Dihydroetorphine: physical dependence and stereotypy after continuous infusion in the rat
Introduction
Dihydroetorphine, a 6,14-endoethenotetrahydro-oripavine derivative is one of the most potent opioids ever synthesized. Its antinociceptive potency estimate was reported to be in the range of 10 000–20 000 times morphine Bentley and Hardy, 1967, Aceto et al., 1997. Although high binding affinities for μ-, κ-, and δ-opioid receptors were reported Magnan et al., 1982, Xu et al., 1992, Niwa et al., 1995, Wang et al., 1995, in vivo testing suggested that dihydroetorphine-induced antinociception was μ-opioid receptor mediated Tokuyama et al., 1993, Kamei et al., 1995, Wang et al., 1995, Aceto et al., 1997. Unexpectedly, physical dependence on dihydroetorphine was not observed in mice, rats and monkeys receiving intermittent doses Wang et al., 1992a, Qin, 1993, Tokuyama et al., 1993, Huang et al., 1994. In this laboratory, even after subjecting rhesus monkeys to four to six injections per day for 42 days at doses which included loss of consciousness, we could not demonstrate physical dependence on dihydroetorphine either after its abrupt withdrawal or after periodic challenges with high doses of naloxone (Aceto et al., 1997). Interestingly, dihydroetorphine was also reported effective in detoxifying human opioid addicts Wang et al., 1992b, Qin, 1993.
Nevertheless, dihydroetrophine evoked heroin-like discriminative stimulus effects in rats and was self-administered by rats and rhesus monkeys Beardsley and Harris, 1997, Martin et al., 1997 and after a decade of use as an analgesic in China, widespread abuse was cited (B.-Y. Qin, personal communication cited in Beardsley and Harris, 1997).
We decided to evaluate dihydroetorphine's physical dependence liability under conditions in which the rats were exposed chronically and continuously to this μ-opioid receptor agonist.
Section snippets
Subjects
All rats received care according to “Guide for the Care and Use of Laboratory Animals”, DHHS Publication, Revised, 1996. The facilities are certified by the American Association for the Accreditation of Laboratory Care. These studies were approved by the Institutional Animal Care and Use Committee at Virginia Commonwealth University.
Continuous-infusion protocol
The experimental procedure was described earlier (Aceto et al., 1998) and is based on the method reported by Teiger (1974). Briefly, adult male Sprague Dawley rats
Results
Because pronounced stereotypy developed in the high-dose-treated rats on day 3 and to avoid the imminent development of autophagia, the infusion of dihydroetorphine was stopped and vehicle was substituted. The abstinence data of this 3-day dose regimen was excluded from the statistical analysis of the 4-day infusion results. However, 24 h later the rats receiving this dose regimen lost approximately 10% of their body weight, were irritable, and developed wet-dog shakes. And, withdrawal was of
Discussion
The literature on dihydroetorphine is replete with studies that suggest fundamental differences between it and other opioids. For example, opioid peptides and etorphine reportedly produced activation and rapid internalization of μ-opioid receptors. In sharp contrast morphine-activated m opioid receptors eluded desensitization and internalization Keith et al., 1996, Keith et al., 1998, Whistler and Von Zastrow, 1998. Consequently, activated G proteins and disturbance of the β arrestin-mediated
Acknowledgements
Supported by NIDA (DA 8-8088).
References (41)
- et al.
Etorphines: μ-opioid receptor-selective antinociception and low physical dependence capacity
Eur. J. Pharmacol.
(1997) - et al.
The addiction cycle to narcotics in the rat and its relation to catecholamines
Biochem. Pharmacol.
(1968) - et al.
Evaluation of the discriminative and reinforcing effects of dihydroetorphine
Drug Alcohol Depend.
(1997) - et al.
After chronic opioid exposure sensory neurons become supersensitive to the excitatory effects of opioid agonists and antagonists as occurs after acute elevation of GM1 ganglioside
Brain Res.
(1992) - et al.
Etorphine elicits anomalous excitatory opioid effects on sensory neurons treated with GM1 ganglioside or pertussis toxin in contrast to its potent inhibitory effects on naive or chronic morphine-treated cells
Brain Res.
(1996) - et al.
Dihydroetorphine, a potent opioid with low dependent potential
Regul. Pept.
(1994) - et al.
Antinociceptive effect of dihydroetorphine in diabetic mice
Eur. J. Pharmacol.
(1995) - et al.
Morphine activates opioid receptors without causing their rapid internalization
J. Biol. Chem.
(1996) Persistence of the effects of amphetamine on stereotyped activity in rats
Eur. J. Pharmacol.
(1969)- et al.
Potent reinforcing effects of dihydroetorphine in rats
Eur. J. Pharmacol.
(1997)
Drug addiction: a model for the molecular basis of neural plasticity
Neuron
Opioid receptor interactions and adenylyl cyclase inhibition of dihydroetorphine: direct comparison with etorphine
Life Sci.
Principles of agonism: undressing efficacy
Trends Pharmacol. Sci.
Chronic selective activation of excitatory opioid receptor functions in sensory neurons results in opioid ‘dependence’ without tolerance
Brain Res.
Antagonists at excitatory opioid receptors on sensory neurons in culture increase potency and specificity of opiate analgesics and attenuate development of tolerance/dependence
Brain Res.
Specific N- or C-terminus modified dynorphin and β-endorphin peptides can selectively block excitatory receptor functions in sensory neurons and unmask potent inhibitory effects of opioid agonists
Brain Res.
Assessment of physical dependence techniques for the evaluation of abused drugs
Anandamide, an endogenous cannabinoid, has a very low physical dependence potential
J. Pharmacol. Exp. Ther.
Tolerance of locus coeruleus neurons to morphine and suppression of withdrawal response by clonidine
Nature
The biological, social and clinical bases of drug addiction: commentary and debate
Psychopharmacology
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