UMLS:C0278080 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The dimeric enkephalin biphalin (Try-D-Ala-Gly-Phe-NH)2 was evaluated in mice using antinociceptive, gastrointestinal and physical dependence paradigms and compared with that of morphine (reference mu agonist) and etorphine (ultrapotent opioid agonist). Intracerebroventricular biphalin was 6.7- and 257-fold more potent than etorphine or morphine in eliciting antinociception. When administered i.t., biphalin produced only a 60% maximal antinociceptive effect in the tail-flick test even when given at doses up to 3 orders of magnitude higher than those effective i.c.v.; morphine was equipotent in this assay when given i.c.v. or i.t. Both morphine and biphalin were equipotent after i.p. administration. In spite of its antinociceptive effectiveness after i.p. administration. In spite of its antinociceptive effectiveness after i.p. administration, only a small fraction of [125I]biphalin was shown to penetrate to the brain (0.051 +/- 0.011%, at 20 min). After i.c.v. administration, biphalin antinociception was antagonized by receptor selective doses of beta-funaltrexamine (mu antagonist), naloxonazine (mu 1 antagonist), ICI 174,864 (delta antagonist) and [D-Ala2,Cys4]deltorphin (delta 2 antagonist), but not by [D-Ala2,Leu5,Cys6]enkephalin (delta 1 antagonist) or nor-binaltorphimine (kappa antagonist), whereas etorphine antinociception was significantly antagonized only by beta-funaltrexamine and naloxonazine. Intracerebroventricular biphalin inhibited gastrointestinal propulsion at doses 8-fold higher than those producing i.c.v. antinociception; i.c.v. morphine showed a similar antinociceptive and gastrointestinal propulsion A50. Intraperitoneal biphalin, but not i.p. morphine, showed little, if any, physical dependence, but both biphalin and morphine produced significant physical dependence when equiantinociceptive doses were infused i.c.v.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antinociceptive profile of biphalin, a dimeric enkephalin analog. 838 67

Previous studies measuring opioid inhibition of cyclic adenosine monophosphate in SH-SY5Y cells supported the hypothesis that continuous agonist stimulation causes a gradual conversion of the mu opioid receptor to a sensitized or constitutively active state termed mu*. Conversion to mu* was prevented by the kinase inhibitor H7, but not its close analog H8. Naloxone was proposed to act as a negative antagonist (inverse agonist) blocking mu* activity, whereas D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) appeared to act as a neutral antagonist having no effect on mu* activity. Initial in vivo results indicated that mu* activity may play a role in narcotic tolerance and dependence (Wang et al., Life Sci. 54: PL339-PL350 1994). Our study explores the pharmacology of H7 and H8, naloxone and CTAP in mice after induction of acute tolerance and dependence induced by a single s.c. dose of morphine (100 mg/kg). Physical dependence was defined by withdrawal jumping induced by i.p. naloxone injections 4 hr after the morphine dose, the time of maximal physical dependence. Neither H7 nor H8 (50 nmol or less) induced jumping, affected morphine antinociception or produced significant behavioral effects, when injected by the intracerebroventricular (i.c.v.) or intrathecal (i.th.) routes. When given 30 min before the naloxone challenge, H7, but not H8, significantly reduced naloxone jumping by i.c.v. injection. Administration of naloxone into the central nervous system, rather than by i.p. administration, required coinjection by both i.c.v. and i.th. routes to elicit full withdrawal jumping (30 nmol at each site). In contrast, the putative neutral antagonist CTAP caused little withdrawal jumping when coinjected i.c.v. and i.th., as expected if modulation of mu* activity played a role in dependence. However, CTAP was capable of partially reversing naloxone (i.p.) induced jumping when given either i.c.v. or i.th., indicating that CTAP competes with naloxone at mu*. Moreover, these results demonstrate that both spinal and supraspinal sites are required for full opioid withdrawal jumping in mice. Antinociceptive tolerance was also evaluated by determining the response to morphine in the 55 degrees C warm-water tail-flick test. Morphine pretreatment (100 mg/kg, s.c., -5 hr) produced antinociceptive tolerance as shown by a 2.7-fold increase in the calculated morphine A50 value. Tolerance was reversed by H7, but not H8, treatment (50 nmol, i.c.v., -30 min). These results are consistent with the hypothesis that a sensitized or constitutively active mu* state plays a role in narcotic tolerance and dependence.
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PMID:Effects of naloxone and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 and the protein kinase inhibitors H7 and H8 on acute morphine dependence and antinociceptive tolerance in mice. 861 58

