Regulation of<i>µ</i>-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance

Williams, John T.; Ingram, Susan; Henderson, Graeme; Chavkin, Charles; Zastrow, Mark von; Schulz, Stefan; Koch, Thomas; Evans, Christopher J.; Christie, MacDonald J.

doi:10.1124/pr.112.005942

Cited by 683 publications

(722 citation statements)

References 278 publications

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“…The unsuitableness of therapy is often related to legal restrictions on the availability of opioid analgesics (Weber et al, 2012), furthermore adverse effects limit the use of these drugs (Morgan, 1989). Along with increase in the prevalence of chronic pain, long-term therapies with opioids exacerbate toxicity and the development of analgesic tolerance (Williams et al, 2013) and dependence is a significant limit in their clinical applications (Koob and Bloom, 1988). Research efforts in the field of analgesics are focused on the discovery of new compounds as well as of new pharmaceutical forms and routes of administration.…”

Section: Discussionmentioning

confidence: 99%

Acute and subchronic antinociceptive effects of nociceptin/orphanin FQ receptor agonists infused by intrathecal route in rats

Micheli

Mannelli

Guerrini

et al. 2015

European Journal of Pharmacology

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a b s t r a c tSevere pain occurs in the context of many diseases and conditions and is a leading cause of disability. Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of the N/OFQ peptide (NOP) receptor. This peptidergic system controls pain transmission and in particular spinally administered N/OFQ has robust antinociceptive properties.The aim of this study was to investigate the spinal antinociceptive properties of NOP peptide agonists after acute and subchronic treatment in rats. Doses unable to alter motor coordination were selected. UFP-112 (full NOP agonist) and UFP-113 (partial NOP agonist) were administered intrathecally (i.t.) by spinal catheterization. Acute injection of UFP-112 induced antinociceptive response at lower dosages (0.03-1 nmol i.t.) compared to morphine and similar to N/OFQ. UFP-113 was effective in a 0.001-1 nmol i.t. dose range. The antinociceptive effects of NOP ligands were no longer evident in rats knockout for the NOP gene, while those of morphine were maintained. The continuous spinal infusion (by osmotic pumps) of 0.1 nmol/h UFP-112 and UFP-113 showed antinociceptive action comparable to 1-3 nmol/h morphine or N/OFQ. The antinociceptive effect of morphine progressively decreased and was no longer significant after 6 days of treatment. Similar results were obtained with N/OFQ, UFP-112, and UFP-113. The acute i.t. injection of morphine in animals tolerant to N/OFQ and UFP-112 evoked analgesic effects. Neither morphine nor N/OFQ induced antinociceptive effects in morphine-and UFP-113-tolerant rats. In conclusion this study highlights the analgesic efficacy and potency of UFP-112 and UFP-113 underlining the relevance of NOP system in analgesia.

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Section: Discussionmentioning

confidence: 99%

Acute and subchronic antinociceptive effects of nociceptin/orphanin FQ receptor agonists infused by intrathecal route in rats

Micheli

Mannelli

Guerrini

et al. 2015

European Journal of Pharmacology

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“…Addiction results in significant changes in mood and affective behavior, while withdrawal syndrome consists of severe somatic alterations (26). Morphine, a clear example, has significant inhibitory effects on numerous types of intense pain; however, the use of morphine is strictly controlled (27). In the present study, morphine caused a significant bodyweight loss after 30 days of administration in rats, and extremely high withdrawal behaviors were observed in morphine-dependent rats compared with non-treated animals.…”

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confidence: 57%

Study of the analgesic activities, chronic toxicity and addictive potential of Jia-Yuan-Qing pill in rats

Tian

Teng

Wang

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Jia-Yuan-Qing pill (JYQP) composed of Porcellio laevis Latreille, Corydalis Rhizoma and Radix Cynanchi Paniculati at a ratio of 9:7:7 has been found to be an effective analgesic agent. The present study aimed to evaluate the safety, addictive potential and anti-cancer pain activity of JYQP in a rat model. During the 6-month chronic toxicity test, no significant changes in general behavior, defecation, postural abnormalities, dietary or water intake or blood biochemical parameters were observed in male and female rats. Although a high dose of JYQP (5 g/kg) caused swelling of the liver, spleen and kidney in male and female rats, no pathological changes were observed in all organs examined via hematoxylin and eosin staining. The analgesic effect of JYQP on bone cancer pain was successfully confirmed in a rat model of Walker 256 cell-induced bone cancer. In contrast to morphine, in a physical dependence test, JYQP produced no withdrawal symptoms following chronic administration. The data from this study provide experimental evidence supporting the clinical use of JYQP as an effective, safe and non-addictive agent for the treatment of bone cancer pain.

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“…Pregabalin took a "preventive" effect (evaluated as a relief maintained over 24 h) after 14 days of treatment. Morphine was not repeatedly administered, since the wellknown development of tolerance to the anti-nociceptive effect [35,36].…”

Section: Discussionmentioning

confidence: 99%

A rat model of FOLFOX-induced neuropathy: effects of oral dimiracetam in comparison with duloxetine and pregabalin

Mannelli

Maresca

Micheli

et al. 2017

Cancer Chemother Pharmacol

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Results FOLFOX reduced the pain threshold in response to mechanical noxious and thermal (cold) non-noxious stimuli beginning from day 14 up to day 42 comparably to oxaliplatin alone. A fifth FOLFOX injection enhanced the severity but not the duration of painful alterations. Spontaneous activity, behavioural, autonomic, and neurological functions were also affected, whereas the motor coordination was not altered. On day 22, duloxetine (15 mg kg −1 , per os), morphine (10 mg kg −1 , subcutaneously), or pregabalin (20 mg kg −1 , per os), acutely administered, reduced the FOLFOX-dependent hypersensitivity. Repeated treatments with dimiracetam (150 mg kg −1 , per os, twice daily, from day 22) significantly protected rats from FOLFOX-induced alterations of pain threshold as well as from autonomic and neurological impairments taking effect after 7 days treatment. Pregabalin repeatedly administered (20 mg kg −1 , per os, twice daily, from day 22) was less effective in reducing mechanical hypersensitivity. Conclusion A clinically consistent model of FOL-FOX-induced neurotoxicity has been developed in rats. Dimiracetam fully reduced hypersensitivity and neurological alterations showing a relevant profile as anti-neuropathic resource.

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Regulation ofµ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance

Cited by 683 publications

References 278 publications

Acute and subchronic antinociceptive effects of nociceptin/orphanin FQ receptor agonists infused by intrathecal route in rats

Acute and subchronic antinociceptive effects of nociceptin/orphanin FQ receptor agonists infused by intrathecal route in rats

Study of the analgesic activities, chronic toxicity and addictive potential of Jia-Yuan-Qing pill in rats

A rat model of FOLFOX-induced neuropathy: effects of oral dimiracetam in comparison with duloxetine and pregabalin

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