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.

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The Role of CGRP in the Development of Morphine Tolerance and Physical Dependence

The Scientific World JOURNAL ◽

10.1100/tsw.2001.433 ◽

2001 ◽

Vol 1 ◽

pp. 21-21

Author(s):

K. J. Powell ◽

T. Trang ◽

R. Quirion ◽

K. Jhamandas

Keyword(s):

Physical Dependence ◽

Morphine Tolerance

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Modulatory role of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA), in morphine tolerance and dependence in mice

Journal of Neural Transmission ◽

10.1007/s00702-010-0443-2 ◽

2010 ◽

Vol 117 (9) ◽

pp. 1027-1032 ◽

Cited By ~ 11

Author(s):

Ozgur Gunduz ◽

Cetin Hakan Karadag ◽

Ahmet Ulugol

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Asymmetric Dimethylarginine ◽

Morphine Tolerance ◽

Nitric Oxide Synthase Inhibitor ◽

Endogenous Nitric Oxide ◽

Synthase Inhibitor ◽

Oxide Synthase

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Honey potentially mitigates morphine analgesic tolerance and physical dependence in rats

Bangladesh Journal of Medical Science ◽

10.3329/bjms.v17i1.35294 ◽

2018 ◽

Vol 17 (1) ◽

pp. 138-143

Author(s):

Siti Norhajah Hashim ◽

Nasir Mohamad ◽

Zulkifli Mustapha ◽

Nor Hidayah Abu Bakar ◽

Rohayah Husain ◽

...

Keyword(s):

Analgesic Effect ◽

Physical Dependence ◽

Medical Science ◽

Morphine Tolerance ◽

Morphine Dependence ◽

P Value ◽

Concomitant Treatment ◽

Sprague Dawley ◽

Chronic Morphine ◽

Analgesic Tolerance

Introduction:Honey has been used traditionally in medicine as well as food supplements. Honeybees are said to be able to cure many diseases. However, its influences on opioid tolerance and dependence have not yet been clarified.Materials and Methods:Adult male Sprague- Dawley rats were rendered tolerant to the analgesic effect of morphine by injection of morphine (10 mg/kg, i.p.) twice daily for 14 days. To develop morphine dependence rats given escalating doses of chronic morphine. To determine the effect of stingless bee honey on the development of morphine tolerance and dependence. The hotplate and naloxone precipitation tests were used to assess the degree of tolerance and dependence, respectively.The results: Our results showed that chronic morphine-injected rats displayed tolerance to the analgesic effect of morphine as well as morphine dependence. Methadone+morphine (MetM), methadone+morphine+ honey (MetMH) and morphine+Honey (MH) significantlylower the development of morphine tolerance with p-value p<0.05. In addition, concomitant treatment of morphine with MH and MetMH attenuated almost all of the naloxone-induced withdrawal signs which include abdominal contraction, diarrhea, pertussis, teeth chattering, and jumping.Conclusion: The data indicate that honey has a potential to reduce tolerant and dependence property.Bangladesh Journal of Medical Science Vol.17(1) 2018 p.138-143

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Alteration of calcitonin gene related peptide and its receptor binding sites during the development of tolerance to μ and δ opioids

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y95-156 ◽

1995 ◽

Vol 73 (7) ◽

pp. 1089-1095 ◽

Cited By ~ 17

Author(s):

D. P. Ménard ◽

D. van Rossum ◽

S. Kar ◽

R. Quirion

Keyword(s):

Spinal Cord ◽

Binding Sites ◽

Specific Interaction ◽

Calcitonin Gene Related Peptide ◽

Opioid Agonist ◽

Pain Mechanisms ◽

Related Peptide ◽

Calcitonin Gene ◽

Antinociceptive Effects ◽

Development Of Tolerance

Calcitonin gene related peptide (CGRP), one of the most abundant peptides in the spinal cord, is localized in primary afferents and released following nociceptive stimuli. Its colocalization and corelease with substance P, a well-known nociceptive neuropeptide, support the importance of CGRP in pain mechanisms. However, its distinctive function in that regard remains to be fully established. Recently, we reported that increases in CGRP-like immunostaining and decrements in specific 125I-labelled human CGRPα ([125I]hCGRPα) binding sites in the spinal cord were correlated with the development of tolerance to the spinal antinociceptive action of a μ opioid agonist, morphine. The goal of the present study was to investigate whether the development of tolerance to other classes of opioids, namely, δ and κ agonists, can also alter CGRP-like immunostaining and receptors in the rat spinal cord. The antinociceptive effects of all opioids were monitored by the tail-immersion test. Tolerance to their antinociceptive properties was induced by the infusion for 7 days of μ (morphine sulfate, 7.5 μg/h), δ ([D-Pen2,D-Pen5]enkephalin (DPDPE), 2.0 μg/h), and κ (U-50488H, 10.0 μg/h) related agonists at the spinal level (L4), using osmotic minipumps. We confirmed that rats chronically treated with morphine showed significant decreases in [125I]CGRPα binding in laminae I, II, and III of the L4 spinal cord, while CGRP-like immunostaining was increased in these same laminae. Similar effects were observed following a treatment with the δ agonist, DPDPE, while the κ agonist, U-50488H, apparently only slightly decreased [125I]CGRPα binding in lamina II. Binding in other laminae and CGRP-like immunostaining were not affected. These results suggest a specific interaction between spinal CGRP systems and the development of tolerance to the spinal antinociceptive effects of μ- and δ-related agonists.Key words: opioid tolerance, calcitonin gene related peptide, sensory neurons, immunostaining, receptor autoradiography.

