Mu receptor binding of some commonly used opioids and their metabolites

Chen, Zhao Rong; Irvine, Rodney J.; Somogyi, Andrew A.; Bochner, Felix

doi:10.1016/0024-3205(91)90150-a

Cited by 234 publications

(156 citation statements)

References 11 publications

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“…While glucuronidation at C-6 or N-demethylation did not change affinity or were related to a small decrease in affinity only, O-demethylation brought about a pronounced increase in affinity. 7,8-Dihydro derivatives had slightly higher affinities when compared to their unsaturated counterparts (Chen et al 1991;Mignat et al 1995;Lö ser et al 1996). 3-O-Glucuronides had essentially no relevant affinity to opioid receptors, and the apparent displacement of the radioactive ligands observed may well result from contamination with the more active parent substances (Bartlett & Smith 1995;Löser et al 1996).…”

Section: Discussionmentioning

confidence: 97%

Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors

Schmidt¹,

Vormfelde

Klinder³

et al. 2002

Pharmacology & Toxicology

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Dihydrocodeine is metabolized to dihydromorphine, dihydrocodeine-6-O-, dihydromorphine-3-O-and dihydromorphine-6-O-glucuronide, and nordihydrocodeine. The current study was conducted to evaluate the affinities of dihydrocodeine and its metabolites to m-, d-and k-opioid receptors. Codeine, morphine, d,l-methadone and levomethadone were used as controls. Displacement binding experiments were carried out at the respective opioid receptor types using preparations of guinea pig cerebral cortex and the specific opioid agonists [ 3 H]DAMGO (m-opioid receptor), [ 3 H]DPDPE (d-opioid receptor) and [ 3 H]U69,593 (k-opioid receptor) as radioactive ligands at concentrations of 0.5, 1.0 and 1.0 nmol/l, respectively. All substances had their greatest affinity to the m-opioid receptor. The affinities of dihydromorphine and dihydromorphine-6-O-glucuronide were at least 70 times greater compared with dihydrocodeine (K i 0.3 mmol/ l), whereas the other metabolites yielded lower affinities. For the d-opioid receptor, the order of affinities was similar with the exception that dihydrocodeine-6-O-glucuronide revealed a doubled affinity in relation to dihydrocodeine (K i 5.9 mmol/ l). In contrast, for the k-opioid receptor, dihydrocodeine-6-O-and dihydromorphine-6-O-glucuronide had clearly lower affinities compared to the respective parent compounds. The affinity of nordihydrocodeine was almost identical to that of dihydrocodeine (K i 14 mmol/l), whereas dihydromorphine had a 60 times higher affinity. These results suggest that dihydromorphine and its 6-O-glucuronide may provide a relevant contribution to the pharmacological effects of dihydrocodeine. The O-demethylation of dihydrocodeine to dihydromorphine is mediated by the polymorphic cytochrome P-450 enzyme CYP2D6, resulting in different metabolic profiles in extensive and poor metabolizers. About 7% of the caucasian population which are CYP2D6 poor metabolizers thus may experience therapeutic failure after standard doses.The semisynthetic opioid dihydrocodeine is an analgesic and antitussive drug. It exerts its actions by interaction with opioid receptors of different types (m-, d-and k-opioid receptors). Since the beginning of the 1960s dihydrocodeine and dihydrocodeine-containing drugs were used by opioid addicts as a substitute drug to heroin. Recently this use increased by prescribing dihydrocodeine in maintenance treatment of addicts. Individual doses prescribed vary from 60 to 3000 mg dihydrocodeine daily (Frießem & Täschner 1991).Dihydrocodeine, the 7,8-dihydro analogue of codeine, has similar metabolic pathways as codeine (Fromm et al. 1995;Hufschmid et al. 1995). These include O-demethylation to dihydromorphine, formation of the corresponding 6-and/ or 3-O-glucuronides dihydrocodeine-6-O-, dihydromorPart of these results have been presented at

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Section: Discussionmentioning

confidence: 97%

Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors

Schmidt¹,

Vormfelde

Klinder³

et al. 2002

Pharmacology & Toxicology

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“…Increased synaptic excitatory amino acids, such as glutamate, would potentiate the NMDA receptor. Further, it has been suggested that large doses of systemic morphine may potentiate excitotoxic cell death through a kappa-opiate mediated cascade [47,48,49,50,51] potentiating NMDA receptor function and enhancing neurotransmitter release in the spinal cord [46,52,53]. Interactions between opioid exposure and sensitization of primary afferent nociceptive neurons (i.e., by tissue injury or inflammation) have been previously reported [for review see 54,55].…”

