Search

Rotigotine-loaded microspheres (RoMS) are sustained-release formulations with prolonged anti-Parkinson's effects. Given that pain is a non-motor symptom of Parkinson's disease, this study investigated the antinociceptive effects of RoMS and their synergistic effects with analgesics on inflammatory pain. A model of inflammatory pain was prepared by intraplantarly injecting male Sprague-Dawley rats with carrageenan. The antinociceptive effects of RoMS, acetaminophen, and tramadol, both alone and in combination, were evaluated using the hind paw withdrawal latency in the hot plate test and Randall-Selitto test. The rotigotine concentrations in serum and tissues were assayed using ultra-performance liquid chromatography-tandem mass spectrometry. Isobolographic analysis was performed to evaluate the nature of the interactions of RoMS with acetaminophen or tramadol. The results showed that hind paw withdrawal latency to thermal and mechanical stimuli was significantly increased on day 3 and 7 after administered RoMS. Rotigotine could be detected in serum and tissues 3 and 7 days after an intramuscular injection of RoMS. However, the rotigotine concentration fell the detection limit of the assay on day 14 after administration. RoMS produced synergistic antinociceptive effects in the inflammatory pain model when RoMS is combined with acetaminophen or tramadol. These findings suggest that RoMS can relieve inflammatory pain in rats. Furthermore, the combination of RoMS with acetaminophen or tramadol produces synergistic antinociception, which may be clinically worthy because combination therapies may reduce the drug doses required for antinociception., (Copyright © 2020. Published by Elsevier B.V.)

Anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic, neuropathic pain. We obtained a phenoxyalkylaminoalkanol derivative, KM-416 which had previously demonstrated a significant anticonvulsant activity and had also been shown to bind to 5-HT 1A , α 2 -receptors and SERT and not to exhibit mutagenic properties. As KM-416 is a promising compound in our search for drug candidates, in the present study we further assessed its pharmacological profile (analgesic, local anesthetic, and antidepressant-like activities) accompanied with patch-clamp studies. Considering the importance of drug safety, its influence on the cardiovascular system was also evaluated. Moreover, KM-416 was subjected to forced degradation and pharmacokinetic studies to examine its stability and pharmacokinetic parameters. KM-416 revealed a significant antinociceptive activity in the tonic - the formalin test, neurogenic - the capsaicin test, and neuropathic pain model - streptozotocin-induced peripheral neuropathy. Moreover, it exerted a local anesthetic effect. In addition, KM-416 exhibited anti-depressant like activity. The results from the patch-clamp studies indicated that KM-416 can inhibit currents elicited by activation of NMDA receptors, while it also exhibited a voltage-dependent inhibition of Na + currents. KM-416 did not influence ventricular depolarization and repolarization. Following oral administration, pharmacokinetics of KM-416 was characterized by a rapid absorption in the rat. The brain-to-plasma AUC ratio was 6.7, indicating that KM-416 was well distributed to brain. The forced degradation studies showed that KM-416 was very stable under stress conditions. All these features made KM-416 a promising drug candidate for further development against neuropathic pain and epilepsy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Exogenous cannabinoid receptor agonists are clinically effective for treating chronic pain but frequently cause side effects in the central nervous system. Fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme for anandamide, an endogenous cannabinoid agonist. 3-Pyridyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (ASP8477) is a potent and selective FAAH inhibitor that is orally active and able to increase the brain anandamide level and is effective in rat models of neuropathic and osteoarthritis pain without causing motor coordination deficits. In the present study, we examined the pharmacokinetics and pharmacodynamics, analgesic spectrum in pain models, and the anti-nociceptive mechanism of ASP8477. Single and four-week repeated oral administration of ASP8477 ameliorated mechanical allodynia in spinal nerve ligation rats with similar improvement rates. Further, single oral administration of ASP8477 improved thermal hyperalgesia and cold allodynia in chronic constriction nerve injury rats. ASP8477 also restored muscle pressure thresholds in reserpine-induced myalgia rats. This analgesic effect of ASP8477 persisted for at least 4 h, consistent with the inhibitory effect observed in an ex vivo study using rat brain as well as the increasing effect on oleoylethanolamide and palmitoylethanolamide levels but not the ASP8477 concentration in rat brain. ASP8477 also improved α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-, N-methyl-D-aspartic acid (NMDA)-, prostaglandin E 2 -, prostaglandin F 2α -, and bicuculline-induced allodynia in mice, showing broader analgesic spectra than existing drugs. In contrast, however, ASP8477 did not affect acute pain. These results indicate that the FAAH inhibitor ASP8477 exerts analgesic effects on neuropathic and dysfunctional pain, and its pharmacological properties are suitable for use in treating chronic pain., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cathepsin S (CatS) is a cysteine protease found in lysosomes of hematopoietic and microglial cells and in secreted form in the extracellular space. While CatS has been shown to contribute significantly to neuropathic pain, the precise mechanisms remain unclear. In this report, we describe JNJ-39641160, a novel non-covalent, potent, selective and orally-available CatS inhibitor that is peripherally restricted (non-CNS penetrant) and may represent an innovative class of immunosuppressive and analgesic compounds and tools useful toward investigating peripheral mechanisms of CatS in neuropathic pain. In C57BL/6 mice, JNJ-39641160 dose-dependently blocked the proteolysis of the invariant chain, and inhibited both T-cell activation and antibody production to a vaccine antigen. In the spared nerve injury (SNI) model of chronic neuropathic pain, in which T-cell activation has previously been demonstrated to be a prerequisite for the development of pain hypersensitivity, JNJ-39641160 fully reversed tactile allodynia in wild-type mice but was completely ineffective in the same model in CatS knockout mice (which exhibited a delayed onset in allodynia). By contrast, in the acute mild thermal injury (MTI) model, JNJ-39641160 only weakly attenuated allodynia at the highest dose tested. These findings support the hypothesis that blockade of peripheral CatS alone is sufficient to fully reverse allodynia following peripheral nerve injury and suggest that the mechanism of action likely involves interruption of T-cell activation and peripheral cytokine release. In addition, they provide important insights toward the development of selective CatS inhibitors for the treatment of neuropathic pain in humans., Competing Interests: Declaration of competing interest All authors are current or former (Cai, Karlsson, Wiener) employees of Janssen Research & Development, L.L.C., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic pain. The aim of the present experiments was to examine analgesic activity of three new 3,3-diphenyl-propionamides, which had previously demonstrated anticonvulsant activity in the MES (maximal electroshock seizure), scPTZ (subcutaneous pentylenetetrazole) and/or 6Hz (psychomotor seizure) tests in mice. Antinociceptive activity was examined in mouse models of acute pain (the hot plate test) and tonic pain (the formalin test) in mice. Antiallodynic and antihyperalgesic activity was estimated in the oxaliplatin-induced neuropathic pain model of chemotherapy-induced peripheral neuropathy and in the streptozotocin-induced model of painful diabetic neuropathy in mice. Considering the drug safety evaluation, the influence on locomotor activity was checked. Moreover, using in vitro methods, selected compound was tested for potential hepatotoxicity on human hepatocellular carcinoma cell line and for metabolic stability. To determine the plausible mechanism of anticonvulsant and antinociceptive action, in vitro binding and functional assays were carried out. Among tested molecules two of them JOA 122 (3p) and JOA 123 (3q) revealed significant antinociceptive activity in the model of tonic pain - the formalin test and neuropathic pain models - the oxaliplatin and streptozotocin-induced peripheral neuropathy. In the binding studies JOA 122 (3p) revealed the high affinity to voltage-gated sodium channels (Na v 1.2), as well as for 5-HT 1A receptors. Metabolism studies in mouse liver microsomes showed a low metabolic stability of this compound., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Pregabalin, a ligand of alpha(2)delta subunits of voltage-gated calcium channels, reduces visceral hypersensitivity associated with irritable bowel syndrome. However, effects of pregabalin on bowel function are not well described. We investigated the effects of pregabalin on bowel dysfunction and colonic nociceptive threshold in sensitized rats. Increased fecal pellet output was evoked by non-ulcerogenic stress. Decreased colonic nociceptive threshold was induced in separate rats by administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the lumen of the proximal colon. Fecal pellet output was significantly increased during 2h restraint stress. Oral pregabalin (10-100mg/kg, p.o.) inhibited this increased fecal output dose-dependently, but did not change fecal output in naïve rats. The response threshold to distension of the non-inflamed distal colon was significantly decreased seven days after TNBS administration. An anti-hyperalgesic effect of pregabalin (30-100mg/kg, p.o.) that opposed the decreased colonic nociceptive threshold in TNBS-sensitized rats was observed, but nociceptive thresholds were not changed in naïve rats. Moreover, pregabalin was more potent in reducing disturbed defecation compared with reduction in nociceptive threshold to distension in TNBS-sensitized rats. This is the first report that pregabalin modulates stress-induced defecation in rats. These data indicate that pregabalin can ameliorate both altered defecation and decreases in colonic nociceptive threshold, suggesting that pregabalin might warrant investigation for the treatment of irritable bowel syndrome., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Metabotropic glutamate receptor 1 (mGlu(1) receptor) has been suggested to play an important role in pain transmission. In this study, the effects of a newly-synthesized mGlu(1) receptor antagonist, (R)-N-cycloheptyl-6-({[(tetrahydro-2-furyl)methyl]amino}methyl)thieno[2,3-d]pyrimidin-4-ylamine (YM-230888), were examined in a variety of rodent chronic pain models in order to characterize the potential analgesic profile of mGlu(1) receptor blockade. YM-230888 bound an allosteric site of mGlu(1) receptor with a K(i) value of 13+/-2.5 nM and inhibited mGlu(1)-mediated inositol phosphate production in rat cerebellar granule cells with an IC(50) value of 13+/-2.4 nM. It showed selectivity for mGlu(1) versus mGlu(2)-mGlu(7) subtypes and ionotropic glutamate receptors. YM-230888 recovered mechanical allodynia with an ED(50) value of 8.4 mg/kg p.o. in L5/L6 spinal nerve ligation models. It also showed antinociceptive response at doses of 10 and 30 mg/kg p.o. in streptozotocin-induced hyperalgesia models. In addition, it significantly reduced pain parameters at a dose of 30 mg/kg p.o. in complete Freund's adjuvant-induced arthritic pain models. Although YM-230888 showed no significant effect on rotarod performance time at doses of 10 or 30 mg/kg p.o., it significantly decreased it at a dose of 100 mg/kg p.o. On the other hand, YM-230888 showed no significant sedative effect in locomotor activity measurement up to 100 mg/kg p.o. These results suggest that the blockade of mGlu(1) receptors is an attractive target for analgesics. YM-230888 has potential as a new analgesic agent for the treatment of various chronic pain conditions. In addition, YM-230888 may be a useful tool for the investigation of mGlu(1) receptors.

