces Antinociception mediated by mu receptors. N-CBM-TAMO also produces long-term noncompetitive antagonism of Antinociception mediated by mu opioid receptors.
Abbas Haghparast - One of the best experts on this subject based on the ideXlab platform.
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analgesic effect of morphine microinjected into the nucleus raphe magnus after electrolytic lesion of nucleus cuneiformis in tail flick and formalin tests in rat
Physiology and Pharmacology, 2011Co-Authors: Leila Ahmadmolaei, Mehdi Ordikhaniseyedlar, Maryam Ziaei, Raha Khademi, Pegah Rouzmeh, Abbas HaghparastAbstract:Introduction: The antinociceptive effect of morphine is, in part, mediated through the activation of a descending pathway. One of the major components of this pathway is the nucleus raphe magnus (NRM). Our previous study demonstrated the involvement of NRM in the analgesic effect of morphine microinjected into the nucleus cuneiformis (NCF) in a descending manner. The aim of the current study was to investigate another aspect of the interaction between these two nuclei in both acute and chronic inflammatory pain models. Methods: In order to calculate 50% effective dose (ED50) of morphine, animals received bilateral morphine injections (1, 2.5, 5 and 10 μg/0.5 μl saline) into the NRM. The obtained ED50 of morphine was applied into the NRM with/without bilateral electrolytic lesion (500 μA, 30 sec) of the NCF. Tail-flick and formalin tests were applied as behavioral analgesic tests in this study. Results: Results interestingly showed that the intra-NRM morphine injection (ED50; 1 μg/0.5 μl saline) resulted in an increase in tail flick latencies (Morphine-Induced Antinociception) at 30-min intervals, while bilateral electrolytic lesions in the NCF could notably decreased the Morphine-Induced Antinociception during 30-90 min after the injection of morphine. Data also showed that bilateral morphine microinjected into the NRM, dose-dependently increases the antinociceptive responses during both early and late phases of formalin test. The antinociceptive effect of morphine microinjected into the NRM was significantly attenuated at the late phase but not early phase following the bilateral destruction of NCF in formalin test. Conclusion: It could be concluded that there is a reciprocal interaction between NRM and NCF during morphine induced Antinociception in both acute and chronic inflammatory pain models in rat.
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Contribution of the Nucleus Cuneiformis to the Antinociceptive Effects of Systemic Morphine on Inflammatory Pain in Rats
Iran University of Medical Sciences, 2011Co-Authors: Abdolaziz Ronaghi, Mohammad Ebrahimzadeh, Abbas HaghparastAbstract:Introduction: The role of midbrain reticular formation, which includes the nucleus cuneiformis (NCF), as a crucial antinociceptive region in descending pain modulation has long been investigated. In this study, we tried to highlight the role of NCF in Morphine-Induced Antinociception in formalin-induced pain model in rats. Methods: A total of 201 male Wistar rats weighing 260-310 g were used in this study. The effective dose of morphine in systemic administration (intraperitoneal i.p.) was determined after a dose- and time-response protocol. In consequent groups, bilateral electrolytic lesion (500 μA, 30 sec) or reversible inactivation (lidocaine 2%) were used in the NCF before systemic administration of morphine, and then, the nociceptive test was immediately carried out. Results: The results showed that administration of 6 mg/kg morphine, 30 min before the formalin test, is the best dose- and time-response set in these experiments. The obtained data also indicated that bilateral electrical destruction or reversible inactivation of the NCF significantly decreased antinociceptive responses of systemic morphine (6 mg/kg i.p.) during the second phase of formalin test (P
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Contribution of the Nucleus Cuneiformis to the Antinociceptive Effects of Systemic Morphine on Inflammatory Pain in Rats
