Search

(-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) is a novel human opiate receptor-like orphan receptor (ORL-1) antagonist that has high affinity for the clonal human ORL-1 receptor (hORL-1 K(i) = 0.33 nM), selectivity versus mu-(174-fold), delta-(6391-fold), and kappa (486-fold)-opioid receptors and is able to inhibit nociceptin signaling via hORL-1 in a whole cell gene reporter assay. SB-612111 has no measurable antinociceptive effects in vivo in the mouse hot-plate test after intravenous administration but is able to antagonize the antimorphine action of nociceptin [ED(50) = 0.69 mg/kg, 95% confidence limit (CL) = 0.34-1.21]. SB-62111 administration can also reverse tolerance to morphine in this model, established via repeated morphine administration. In addition, intravenous SB-612111 can antagonize nociceptin-induced thermal hyperalgesia in a dose-dependent manner (ED(50) = 0.62 mg/kg i.v., 95% CL = 0.22-1.89) and is effective per se at reversing thermal hyperalgesia in the rat carrageenan inflammatory pain model. These data show that an ORL-1 receptor antagonist may be a useful adjunct to chronic pain therapy with opioids and can be used to treat conditions in which thermal hyperalgesia is a significant component of the pain response.

The specific involvement of the delta-opioid receptor in the control of nociception was explored by investigating the pharmacological activity in vivo of a selective, orally active, and centrally penetrant delta-opioid agonist. [8R-(4bS*,8aalpha,8abeta,12bbeta)]7,10-dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride (SB-235863) is a new pyrrolomorphinan with high affinity (Ki = 4.81 +/- 0.39 nM) for the delta-opioid receptor, full agonist activity, and binding selectivity versus the mu- and kappa-opioid receptors of 189-fold and 52-fold, respectively. Perorally administered SB-236863 was inactive in the rat tail-flick and hot-plate tests of acute pain response, but potently reversed thermal hyperalgesia in rats resulting from a carrageenan-induced inflammatory response. This activity could be blocked by the delta-opioid antagonist naltrindole (3 mg/kg s.c.), but selective mu- and kappa-opioid antagonists were ineffective. Naltrindole (1 microg i.c.v.) also blocked the activity of 10 mg/kg (p.o.) SB-235863, showing that the compound activates delta-opioid receptor sites in the central nervous system. SB-235863 was additionally effective at reversing chronic hyperalgesia in the Seltzer rat model of partial sciatic nerve ligation after peroral administration. These data show that the delta-opioid receptor plays a selective role in regulating evoked and lasting changes in nociceptive pain signaling. Classical side effects of mu- and kappa-opioid receptor activation (slowing of gastrointestinal transit and motor incoordination, respectively) were not observed after administration of 70 mg/kg (p.o.) SB-235863, nor was evoked seizure activity affected. These results suggest a selective and limited role of delta-opioid receptors in the modulation of nociception.

Strategies for developing selective water diuretic agents have involved development of kappa opioid receptor agonists and vasopressin V2 receptor antagonists; however, these two classes of compounds have not been compared directly. We have investigated the activity of three kappa receptor agonists and one nonpeptide vasopressin receptor antagonist in conscious dogs. SB 215520, SB 215519 and niravoline are selective kappa agonists with variable abilities to cause a water diuresis and ataxia in rats. When administered to conscious hydropenic dogs, the kappa agonists resulted in an increase in free water clearance; however, these effects were associated with an antinatriuresis, an increase in heart rate and, at the higher doses, central nervous system side effects. Conversely, the vasopressin receptor antagonist, OPC 31260, resulted in a significant water diuresis without any accompanying changes in sodium excretion and heart rate, and with no apparent central nervous system effects. These studies suggest that, at least in dogs, a vasopressin receptor antagonist is a more selective water diuretic than a kappa receptor agonist.