The antinociceptive profile of selected histamine H(2) and histamine H(3) receptor antagonists led to the discovery of improgan, a non-brain-penetrating analgesic agent which does not act on known histamine receptors. Because no chemical congener of improgan has yet been discovered which has both antinociceptive and brain-penetrating properties, the present study investigated the antinociceptive effects of a series of chemical compounds related to zolantidine, a brain-penetrating histamine H(2) receptor antagonist. The drugs studied presently contain the piperidinomethylphenoxy (PMPO) moiety, hypothesized to introduce brain-penetrating characteristics. Following intracerebroventricular (i.c.v.) dosing in rats, six of eight drugs produced dose- and time-related antinociception on both the tail flick and hot plate tests over a nearly eight-fold range of potencies. Ataxia and other motor side effects were observed after high doses of these drugs, but two of the compounds (SKF94674 and loxtidine) produced maximal antinociception at doses which were completely devoid of these motor effects. Consistent with the hypothesis that PMPO-containing drugs are brain-penetrating analgesics, SKF94674 and another derivative (JB-9322) showed dose-dependent antinociceptive activity 15 to 30 min after systemic dosing in mice, but these effects were accompanied by seizures and death beginning 45 min after dosing. Other drugs showed a similar pattern of antinociceptive and toxic effects. In addition, loxtidine produced seizures without antinociception, whereas zolantidine produced neither effect after systemic dosing in mice. Although several of the drugs tested have histamine H(2) receptor antagonist activity, neither the antinociception nor the toxicity was correlated with histamine H(2) receptor activity. The present results are the first to demonstrate the existence of brain-penetrating antinociceptive agents chemically related to zolantidine and improgan, but further studies are needed to understand the mechanisms of both the pain relief and toxicity produced by these agents.

