Nitric oxide modulates tapentadol antinociceptive tolerance and physical dependence

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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The development of morphine antinociceptive tolerance in nitric oxide synthase-deficient mice

Biochemical Pharmacology ◽

10.1016/j.bcp.2003.08.046 ◽

2004 ◽

Vol 67 (4) ◽

pp. 735-741 ◽

Cited By ~ 39

Author(s):

Erin L Heinzen ◽

Gary M Pollack

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Antinociceptive Tolerance ◽

Oxide Synthase ◽

Deficient Mice

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Attenuation of tolerance to, and physical dependence on, morphine in the rat by inhibition of nitric oxide synthase

General Pharmacology The Vascular System ◽

10.1016/0306-3623(94)00271-n ◽

1995 ◽

Vol 26 (5) ◽

pp. 1049-1053 ◽

Cited By ~ 39

Author(s):

Hemendra N. Bhargava

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Physical Dependence ◽

Oxide Synthase

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Tianeptine reduces morphine antinociceptive tolerance and physical dependence

Behavioural Pharmacology ◽

10.1097/fbp.0b013e32833db7d4 ◽

2010 ◽

Vol 21 (5-6) ◽

pp. 523-529 ◽

Cited By ~ 5

Author(s):

Chin-Chen Chu ◽

Ja-Ping Shieh ◽

Hao-Ai Shui ◽

Jen-Yin Chen ◽

Chung-Hsi Hsing ◽

...

Keyword(s):

Physical Dependence ◽

Antinociceptive Tolerance

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Opioid Tolerance and Physical Dependence: Role of Spinal Neuropeptides, Excitatory Amino Acids and Their Messengers

Pain Research and Management ◽

10.1155/2000/959161 ◽

2000 ◽

Vol 5 (1) ◽

pp. 25-32 ◽

Cited By ~ 5

Author(s):

Khem Jhamandas ◽

Kelly Powell ◽

Remi Quirion ◽

B Milne

Keyword(s):

Nitric Oxide ◽

Amino Acid ◽

Dorsal Horn ◽

Excitatory Amino Acid ◽

Physical Dependence ◽

Opioid Tolerance ◽

Opioid Agonist ◽

Nociceptive Transmission ◽

Neuropeptide Ff

Chronic opioid treatment results in the development of tolerance and physical dependence. The mechanisms underlying opioid tolerance and/or physical dependence are unclear. Recent studies suggest that opioid receptor or nociceptive, neural network-based adaptations contribute to this phenomenon. At the spinal level, the genesis of tolerance and physical dependence is associated with increased excitatory amino acid activity expressed throughN-methyl-D-aspartate receptors in the dorsal horn. However, recent evidence also implicates spinal neuropeptide transmitters such as calcitonin gene-related peptide (CGRP) and substance P in the development of opioid tolerance. Long term spinal morphine treatment increases CGRP-like immunostaining in the dorsal horn, and coadministration of morphine with CGRP8-37, a competitive CGRP1receptor antagonist, prevents this response as well as loss of the analgesic potency. CGRP8-37, likeN-methyl-D-aspartate receptor antagonists, has the potential to restore morphine potency in experimental animals who are already tolerant to the opioid agonist. Recent evidence suggests that the effects of excitatory amino acid and neuropeptide receptor activity may be expressed through the generation of messengers such as nitric oxide and prostanoids. Agents that inhibit the synthesis of nitric oxide and prostanoids have the potential to inhibit and reverse spinal opioid tolerance, suggesting that this phenomenon may be expressed through the activity of these mediators. Nociceptive transmission in the dorsal horn of the spinal cord also involves activity of a number of other mediators including morphine modulatory neuropeptides, neuropeptide FF and neuropeptide SF. The role of these mediators and their relationship with other factors implicated in tolerance remain to be determined.

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Selective Nitric Oxide Synthase Inhibitor 7-Nitroindazole Protects against Cocaine-Induced Oxidative Stress in Rat Brain

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/157876 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Vessela Vitcheva ◽

Rumyana Simeonova ◽

Magdalena Kondeva-Burdina ◽

Mitka Mitcheva

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Physical Dependence ◽

Combination Group ◽

Control Group ◽

Mitochondrial Activity ◽

Antioxidant Enzyme Activities ◽

Repeated Treatment ◽

Oxide Synthase

One of the mechanisms involved in the development of addiction, as well as in brain toxicity, is the oxidative stress. The aim of the current study was to investigate the effects of 7-nitroindazole (7-NI), a selective inhibitor of neuronal nitric oxide synthase (nNOS), on cocaine withdrawal and neurotoxicity in male Wistar rats. The animals were divided into four groups: control; group treated with cocaine (15 mg/kg−1, i.p., 7 days); group treated with 7-NI (25 mg/kg−1, i.p., 7 days); and a combination group (7-NI + cocaine). Cocaine repeated treatment resulted in development of physical dependence, judged by withdrawal symptoms (decreased locomotion, increased salivation and breathing rate), accompanied by an increased nNOS activity and oxidative stress. The latter was discerned by an increased formation of malondialdehyde (MDA), depletion of reduced glutathione (GSH) levels, and impairment of the enzymatic antioxidant defense system measured in whole brain. In synaptosomes, isolated from cocaine-treated rats, mitochondrial activity and GSH levels were also decreased. 7-NI administered along with cocaine not only attenuated the withdrawal, due to its nNOS inhibition, but also reversed both the GSH levels and antioxidant enzyme activities near control levels.

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