Clearance studies in rats using kappa opioid agonists have demonstrated that agonists that can cross the blood-brain barrier are more potent water diuretics than agonists which have limited access to the brain. The mechanism of kappa agonist-induced water diuresis is unclear but may involve inhibition of vasopressin secretion and/or an adrenomedullary factor. In the present study the effect of an alpha-2 adrenoceptor antagonist (yohimbine, 10 micrograms/kg.min i.v.) on kappa agonist-induced water diuresis was evaluated in conscious chronically instrumented rats. BRL 53117 (1-[(3,4-dichlorophenyl)acetyl]-2-[(3-hydroxy-1-pyrrolidinyl) methyl]4,4-dimethyl piperidine), a kappa agonist that can cross the blood-brain barrier, caused a dose-dependent (1-100 micrograms/kg) water diuresis which was attenuated by yohimbine. The effective dose to cause a free water clearnace of zero for BRL 53117 was 13 +/- 5 micrograms/kg in vehicle-treated rats and 37 +/- 12 micrograms/kg in yohimbine-treated rats. BRL 52974 (5-[(3,4-dichlorophenyl)acetyl]4-(1-pyrrolidinylmethyl)-4,5,6,7-te trahydro- 1H-imidazo[4,5-c]pyridine), a compound with limited ability to cross the blood-brain barrier, also caused a dose-dependent water diuresis, albeit at higher doses (30-3000 micrograms/kg), and thus a higher effective dose to cause a free water clearance of zero (129 +/- 61 micrograms/kg); however, the effect was abolished by yohimbine. The data suggest that kappa agonists cause a water diuresis by both a central mechanism involving inhibition of vasopressin secretion and a peripheral mechanism involving stimulation of renal alpha-2 receptors.

Data suggest that kappa opioid agonist-induced water diuresis involves inhibition of vasopressin (AVP) secretion; however, it is not clear whether this action involves kappa receptors in the neurohypophysis or receptors behind the blood-brain barrier (BBB). We have investigated the site of action using three selective kappa agonists, BRL 52656 (S(-)-2-(1-pyrrolidinylmethyl)-1-(4-trifluoromethylphenyl) acetyl piperidine hydrochloride), BRL 53114 ((-)-1-(4-trifluoromethylphenyl) acetyl-2-(1-pyrrolidinymethyl)3,3- dimethyl piperidine hydrochloride) and BRL 52974 (4-(1-pyrrolidinylmethyl)5-(3,4-dichlorophenyl)acetyl-4,5,6,7-t etrahydroimidazo [4,5-c] pyridine), with varying abilities to cross the BBB. Chemical and functional assays indicate that BRL 52974 has limited ability to cross the BBB, whereas BRL 53114 and BRL 52656 can freely penetrate. BRL 52974 was significantly less potent than BRL 52656 and BRL 53114 in causing a water diuresis in conscious rats. The ED10S (i.v. doses to cause a positive free water clearance of 10 microliters/min.100 g) for BRL 52974, BRL 52656 and BRL 53114 were 181, 9 and 3.4 mg/kg, respectively. Furthermore, in dogs BRL 52656 and BRL 53114 but not BRL 52974 (30 micrograms/kg i.v.) were able to cause a significant water diuresis. The data demonstrate that opiate receptors behind the BBB are primarily involved in kappa agonist-induced water diuresis and possibly inhibition of AVP secretion.

The roles of various types of opioid receptors in opioid-induced local inhibition of gastrointestinal transit were studied in rats 5 min after a charcoal meal, injecting i.p. relatively selective agonists and antagonists. The proposed mu agonists, morphine and [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO), and the nonselective delta agonist, [D-Ala2,D-Leu5]enkephalin (DADLE), produced a dose-related inhibition of gastrointestinal transit at the peak time and the i.p. doses producing a 50% reduction of the control values (A50) were 0.015, 0.006 and 0.023 mg/kg, respectively, for morphine, DAMGO and DADLE. The effect of the other nonselective delta agonist, [D-Ser2,L-Leu5]enkephalyl-Thr (DSLET), was not linearly related with the dose. The proposed selective delta agonist, [D-Pen2,D-Pen5]enkephalin (DPDPE), and the selective kappa agonist, U-69,593, up to 2 and 15 mg/kg i.p., respectively, did not delay gastrointestinal transit. Naloxone (0.05 mg/kg i.p.) injected 1 min before each agonist produced a significant parallel shift to the right of the dose-response curves for morphine and DAMGO, but only partly antagonized the effects of DADLE and DSLET. The selective delta antagonist ICI 174,864 (1 mg/kg i.p., injected 1 min before each agonist) shifted the dose-response curve of DADLE, but not of the mu agonists, slightly, but significantly to the right, and had an inconsistent effect on DSLET. Naloxone prevented DADLE's effect on the gut with a nonlinear dose-response curve and much higher doses of naloxone were required to prevent fully DADLE-induced effects than to antagonize doses of morphine equiactive to DADLE on the gut.(ABSTRACT TRUNCATED AT 250 WORDS)