The objective of this investigation was to characterise the pharmacokinetic-pharmacodynamic correlation of adenosine A1 receptor partial agonists in the chronic constriction injury model of neuropathic pain. Following intravenous administration of 8-methylamino-N6-cyclopentyl-adenosine (MCPA; 10 mg/kg) and 2'deoxyribose-N6-cyclopentyl-adenosine (2'dCPA; 20 mg/kg), the time course of the effect on the mechanical paw pressure threshold was determined in conjunction with plasma concentrations. Population pharmacokinetic/pharmacodynamic analysis was applied to derive individual concentration-effect relationships. A composite model consisting of an E(max) model for the anti-hyperalgesic effect in combination with a linear model for the anti-nociceptive effect accurately described the concentration-effect relationship. For both compounds, a full anti-hyperalgesic effect was observed. The values of the EC50 for the anti-hyperalgesic effect were (mean+/-S.D.): 3170+/-1460 and 2660+/-1200 ng/ml for MCPA and 2'dCPA versus 178+/-51 ng/ml for the reference full agonist 5'deoxyribose-N6-cyclopentyl-adenosine (5'dCPA). The values of the slope for the anti-nociceptive effect were 1.9+/-0.30 and 1.2+/-0.20 g.microl/ng, respectively, versus 55+/-8 g microl/ng for 5'dCPA. Adenosine A1 receptor partial agonists behave as full agonists with regard to the anti-hyperalgesic effect in neuropathic pain, but the anti-nociceptive effect is diminished.

Sprague-Dawley rats from two different vendors, Möllegård, Denmark and B&K Universal, Sweden, have been tested for the antinociceptive effect of morphine, methadone, buprenorphine and codeine on the hot plate. Morphine and methadone had significantly weaker effect in Möllegård rats compare to B&K rats. In contrast, the effect of buprenorphine was stronger in Möllegård rats than in B&K rats and the effect of codeine was similar in the two substrains. Plasma levels of morphine, morphine-6-glucuronide, morphine-3-glucuronide, buprenorphine and norbuprenorphine were determined at two time points after drug injection. Möllegård rats had significantly lower mean plasma level of morphine and significantly higher ratio of morphine-3-glucuronide/morphine at 30 min, compared to B&K rats. No difference was seen for the metabolism of buprenorphine in the two substrains. The results suggest that Möllegård rats metabolize morphine to morphine-3-glucuronide to a greater extent than B&K rats, and this may at least partly underlie the substrain difference in the effect of morphine. It is also suggested that the antinociceptive mechanisms of buprenorphne may be different from those of morphine and methadone.

Kynurenic acid as an endogenous ligand antagonizes all types of ionotropic glutamate receptors, with preferential affinity for the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor. The purpose of the present study was to investigate the antinociceptive potency of continuously administered kynurenic acid on carrageenan-induced thermal hyperalgesia by means of a paw withdrawal test in awake rats. The possible interaction between kynurenic acid and the endogenous mu-opioid receptor agonist peptide, endomorphin-1, was examined in the same set-up. Kynurenic acid at the higher doses (1-4 microg/min) significantly decreased the thermal hyperalgesia and increased the paw withdrawal latencies on the non-inflamed side. These doses were also associated with motor impairment on both sides. Low doses of kynurenic acid (0.01-0.1 microg/min) potentiated, but did not prolong, the antinociceptive effect of endomorphin-1 (0.1-1 microg/min) on the inflamed side. There was no sign of motor impairment during the combined treatment. These findings demonstrate that the combination of low doses of these two endogenous ligands provides effective and well-controlled antinociception without side effects.

