No hyperalgesia following opioid withdrawal after the oripavine derivative etorphine compared to remifentanil and sufentanil.

BACKGROUND AND OBJECTIVE: The concept of opioid-induced hyperalgesia has recently gained prominence as a contributing factor for long-term treatment failure. METHODS: To evaluate possible differences of opioids used in anaesthesia, cumulative doses of sufentanil and remifentanil were compared with escalating doses of the oripavine derivative etorphine, in awake and trained canines. This was followed by naloxone unmasking a possible hyperalgesic state, which had developed during opioid administration. Heart rate, blood pressure and propagation of nociceptive volleys in somatosensory-evoked potentials as well as the skin-twitch reflex were evaluated. RESULTS: Opioid-related hypotension and bradycardia were reversed by naloxone with a late (30 min) overshoot of R43 and R17% after remifentanil and sufentanil, respectively. Following etorphine, overshoot in mean blood pressure was R9%, whereas heart rate still remained below S9% when compared with control. Peak hyperalgesia, as detected in the somatosensory-evoked potential and skin-twitch, increased by R70% after remifentanil and by R43% after sufentanil. This reflected a significant (P<0.005) increase in propagation of nociceptive afferents as late as 30 min after naloxone reversal. Such potentiation was not observed in the etorphine group, as peak somatosensory-evoked potential deflection and skin-twitch remained below S80% when compared with control. CONCLUSION: The pure mu-agonists sufentanil or remifentanil seem to induce a 'bimodal' inhibitory followed by an excitatory effect. The latter is unmasked by naloxone in the postadministration period. In contrast, this is not seen with etorphine, a close congener of buprenorphine. The proposed mode of action of such hyperexcitatory effects may involve second-messenger-mediated G-protein activation, originally proposed by others. Ligands of the oripavine series may present an alternative for prevention of opioid-induced hyperalgesia in patients.

Differential neurotoxicity of etorphine-like opiates: lack of correlation with their ability to activate opiate receptors.

The present study was undertaken to compare the neurotoxic effects of three etorphine-like opiates (etorphine, dihydroetorphine, and another derivative of oripavine) and heroin with their ability to activate opiate receptors in human neuroblastoma cell line SK-N-SH as well as in two other neuronal cell lines. Neurotoxicity was measured by using [3H]-thymidine incorporation analysis, cell viability measurement and Cytosensor microphysiometry. It was found that, in spite of the very similar molecular structures of these opiates, they displayed significant differences in cytotoxicity, with etorphine and another derivative of oripavine possessing high potency but dihydroetorphine and heroin little effect. However, neurotoxic potency of the opiates was not directly correlated to their ability to activate opioid receptors, as determined by [35S]-guanylyl-5'-O-(gamma-tho)-triphosphate binding assay. These findings provide clear evidence of differential neurotoxicity of etorphine-like opiates, and suggest that the neurotoxicity is not closely related to the molecular configuration required as opioid receptor agonist but is probably associated with the presence of a double bond in the structure.

[Studies on transdermal delivery system of dihydroetorphine hydrochloride].

A transdermal delivery system of dihydroetorphine hydrochloride (DHE-TDS) was developed. The DHE-TDS mainly composed of polyvinyl alcohol, polyvinyl pyrrolidone and lactose. Tests on rabbits showed only slight skin irritation according to federal hazardous substances act. By giving DHE-TDS to rabbits, DHE release was shown to be governed by first-order mechanism. When DHE-TDS was given to Wistar rats, a relatively stable blood drug concentration was observed from 4-32 h after drug administration. Writhing tests showed that one dose of DHE-TDS would maintain the narcotic action on rats for at least 48 h.

Neuronal cell cultures as toxicologic test systems.

Neuronal cell cultures now represent well-characterized systems with which acute and chronic toxicologic effects of a variety of agents can be evaluated. Extensive synapse formation occurs over a period of days and weeks in these cell cultures and can be assayed semiquantitatively by morphological and electrophysiological means. Detailed morphophysiologic correlations can be made using a technique for injecting an intracellular marker protein, horseradish peroxidase. A variety of neurochemical indices of development, such as transmitter-related enzyme levels, can also be conveniently determined. The developing neuron and its synaptic connections are important objects of investigation since they may be particularly vulnerable to pathogenic materials. Examples of the effects of acute (opiate) and chronic (inhibitory aminoacid) treatments on synaptic function are given.