ABSTRACT(Ϫ)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl) is a novel -opioid receptor (MOR) agonist (K i ϭ 0.1 M; relative efficacy compared with morphine 88% in a [35 S]guanosine 5Ј-3-O-(thio)triphosphate binding assay) and NE reuptake inhibitor (K i ϭ 0.5 M for synaptosomal reuptake inhibition). In vivo intracerebral microdialysis showed that tapentadol, in contrast to morphine, produces large increases in extracellular levels of NE (ϩ450% at 10 mg/kg i.p.). Tapentadol exhibited analgesic effects in a wide range of animal models of acute and chronic pain [hot plate, tail-flick, writhing, Randall-Selitto, mustard oil colitis, chronic constriction injury (CCI), and spinal nerve ligation (SNL)], with ED 50 values ranging from 8.2 to 13 mg/kg after i.p. administration in rats. Despite a 50-fold lower binding affinity to MOR, the analgesic potency of tapentadol was only two to three times lower than that of morphine, suggesting that the dual mode of action of tapentadol may result in an opiate-sparing effect. A role of NE in the analgesic efficacy of tapentadol was directly demonstrated in the SNL model, where the analgesic effect of tapentadol was strongly reduced by the ␣ 2 -adrenoceptor antagonist yohimbine but only moderately attenuated by the MOR antagonist naloxone, whereas the opposite was seen for morphine. Tolerance development to the analgesic effect of tapentadol in the CCI model was twice as slow as that of morphine. It is suggested that the broad analgesic profile of tapentadol and its relative resistance to tolerance development may be due to a dual mode of action consisting of both MOR activation and NE reuptake inhibition.

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Buprenorphine is a potent opioid analgesic with partial agonistic properties at mu-opioid receptors. This study investigated the interaction potential with several full mu-agonists in the tail-flick test in mice. We further examined the reversibility of buprenorphine antinociception by different mu-opioid receptor antagonists. Combination of buprenorphine with morphine, oxycodone, hydromorphone and fentanyl in the analgesic dose range resulted in additive or synergistic effects. When given after the decline of the acute buprenorphine effect, both morphine and fentanyl also showed full efficacy. A moderate antagonistic effect according to the partial mu-agonistic properties of buprenorphine was only seen when high doses exceeding the therapeutic dose ranges were combined. Under these conditions antinociception of morphine was reduced to the effect of buprenorphine alone. Prophylactic administration of naloxone (10 mg/kg i.v.), naltrexone (1 mg/kg i.v.) and clocinnamox (5 mg/kg s.c.) fully and persistently blocked the antinociception of a high dose of buprenorphine. An established effect of buprenorphine was less sensitive, although repeated administration of naloxone induced complete antagonism, as did the irreversible antagonist clocinnamox under prophylactic and curative treatment conditions. Our results suggest that the antinociceptive effect of buprenorphine is mainly, if not exclusively, mediated by activation of mu-opioid receptors. They confirm clinical experience that in the analgesic dose range a switch between buprenorphine and full mu-agonists is possible without loss of analgesic efficacy and without a refractory period between the termination of buprenorphine analgesia and the onset of action of the new mu-opioid treatment. Antinociception of buprenorphine is sensitive towards mu-opioid receptor antagonists and incomplete inhibition can be improved by increasing the dose or repetitive dosing.

1 The centrally acting analgesic tramadol has recently been reported to cause seizures at recommended dosages in patients, whereas animal experiments had indicated that seizures only occur in high, toxic doses. Tramadol has a dual mechanism of action that includes weak agonistic eects at the mu-opioid receptor as well as inhibition of monoamine (serotonin, norepinephrine) re-uptake. Its major (M1) metabolite mono-O-desmethyltramadol, which is rapidly formed in vivo, has a markedly higher anity for mu receptors and may thus contribute to the eects of the parent compound. Furthermore, the pharmacological eects of tramadol appear to be related to the dierent, but complementary and interactive pharmacologies of its enantiomers. In the present study, we evaluated (+)-tramadol, its enantiomers, and its M1 metabolite ((+)-enantiomer) in the amygdala kindling model of epilepsy in rats. Adverse eects determined in kindled rats were compared to those in nonkindled rats. 2 At doses within the analgesic range, (+)-tramadol and its enantiomers induced anticonvulsant eects in kindled rats. However, at only slightly higher doses seizures occurred. With (+)-tramadol, generalized seizures were observed at 30 mg kg 71 in most kindled but not in nonkindled rats. The (7)-enantiomer induced myoclonic seizures at 30 mg kg 71 in most kindled but not in nonkindled rats, although myoclonic seizure activity was observed in some nonkindled rats at 10 or 20 mg kg 71 . Seizures were also observed after the (+)-enantiomer and the (+)-enantiomer of the M1 metabolite, but experiments with higher doses of these compounds were limited by marked respiratory depression. 3 The data demonstrate that kindling enhances the susceptibility of rats to convulsant adverse eects of tramadol and its enantiomers, indicating that a preexisting lowered seizure threshold increases the risk of tramadol-induced seizures.