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*Clinics of Vascular Surgery and Renal Transplantation, University Clinics of Düsseldorf, Düsseldorf, Germany;
Institute of Organic and Pharmaceutical Chemistry, University of Innsbruck, Innsbruck, Austria; and
Department of Anesthesia, Nordwest Hospital, Frankfurt, Germany
Address correspondence and reprint requests to Enno Freye MD, Hamannstr. 37, 40882 Ratingen, Germany.
Abstract
Opioids of the µ-receptor type depress respiration and induce addiction. At 10-min intervals 14-methoxymetopon (HS-198), which is 20,000 times more potent than morphine in the acethylcholine-writhing test, was given in graded IV doses (3, 6, and 12 µg/kg) to awake, trained canines (n = 7). The following variables were derived: PaO2, PaCO2, heart rate (lead II of the electrocardiogram), mean arterial blood pressure, relative changes in the 
domain and the ß domain of the electroencephalogram, the somatosensory evoked potential, and the skin-twitch reflex to electrical stimuli. Thereafter, 20 µg/kg naltrexone was given for reversal. After a washout period, the same animals were exposed to similar doses of sufentanil (SUF) followed by naltrexone. Both opioids induced a dose-related bradycardia and hypotension. The maximal bradycardic effect was 19% after HS-198 and 42% after SUF (P < 0.005). The maximal hypotension was 6% after HS-198 and 20% after SUF (P < 0.01). In the electroencephalogram, power in the band increased by 288% after HS-198 and by 439% after SUF (P < 0.01); simultaneously, power in the ß band decreased by 71% and by 95.7%, respectively (P < 0.01). PaO2 decreased by 41% after SUF and by 4% after HS-198, and PaCO2 increased by 56.8% and 6.6% in SUF and HS-198, respectively (P < 0.001). Both opioids induced a dose-related depression in the somatosensory evoked potential and increased tolerance to skin-twitch. The maximal effect was 92.7% after SUF and 81.3% after HS-198 was not significant. Naltrexone reversed all changes back to control. Compared with SUF, HS-198 does not induce hypoxia and hypercarbia, induces less hypotension and bradycardia, and induces less sedative effects.
Implications: Compared with sufentanil, 14-methoxymetopone does not induce hypoxia and hypercarbia, induces less hypotension and bradycardia, and induces less sedative effects (electroencephalogram). Antinociception is similar to sufentanil (skin-twitch method, amplitude depression in the evoked potential). All effects are reversed by naltrexone. Interaction of 
-receptor is suggested.
Amajor side effect of potent opioids of the µ-receptor type is the impairment of respiratory drive and the development of addiction. In this regard, analgesic potency, the degree of respiratory depression, and the addictive potential of opioids appear to be closely related (1), setting a limit to the use of such compounds. Although respiratory depression can be easily reversed by an antagonist, if not titrated to the desired effect one may provoke sympathetic hyperactivity with vomiting, tachycardia, hypertension, and even provoke the development of pulmonary edema (2). Agonists that interact only with the receptor site mediating antinociception, but with no respiratory depression and a low addiction profile, would be a clinically attractive solution (3,4). At present no such ligands are available.
Opiates that selectively interact with the -receptor do not induce respiratory depression (5); however, they inherit the disadvantage of inducing dysphoria. In the search for potent agonists not showing the usual addiction profile of other opioids, we came across a derivative of the alkoxymorphinans differing from classical µ-type opioids. This derivative induces less intensity in withdrawal symptoms when antagonized, has a low dependence liability, and produces less development of tolerance in mice and rats (6). We evaluated a derivative of this class of 14-alkoxymorphinans, i.e., 5,14-O-dimethyloxymorphone or 14-methoxymetopon (HS-198), for its potential clinical benefit because it is 20,000-fold more potent than morphine and 1500-fold more potent than oxymorphone in the acetylcholine-writhing test in rats and mice (7). By using an awake, trained canine model, we evaluated a dose-response of the opioid to its cardiovascular (heart rate and blood pressure), hypnotic (electroencephalography), respiratory (PaO2, PaCO2), and antinociceptive (skin twitch, somatosensory evoked potentials) properties. The effects were compared with the same dosages of sufentanil (SUF) given to the same animals after washout, and potential reversal was determined by subsequent injection of the potent antagonist naltrexone (NAL).