Section: Discussionmentioning

confidence: 99%

The impact of morphine after a spinal cord injury

Hook

Liu

Washburn

et al. 2007

Behavioural Brain Research

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Nociceptive stimulation, at an intensity that elicits pain-related behavior, attenuates recovery of locomotor and bladder functions, and increases tissue loss after a contusion injury. These data imply that nociceptive input (e.g., from tissue damage) can enhance the loss of function after injury, and that potential clinical treatments, such pretreatment with an analgesic, may protect the damaged system from further secondary injury. The current study examined this hypothesis and showed that a potential treatment (morphine) did not have a protective effect. In fact, morphine appeared to exacerbate the effects of nociceptive stimulation. Experiment 1 showed that after spinal cord injury 20 mg/kg of systemic morphine was necessary to induce strong antinociception and block behavioral reactivity to shock treatment, a dose that was much higher than that needed for sham controls. In Experiment 2, contused rats were given one of three doses of morphine (Vehicle, 10, 20 mg/kg) prior to exposure to uncontrollable electrical stimulation or restraint alone. Despite decreasing nociceptive reactivity, morphine did not attenuate the long-term consequences of shock. Rats treated with morphine and shock had higher mortality rates, and displayed allodynic responses to innocuous sensory stimuli three weeks later. Independent of shock, morphine per se undermined recovery of sensory function. Rats treated with morphine alone also had significantly larger lesions than those treated with saline. These results suggest that nociceptive stimulation affects recovery despite a blockade of pain-elicited behavior. The results are clinically important because they suggest that opiate treatment may adversely affect the recovery of function after injury.

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“…M6G is also more potent than morphine (146 : 1) at producing rewarding e ects measured with place preference testing following intracerebral administration (Abbott & Franklin, 1991). Binding studies show that M6G has an equal or lower a nity for the muopioid receptor than morphine (Abbott & Palmour, 1988;Chen et al, 1991;Hucks et al, 1992;Lambert et al, 1993;Mignat et al, 1995;LoÈ ser et al 1996;Brown et al, 1997b;Pan et al, 1999). In order to explain these di erences in the potencies of M6G and morphine, it has recently been hypothesized that M6G has selective antinociceptive and other behavioural agonist e ects at a receptor that is not activated by morphine (reviewed by Pasternak & Standifer, 1995).…”

Section: Introductionmentioning

confidence: 98%

Morphine‐6β‐glucuronide has a higher efficacy than morphine as a mu‐opioid receptor agonist in the rat locus coeruleus

Osborne

Chieng

Christie

2000

British J Pharmacology

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1 The pharmacological properties of the active morphine metabolite, morphine-6b-D-glucuronide (M6G), and the parent compound were compared in rat locus coeruleus neurons by electrophysiological recording in brain slices. 2 M6G and morphine activated potassium currents in voltage clamped neurons, which were blocked by the opioid receptor antagonist naloxone. 3 Both M6G and morphine behaved as partial agonists that produced maximal responses smaller than the system maximum, which was measured using [Met 5 ]-enkephalin. M6G produced a larger maximal response (78%) than morphine (62%), which we estimated was due to a 2 ± 4 fold di erence in the relative e cacy of the agonists. 4 3-O-methoxynaltrexone, which has been reported to behave as a selective antagonist of a M6G preferring receptor, was equally e ective at blocking currents produced by M6G and the selective mu-opioid receptor agonist DAMGO. 5 M6G currents were occluded by a prior application of morphine, and were reduced when muopioid receptors were desensitized by using [Met 5 ]-enkephalin. 6 Morphine-3b-D-glucuronide did not a ect action potential ®ring or membrane currents in locus coeruleus neurons and had no e ect on currents produced by M6G. 7 These results show that the relative e cacy of M6G is higher than morphine in locus coeruleus neurons, contrary to what has been shown using mu-opioid receptors expressed in cell clones.

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Mu receptor binding of some commonly used opioids and their metabolites

Cited by 234 publications

References 11 publications

Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors

Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors

The impact of morphine after a spinal cord injury

Morphine‐6β‐glucuronide has a higher efficacy than morphine as a mu‐opioid receptor agonist in the rat locus coeruleus

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