Iran University of Medical Sciences, 2011Co-Authors: Abdolaziz Ronaghi, Mohammad Ebrahimzadeh, Abbas HaghparastAbstract:Introduction: The role of midbrain reticular formation, which includes the nucleus cuneiformis (NCF), as a crucial antinociceptive region in descending pain modulation has long been investigated. In this study, we tried to highlight the role of NCF in Morphine-Induced Antinociception in formalin-induced pain model in rats. Methods: A total of 201 male Wistar rats weighing 260-310 g were used in this study. The effective dose of morphine in systemic administration (intraperitoneal; i.p.) was determined after a dose- and time-response protocol. In consequent groups, bilateral electrolytic lesion (500 μA, 30 sec) or reversible inactivation (lidocaine 2%) were used in the NCF before systemic administration of morphine, and then, the nociceptive test was immediately carried out. Results: The results showed that administration of 6 mg/kg morphine, 30 min before the formalin test, is the best dose- and time-response set in these experiments. The obtained data also indicated that bilateral electrical destruction or reversible inactivation of the NCF significantly decreased antinociceptive responses of systemic morphine (6 mg/kg; i.p.) during the second phase of formalin test (P<0.05). Discussion: Therefore, it seems that opioid receptors located in the NCF may be involved in modulation of central sensitization which occurred in inflammatory pain in rats
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electrolytic lesion of the nucleus raphe magnus reduced the antinociceptive effects of bilateral morphine microinjected into the nucleus cuneiformis in rats
Neuroscience Letters, 2008Co-Authors: Abbas Haghparast, Mehdi Ordikhaniseyedlar, Maryam ZiaeiAbstract:Several lines of investigation show that the rostral ventromedial medulla is a critical relay for midbrain regions, including the nucleus cuneiformis (CnF), which control nociception at the spinal cord. There is some evidence that local stimulation or morphine administration into the CnF produces the effective analgesia through the nucleus raphe magnus (NRM). The present study tries to determine the effect of Morphine-Induced analgesia following microinjection into the CnF in the absence of NRM. Seven days after the cannulae implantation, morphine was microinjected bilaterally into the CnF at the doses of 0.25, 1, 2.5, 5, 7.5 and 10 microg/0.3 microl saline per side. The Morphine-Induced antinociceptive effect measured by tail-flick test at 30, 60, 90 and 120 min after microinjection. The results showed that bilateral microinjection of morphine into the CnF dose-dependently causes increase in tail-flick latency (TFL). The 50% effective dose of morphine was determined and microinjected into the CnF (2.5 microg/0.3 microl saline per side) in rats after NRM electrolytic lesion (1 mA, 30 s). Lesion of the NRM significantly decreased TFLs, 30 (P<0.01) and 60 (P<0.05) but not 90-120 min after morphine microinjection into the CnF, compared with sham-lesion group. We concluded that morphine induces the analgesic effects through the opioid receptors in the CnF. It is also appeared that Morphine-Induced Antinociception decreases following the NRM lesion but it seems that there are some other descending pain modulatory pathways that activate in the absence of NRM.
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role of glutamatergic receptors located in the nucleus raphe magnus on antinociceptive effect of morphine microinjected into the nucleus cuneiformis of rat
Neuroscience Letters, 2007Co-Authors: Abbas Haghparast, Ava Soltanihekmat, Abbas Khani, Alireza KomakiAbstract:Abstract Neurons in the nucleus cuneiformis (CnF), located just ventrolateral to the periaqueductal gray, project to medullary nucleus raphe magnus (NRM), which is a key medullary relay for descending pain modulation and is critically involved in opioid-induced analgesia. Previous studies have shown that antinociceptive response of CnF-microinjected morphine can be modulated by the specific subtypes of glutamatergic receptors within the CnF. In this study, we evaluated the role of NMDA and kainate/AMPA receptors that are widely distributed within the NRM on Morphine-Induced Antinociception elicited from the CnF. Hundred and five male Wistar rats weighing 250–300 g were used. Morphine (10, 20 and 40 μg) and NMDA receptor antagonist, MK-801 (10 μg) or kainate/AMPA receptor antagonist, DNQX (0.5 μg) in 0.5 μl saline were stereotaxically microinjected into the CnF and NRM, respectively. The latency of tail-flick response was measured at set intervals (2, 7, 12, 17, 22, 27 min after microinjection) by using an automated tail-flick analgesiometer. The results showed that morphine microinjection into the CnF dose-dependently causes increase in tail-flick latency (TFL). MK-801 microinjected into the NRM, just 1 min before morphine injection into the CnF, significantly attenuated antinociceptive effects of morphine. On the other hand, DNQX microinjected into the NRM, significantly increased TFL after local application of morphine into the CnF. We suggest that morphine related antinociceptive effect elicited from the CnF is mediated, in part, by NMDA receptor at the level of the NRM whereas kainite/AMPA receptor has a net inhibitory influence at the same pathway.
Jose M Baeyens - One of the best experts on this subject based on the ideXlab platform.