The dermorphin-derived peptide [Dmt(1)]DALDA (H-Dmt-D-Arg-Phe-Lys-NH(2)), labels mu-opioid receptors with high affinity and selectivity in receptor binding assays. In mouse, radiant heat tail-flick assay [Dmt(1)]DALDA produced profound spinal and supraspinal analgesia, being approximately 5000- and 100-fold more potent than morphine on a molar basis, respectively. When administered systemically, [Dmt(1)]DALDA was over 200-fold more potent than morphine. Pharmacologically, [Dmt(1)]DALDA was distinct from morphine. [Dmt(1)]DALDA displayed no cross-tolerance to morphine in the model used and it retained supraspinal analgesic activity in morphine-insensitive CXBK mice. Supraspinally, it also differed from morphine in its lack of sensitivity towards naloxonazine. Finally, in antisense mapping studies, [Dmt(1)]DALDA was insensitive to MOR-1 exon probes that reduced morphine analgesia, implying a distinct receptor mechanism of action. Thus, [Dmt(1)]DALDA is an interesting and extraordinarily potent, systemically active peptide analgesic, raising the possibility of novel approaches in the design of clinically useful drugs.

The objective of this study was to investigate the effects of single and repeated administration of CP-55,940 [(-)-cis-3-[2-hydroxy-4-(1, 1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol)] on behaviour, energy metabolism and biotransformation. Single intraperitoneal administration to male Sprague-Dawley rats of CP-55,940 (0.4 mg/kg), induced a behavioural response characterized by 'splayed hind limbs', antinociception, hypothermia and a decrease in locomotor activity. Brain and liver mitochondria of the CP-55,940-treated rats exhibited an increase in respiration and no changes in ADP/O and citrate synthase specific activity. Repeated intraperitoneal administration of CP-55,940 (0.4 mg/kg, 11 days) induced behavioural tolerance, disappearance of the increase in the mitochondrial oxygen consumption as well as an increase in the monooxygenase activities and the content of liver microsomal cytochrome P450. Some hepatic metabolizing enzymes of the cytosolic glutathione-centre system were also affected. Previous studies had indicated that the tolerance after chronic administration of CP-55,940 could be due to down-regulation of brain cannabinoid receptors. The present findings demonstrate that the behavioural tolerance occurs together with modified biotransformation activities.

Past studies have shown antagonists of excitatory amino acid receptors, both N-methyl-D-aspartate (NMDA) and non-NMDA, to produce an antinociceptive effect in vitro and in vivo. Additionally, NMDA receptor antagonists have been demonstrated to prevent morphine tolerance. We had found that one NMDA receptor antagonist, ketamine, potentiates morphine's analgesic effect in post-operative patients. Our latest experiment was performed to examine the modulatory effect of competitive and non-competitive NMDA receptor antagonists on morphine antinociception and tolerance. A PE10 catheter was intrathecally (i.t.) implanted in male Sprague-Dawley rats for drug administration. The antinociceptive effect of morphine, D-(-)-2-amino-5-phosphonovaleric acid (D-AP5) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate (MK-801) was measured using the hot-water tail immersion test. Neither competitive nor non-competitive NMDA receptor antagonists had an antinociceptive effect by themselves, but they did potentiate the antinociceptive effect of morphine. Both D-AP5 (AD50 = 0.18 micrograms) and MK-801 (AD50 = 0.57 micrograms) shifted the antinociceptive dose-response curve of morphine (AD50 = 4.2 micrograms) to the left. Both D-AP5 (4 micrograms/h) and MK-801 (10 micrograms/h) when co-administered with i.t. morphine infusions (10 micrograms/h) also inhibited the development of tolerance. In [3H][D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin ([3H]DAMGO) binding assays, MK-801 (Bmax = 32.90 +/- 3.33 fmol/mg) treatment prevented the down-regulation of mu-opioid receptor high-affinity sites induced by continuous morphine infusions alone (Bmax = 13.97 +/- 1.47 fmol/mg). D-AP5 (Bmax = 20.78 +/- 3.36 fmol/mg) did not prevent the reduction of mu-opioid receptor high-affinity sites. However, high-affinity sites in rats treated with D-AP5 and morphine displayed a higher affinity (KD = 0.45 +/- 0.09 nM) than those of control animals (KD = 0.95 +/- 0.08 nM). Results of this study indicate that competitive as well as non-competitive NMDA receptor antagonists enhance morphine's antinociceptive effect, and prevent the development of morphine tolerance. Thus, in our opinion, there opens a new frontier in clinical pain management, especially for those patients who require long-term opioid treatment for pain relief.