Methods
After approval by our local animal care and use committee, graded doses (3, 6, and 12 µg/kg) of HS-198 were given IV every 10 min to awake, trained canines (n = 7) bred in the animal facilities. These doses were selected to compare results with SUF, presently the most potent opioid used clinically, which is up to 1000-fold more potent than morphine in the canine (8). Before and after the injection of HS-198, the following variables were derived: 1) PaO2 and PaCO2 of blood from the femoral artery to evaluate the degree of respiratory depression; 2) heart rate and mean arterial blood pressure from a noninvasive blood pressure measurement device wrapped around the front leg; and 3) changes in the electroencephalogram (EEG) from the frontal cortex by using two stainless steel needle electrodes at the montage of CZ (active) and 2 cm rostral to the intraauricular plane of the animal scalp (modified 10/20 system adapted to the dog). Having passed a preamplifier, artifact-free signals were fed into an EEG analysis system (pEEG; Dräger, Lübeck, Germany), and power spectra were computed by using a system-adapted laptop computer that yielded the relative changes in EEG power spectra. The (0.5–3 Hz) and ß (15–30 Hz) bands were used because they reflected the hypnotic effects for 60 s.
To evaluate and quantify somatic antinociceptive properties of HS-198, the skin-twitch technique (8a) and the somatosensory evoked potentials (SEP) were derived. By using both techniques, it was possible to quantify the somatic antinociceptive effects of both opioids. After measurements of cardiovascular, respiratory, and EEG variables, a rectangular stimulus of electrical origin (0.2 ms duration, 5 Hz frequency), was applied via two stick-on electrodes (Digi Stim IITM; Neuro Technology, Houston, TX) to the ventral part of the shaven thoracic cage. Pain thresholds were determined by increasing the intensity of the electrical stimulus (mA) to a point where the animal either showed motor responses (turning the head to the site of stimulation) or reacted by vocalization. To assess the degree of depression of sensory afferent nerve input to higher cortical centers, SEPs were derived (LifescanTM; Neurometrics, San Diego, CA). Nociceptive propagation in afferent pathways was evaluated by means of intermittent electrical stimuli applied to the right forepaw (Digi Stim IITM; Neuro Technology). A square-wave impulse of 0.2-ms duration, 1 mA above the motor threshold, was induced at a frequency at 5 Hz. Sensory input to the cortex was derived contralaterally from the two stainless steel needle electrodes used for EEG recording. By averaging 256 evoked responses, it was possible to identify and plot, after cursor positioning, latency changes (ms) and amplitude depression (mV) of a peak with a mean latency of 50 ms (N50) from the time of stimulus onset. The peak-to-peak amplitude was regarded as the intensity of sensory input to the cortex measured before and after incremental doses of HS-198 and SUF, respectively. In this regard, any reduction in amplitude height after opioids can be regarded as a functional deficit of afferent volleys reaching the sensory cortical areas in humans (9–12), as well as canines (13,14). After the last dose of the opioid, 20 µg/kg naltrexone IV was given for reversal.
After a washout period of at least 14 days, the same animals were exposed to increasing doses of SUF, 3, 6, and 12 µg/kg, an opioid which purportedly shows selective interaction with the µ-receptor system (14a). Also after SUF, the same dose of NAL was given for reversal.
All data were given as mean ± SD or in percent change to control. For calculation of statistical significance, absolute values of blood pressure, heart rate, and blood gases, as well as tolerance to increasing electrical intensities (mA) during skin-twitch, were taken. In the EEG, power spectra changes were computed from total power (100%) yielding relative change (%) of the most relevant spectra in the low (0.5–3 Hz) and the fast ß (13–30 Hz) domain to demonstrate changes in vigilance over a time period of 60 s. Also, amplitude changes in the SEP were computed from control (100%) yielding the relative changes (%) after increasing dosages of SUF, HS-198, and NAL, respectively.
Friedmann’s analysis of variance was used to evaluate statistical significance. This was followed by the Wilcoxon and Wilcox procedure for multiple comparisons by using Bonferroni correction. Statistical significance was P > 0.05.
Results
Both opioids induced dose-related bradycardia and hypotension (Fig. 1). The maximal bradycardic effect was 19% after HS-198 and 42% after SUF when compared with control. The maximal decrease in mean arterial blood pressure was 6% after HS-198 (not significant [NS]) and 20% after SUF (P < 0.01) at the largest dose when compared with control. After the largest dose, heart rate and mean arterial blood pressure were statistically significant (P < 0.05) among both groups.
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In the EEG, both opioids induced a dose-related increase in the band and a decrease in the ß band. After the largest dose of HS-198, power increased by 288% and after the largest dose of SUF, power increased by 439%. Increase of power in the band was significant (P < 0.01) for SUF compared with HS-198. Simultaneously, power in the ß band decreased by 71% and 95.7% after HS-198 and SUF, respectively at the largest dose level (Table 1). This decrease was significant for the SUF group (P < 0.05) compared with the HS-198 group. All EEG-changes reversed back to control after the injection of NAL (Table 1).