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potentiation of morphine induced mechanical Antinociception by σ1 receptor inhibition role of peripheral σ1 receptors
Neuropharmacology, 2013Co-Authors: Cristina Sanchezfernandez, Jose M Baeyens, F Nieto, Rafael Gonzalezcano, Antonia Artachocordon, Lucia Romero, Angeles Montillagarcia, Daniel Zamanillo, Jose Manuel Entrena, Enrique J CobosAbstract:We studied the modulation of Morphine-Induced mechanical Antinociception and side effects by σ₁ receptor inhibition. Both wild-type (WT) and σ₁ receptor knockout (σ₁-KO) mice showed similar responses to paw pressure (100-600 g). The systemic (subcutaneous) or local (intraplantar) administration of σ₁ antagonists (BD-1063, BD-1047, NE-100 and S1RA) was devoid of antinociceptive effects in WT mice. However, σ₁-KO mice exhibited an enhanced mechanical Antinociception in response to systemic morphine (1-16 mg/kg). Similarly, systemic treatment of WT mice with σ₁ antagonists markedly potentiated Morphine-Induced Antinociception, and its effects were reversed by the selective σ₁ agonist PRE-084. Although the local administration of morphine (50-200 μg) was devoid of antinociceptive effects in WT mice, it induced dose-dependent Antinociception in σ₁-KO mice. This effect was limited to the injected paw. Enhancement of peripheral morphine Antinociception was replicated in WT mice locally co-administered with σ₁ antagonists and the opioid. None of the σ₁ antagonists tested enhanced morphine-Antinociception in σ₁-KO mice, confirming a σ₁-mediated action. Morphine-Induced side-effects (hyperlocomotion and inhibition of gastrointestinal transit) were unaltered in σ₁-KO mice. These results cannot be explained by a direct interaction of σ₁ ligands with μ-opioid receptors or adaptive changes of μ-receptors in σ₁-KO mice, given that [(3)H]DAMGO binding in forebrain, spinal cord, and hind-paw skin membranes was unaltered in mutant mice, and none of the σ₁ drugs tested bound to μ-opioid receptors. These results show that σ₁ receptor inhibition potentiates Morphine-Induced mechanical analgesia but not its acute side effects, and that this enhanced analgesia can be induced at peripheral level.
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effects of serine threonine protein phosphatase inhibitors on morphine induced Antinociception in the tail flick test in mice
European Journal of Pharmacology, 2003Co-Authors: Ana Moncada, Jose M Baeyens, Cruz Miguel Cendan, Esperanza Del PozoAbstract:The aim of this study was to evaluate the effects of serine/threonine protein phosphatase (PP) inhibitors on Morphine-Induced Antinociception in the tail flick test in mice, and on [3H]naloxone binding to the forebrain crude synaptosome fraction. Neither okadaic acid nor cantharidin (1-10000 nM) displaced [3H]naloxone from its specific binding sites, which indicates that they do not interact at the opioid receptor level. The i.c.v. administration of very low doses of okadaic acid (0.001-1 pg/mouse) and cantharidin (0.001-1 ng/mouse), which inhibit PP2A, produced a dose-dependent antagonism of the Antinociception induced by morphine (s.c.). However, L-nor-okadaone (0.001 pg/mouse-1 ng/mouse, i.c.v.), an analogue of okadaic acid lacking activity against protein phosphatases, did not affect the antinociceptive effect of morphine. On the other hand, high doses of okadaic acid (10 ng/mouse, i.c.v.) and cantharidin (1 microg/mouse, i.c.v.), which also block PP1, and calyculin-A (0.1 fg/mouse-1 ng/mouse, i.c.v.), which inhibits equally both PP1 and PP2A, did not modify the Morphine-Induced Antinociception. These results suggest that the activation of type 2A serine/threonine protein phosphatases may play a role in the antinociceptive effect of morphine, and that PP1 might counterbalace this activity.
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gliquidone an atp dependent k channel antagonist antagonizes morphine induced hypermotility
European Journal of Pharmacology, 1993Co-Authors: Maria Ocana, Esperanza Del Pozo, Jose M BaeyensAbstract:Abstract The effect of gliquidone, an ATP-dependent K+ (KATP) channel blocker, on Morphine-Induced hypermotility in mice was studied. Morphine (5–40 mg/kg s.c.)dose dependently increased ambulatory activity. Gliquidone (10 μg/mouse i.c.v.) induced a parallel displacement to the right of the morphine dose-response curve. Moreover, gliquidone (10 and 40 μg/mouse i.c.v.) produced a dose-dependent antagonism of morphine (20 mg/kg s.c.)-induced hypermotility. These results suggest that KATP channels are involved in Morphine-Induced hypermotility. The present data, together with those of previous studies showing antagonism by KATP channel blockers of Morphine-Induced Antinociception and hyperthermia, further indicate that the opening of KATP channels plays an important role in the mechanism of action of morphine.