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The role of vasopressin on the effect of U-50,488 to block the development of morphine tolerance and physical dependence

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/pl00004944 ◽

1997 ◽

Vol 355 (2) ◽

pp. 281-287 ◽

Cited By ~ 5

Author(s):

P.-L. Tao ◽

Wan-Cherng Liu ◽

Yuan-Sheng Tsuei ◽

Chen-Yu Cheng

Keyword(s):

Physical Dependence ◽

Morphine Tolerance

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The mineralocorticoid receptor antagonist spironolactone enhances morphine antinociception

Scandinavian Journal of Pain ◽

10.1016/j.sjpain.2013.07.013 ◽

2013 ◽

Vol 4 (4) ◽

pp. 259-259

Author(s):

Viljami Jokinen ◽

Tuomas O. Lilius ◽

Mikko S. Neuvonen ◽

Antti J. Väänänen ◽

Mikko O. Niemi ◽

...

Keyword(s):

Antinociceptive Effect ◽

Morphine Tolerance ◽

Tail Flick ◽

Hot Plate ◽

Hot Plate Test ◽

Mineralocorticoid Receptor Antagonist ◽

P Glycoprotein ◽

Antinociceptive Effects ◽

The Brain ◽

Glycoprotein Inhibition

Abstract Aims Spironolactone, an antimineralocorticoid, has been reported to potentiate the cataleptic effect of morphine in the rat. Since no previous research exists on the matter and the interaction might be clinically significant, the effects of spironolactone on morphine antinociception and pharmacokinetics in the rat were investigated. Methods Male SD rats were used to assess the effects of spironolactone on acute morphine-induced antinociception, development of morphine tolerance, and established morphine tolerance in the tail-flick and hot plate tests. Spironolactone was also administered with loperamide to assess whether spironolactone enhances the brain distribution of the acknowledged P-glycoprotein substrate across the blood-brain barrier. Results Spironolactone had no antinociceptive effects of its own but when co-administrated with morphine the antinociceptive effect of morphine was greatly enhanced. Morphine concentrations in the brain were increased fourfold in the spironolactone co-administrated group. Spironolactone did not inhibit the formation of pro-nociceptive morphine-3-glucuronide, nor did inhibit the development of tolerance. The peripherally restricted opioid, loperamide, had no antinociceptive effects by itself, but co-administration with spironolactone produced a clear change in the hot plate test. Conclusions Although mineralocorticoids have been proposed to take part in pain signaling, in our setting spironolactone did not have antinociceptive properties of its own. The increased antinociceptive effect of morphine is apparently caused by the increased morphine brain concentrations. We suggest this to be due to P-glycoprotein inhibition, as indicated by the loperamide assay. The clinical relevance of P-glycoprotein inhibition by spironolactone should be studied.

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N-Acylethanolamine Acid Amidase Inhibition Potentiates Morphine Analgesia and Delays the Development of Tolerance

Neurotherapeutics ◽

10.1007/s13311-021-01116-4 ◽

2021 ◽

Author(s):

Mauro Congiu ◽

Laura Micheli ◽

Michele Santoni ◽

Claudia Sagheddu ◽

Anna Lisa Muntoni ◽

...

Keyword(s):

Opioid Analgesic ◽

Morphine Tolerance ◽

Mechanical Stimuli ◽

Chronic Morphine ◽

Analgesic Effects ◽

Electrophysiological Recordings ◽

Antinociceptive Effects ◽

Hydrolyzing Enzymes ◽

Development Of Tolerance

AbstractOpioids are essential drugs for pain management, although long-term use is accompanied by tolerance, necessitating dose escalation, and dependence. Pharmacological treatments that enhance opioid analgesic effects and/or attenuate the development of tolerance (with a desirable opioid-sparing effect in treating pain) are actively sought. Among them, N-palmitoylethanolamide (PEA), an endogenous lipid neuromodulator with anti-inflammatory and neuroprotective properties, was shown to exert anti-hyperalgesic effects and to delay the emergence of morphine tolerance. A selective augmentation in endogenous PEA levels can be achieved by inhibiting N-acylethanolamine acid amidase (NAAA), one of its primary hydrolyzing enzymes. This study aimed to test the hypothesis that NAAA inhibition, with the novel brain permeable NAAA inhibitor AM11095, modulates morphine’s antinociceptive effects and attenuates the development of morphine tolerance in rats. We tested this hypothesis by measuring the pain threshold to noxious mechanical stimuli and, as a neural correlate, we conducted in vivo electrophysiological recordings from pain-sensitive locus coeruleus (LC) noradrenergic neurons in anesthetized rats. AM11095 dose-dependently (3–30 mg/kg) enhanced the antinociceptive effects of morphine and delayed the development of tolerance to chronic morphine in behaving rats. Consistently, AM11095 enhanced morphine-induced attenuation of the response of LC neurons to foot-shocks and prevented the attenuation of morphine effects following chronic treatment. Behavioral and electrophysiological effects of AM11095 on chronic morphine were paralleled by a decrease in glial activation in the spinal cord, an index of opioid-induced neuroinflammation. NAAA inhibition might represent a potential novel therapeutic approach to increase the analgesic effects of opioids and delay the development of tolerance.

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