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Discussion
Our data contradict the commonly accepted notion that highly potent opioids are necessarily linked to respiratory impairment. Regarding the antinociceptive potency of compound HS-198, rodent studies have shown it to be similar to SUF (6). These data are corroborated by our study by using the skin-twitch technique to assess antinociception. Whereas increase of tolerance in the skin-twitch method suggests antinociception, depression of amplitude height of the SEP reflects laboratory attenuation of pain by inhibition in the propagation of sensory nervous afferents to higher cortical centers (15, 16). However, aside from its potency, HS-198 does not induce the usual respiratory depressive effect of the classical µ-ligand SUF as demonstrated by the changes in PaO2 and PaCO2. Although HS-198 resulted in no respiratory effect, it should be substantiated by a CO-response curve study. However, we felt the rebreathing technique is unsuitable in the present experimental paradigm, because it would result in manipulation of the animal with a substantial increase in vigilance effecting respiration (17,18). Thus, to evaluate any dose-related change in respiratory drive, one would need an experimental paradigm devoid of any stimulation, as it more closely reflects the clinical situation. This is also underlined by clinical observations in which the respiratory depressive effect of an opioid can be partially antagonized simply by increasing vigilance through a painful or auditory stimulus. As to the mode of action of the lesser respiratory depressive effect of HS-198, several lines of evidence suggest that the compound has partial agonist activity. This assumption is underlined by the following: 1) Changes in the band and ß band of the EEG demonstrate a ceiling effect at the larger doses (<6 µg/kg). Such a U-shape dose-response is typical for other partial agonists, such as pentazocine (19) and nalbuphine (20) showing limited respiratory depression. 2) There was no full reversal of the increase of tolerance to the skin-twitch by NAL. The antagonist, although being a selective µ-antagonist (21), is not selective enough to antagonize other opioid subreceptor-related antinociceptive properties. Our data support the notion that antinociceptive activity of HS-198 is not mediated totally via µ-receptor binding. Opioid binding at µ-isosites that mediate morphine-related analgesia, but not respiratory impairment, have to be considered (3). This suggestion is corroborated by data from others (22) demonstrating that µ-deficient CXBK strain of mice totally lacked HS-198-related analgesia. On the other hand, simultaneous -interaction is also possible. The latter assumption is underlined by data with SUF which, given together with a pure -ligand U-50,488H, resulted in additive antinociceptive effect, however, with less respiratory impairment (23).
Similar to SUF, HS-198 induced marked sedative properties. In this regard, the EEG is a reliable method to quantify any centrally mediated sedative properties of opioids. Any increase in domain with simultaneous decline of power in the ß domain is a definite sign for sedative properties of opioids (24,25). However, sedation was more pronounced after SUF than after HS-198, supporting the notion that other receptor sites are involved in the mediation of central effects. This is emphasized by the observation that the increase of power in the band of the EEG reached a ceiling effect at dosages >6 µg/kg. A ceiling effect had also been demonstrated for antinociception in mice (6) and other partial agonists, such as buprenorphine (26,27); and mixed agonist/antagonists, such as nalbuphine (20) and pentazocine (28), also demonstrate such a trait. Although having similar antinociceptive potency, HS-198 induced a less bradycardic and hypotensive effect compared with the same dose of the potent µ-type ligand SUF. This supports the assumption that bradycardia and respiratory impairment tentatively are mediated via opioid receptors which represent a distinct entity apart of the usual µ-receptor system (29,30).
Our findings with HS-198 thus support the hypothesis that, aside from µ-receptor mediated antinociception, other receptor site(s) are involved in the mediation of sedation, respiratory depression, and bradycardia (4,30). Because pure -ligands, such as bremazocine (31) or tifluadom (32), also result in no respiratory impairment, have little effect on the cardiovascular system, induce pronounced sedation, and demonstrate a ceiling effect for antinociception, -receptor interaction may be the common denominator of cardiovascular and EEG effects after HS-198 ingestion. However, before making such a definite conclusion on the mode of action of HS-198, a selective -antagonist, such as nor-BNI (33) would have to demonstrate full reversal of HS-198-related changes.
In conclusion, HS-198 appears to be a very potent opioid analgesic with partial agonist activity. As to the mode of action, it is unclear whether µ-isoreceptors or -opioid binding sites are involved in the mediation of effects. Its lack in respiratory impairment, however, makes it a very promising drug which warrants further studies of its exact mode of action and its potential usefulness in humans.
Footnotes
Preliminary results were presented at the International Anesthesia Research Society (IARS) Meeting, Los Angeles, March 1999.
References
This article has been cited by other articles:
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  L. Mahurter, C. Garceau, J. Marino, H. Schmidhammer, G. Toth, and G. W. Pasternak Separation of Binding Affinity and Intrinsic Activity of the Potent {micro}-Opioid 14-Methoxymetopon J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 247 - 253. [Abstract] [Full Text] [PDF]
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