Influence of dosing time on pharmacological effects and toxicity of acetylsalicylic acid was investigated in ICR male mice under light-dark (12:12) cycle. Significant circadian rhythms (day-night rhythms) were demonstrated for hypothermal and analgesic effects at 1 h after an injection of acetylsalicylic acid (200 mg/kg, i.p.) (P < 0.01, respectively). The rhythmic patterns of acetylsalicylic acid induced analgesia and hypothermia resembled overall the rhythms occurring in the non-drugged state. Injection of acetylsalicylic acid resulted in a parallel increase in latency to hot plate and a parallel decrease in rectal temperature. The relationship between plasma salicylate concentrations and responses was not clear. There was also a significant circadian rhythm in acetylsalicylic acid (850 mg/kg, i.p.) induced toxicity with the highest mortality at 17:00 and the lowest one at 05:00 (P < 0.05). Dosing time dependent kinetics of salicylate seems to be related to the rhythm of toxicity of the drug. The time in circadian stage at which acetylsalicylic acid is administered is essentially important in the actions of acetylsalicylic acid.

This study tested the hypothesis that compounds which may bind simultaneously to delta and mu receptors may be more potent antinociceptive agents than would be predicted from their binding affinities at individual mu and delta opioid receptors. D-Tca-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 ([D-Tca1]CTAP) (where D-Tca is a cyclic D-tryptophan analogue) was synthesized and evaluated in radioligand competition assays, opioid bioassays, and in an antinociceptive assay (the tail-flick test in mice). Additionally, the metabolic stability of [D-Tca1]CTAP was evaluated in striatal and cerebellar tissue slices. In rat brain in vitro, [D-Tca1]CTAP competed weakly for sites labelled by [3H]D-Phe-Cys-Tyr-D-Trp-Om-Thr-Pen-Thr-NH2 ([3H]CTOP) (mu-ligand), and [3H][D-Pen2,pCl-Phe4,D-Pen5]enkephalin (delta-ligand); [D-Pen2,D-Pen5]enkephalin (DPDPE) (delta-agonist) was 6.5-fold less and 230-fold more potent, respectively, against these ligands. Additionally, in mouse isolated vas deferens and guinea pig isolated ileum smooth muscle preparations, [D-Tca1]CTAP proved to be weak as either a delta (IC50 of approximately 2 microM) or mu (IC50 > 8 microM) receptor agonist. Surprisingly, however, i.c.v. [D-Tca1]CTAP produced antinociception with potency similar to DPDPE. The antinociceptive actions of [D-Tca1]CTAP were apparently not due to a metabolite or the release of endogenous opioids, as this compound proved stable in both striatal and cerebellar tissue slices and its antinociceptive actions were not enhanced by the 'enkephalinase' inhibitor thiorphan. The suggestion that [D-Tca1]CTAP might be acting by binding simultaneously to mu and delta receptors to produce its antinociceptive effect is supported by the demonstrated antagonism resulting from mu receptor blockade with either beta-funaltrexamine (beta-FNA) or naloxonazine, or by delta receptor blockade by ICI 174,864 ([N,N-diallyl-Tyr1,Aib2,3,Leu5] enkephalin). Furthermore, the antinociceptive properties of [D-Tca1]CTAP were antagonized by (naltrindole-5'-isothiocyanate) (5'-NTII), an antagonist at the delta 2 opioid receptor subtype, but not by the delta 1 antagonist [D-Ala2,D-Leu5,Cys6]enkephalin (DALCE). Additionally, no antagonism was produced by nor-binaltorphimine (nor-BNI), a kappa antagonist. From these data, [D-Tca1]CTAP appears to bind to mu, and 5'-NTII-sensitive delta 2, opioid receptors, and may represent the first of a class of compounds which may act at an opioid receptor complex via 'self-potentiation'.