1. Morphine produces a plethora of pharmacological effects and its chronic administration induces several side-effects. The cellular mechanisms by which opiates induce these side-effects are not fully understood. Several studies suggest that regulation of adenylyl cyclase activity by opioids and other transmitters plays an important role in the control of neural function. 2. The aim of this study was to evaluate desensitization of mu- and delta- opioid receptors, defined as a reduced ability of opioid agonists to inhibit adenylyl cyclase activity, in four different brain structures known to be involved in opiate drug actions: caudate putamen, nucleus accumbens, thalamus and periaqueductal gray (PAG). Opiate regulation of adenylyl cyclase in these regions has been studied in control and morphine-dependent rats. 3. The chronic morphine treatment used in the present study (subcutaneous administration of 15.4 mg morphine/rat/day for 6 days via osmotic pump) induced significant physical dependence as indicated by naloxone-precipitated withdrawal symptoms. 4. Basal adenylyl cyclase in the four brain regions was not modified by this chronic morphine treatment. In the PAG and the thalamus, a desensitization of mu- and delta-opioid receptors was observed, characterized by a reduced ability of Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO; mu), Tyr-D-Pen-Gly-Phe-D-Pen (DPDPE; delta) and [D-Ala2]-deltorphin-II (DT-II; delta) to inhibit adenylyl cyclase, activity following chronic morphine treatment. 5. The opioid receptor desensitization in PAG and thalamus appeared to be heterologous since the metabotropic glutamate receptor agonists, L-AP4 and glutamate, and the 5-hydroxytryptamine (5-HT)1A receptor agonist, R(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), also showed reduced inhibition of adenylyl cyclase activity following chronic morphine treatment. 6. In the nucleus accumbens and the caudate putamen, desensitization of delta-opioid receptor-mediated inhibition without modification of mu-opioid receptor-mediated inhibition was observed. An indirect mechanism probably involving dopaminergic systems is proposed to explain the desensitization of delta-mediated responses and the lack of mu-opioid receptor desensitization after chronic morphine treatment in caudate putamen and nucleus accumbens. 7. These results suggest that adaptive responses occurring during chronic morphine administration are not identical in all opiate-sensitive neural populations.
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PMID:Differential desensitization of mu- and delta- opioid receptors in selected neural pathways following chronic morphine treatment. 882 58

Opioid compounds with mixed mu agonist/delta antagonist properties are expected to be analgesics with low propensity to produce tolerance and dependence. In an effort to strengthen the mu agonist component of the mixed mu agonist/delta antagonist H-Tyr-Tic-Phe-Phe-NH(2) (TIPP-NH(2)), analogues containing structurally modified tyrosine residues in place of Tyr(1) were synthesized. Among the prepared compounds, H-Dmt-Tic-Phe-Phe-NH(2) (DIPP-NH(2); Dmt = 2',6'-dimethyltyrosine) and H-Dmt-TicPsi[CH(2)NH]Phe-Phe-NH(2) (DIPP-NH(2)[Psi]) retained a mixed mu agonist/delta antagonist profile, as determined in the guinea pig ileum and mouse vas deferens assays, whereas H-Tmt-Tic-Phe-Phe-NH(2) (Tmt = N,2',6'-trimethyltyrosine) was a partial mu agonist/delta antagonist and H-Tmt-TicPsi[CH(2)NH]Phe-Phe-NH(2) was a mu antagonist/delta antagonist. DIPP-NH(2)[Psi] showed binding affinities in the subnanomolar range for both mu and delta receptors in the rat brain membrane binding assays, thus representing the first example of a balanced mu agonist/delta antagonist with high potency. In the rat tail flick test, DIPP-NH(2)[Psi] given icv produced a potent analgesic effect (ED(50) = 0.04 microg), being about 3 times more potent than morphine (ED(50) = 0.11 microg). It produced less acute tolerance than morphine but still a certain level of chronic tolerance. Unlike morphine, DIPP-NH(2)[Psi] produced no physical dependence whatsoever upon chronic administration at high doses (up to 4.5 microg/h) over a 7-day period. In conclusion, DIPP-NH(2)[Psi] fulfills to a large extent the expectations based on the mixed mu agonist/delta antagonist concept with regard to analgesic activity and the development of tolerance and dependence.
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PMID:The opioid mu agonist/delta antagonist DIPP-NH(2)[Psi] produces a potent analgesic effect, no physical dependence, and less tolerance than morphine in rats. 1047 85

The discovery of the prototype delta opioid antagonists TIPP (H-Tyr-Tic-Phe-Phe-OH) and TIP (H-Tyr-Tic-Phe-OH) in 1992 was followed by extensive structure-activity relationship studies, leading to the development of analogues that are of interest as pharmacological tools or as potential therapeutic agents. Stable TIPP-derived delta opioid antagonists with subnanomolar delta receptor binding affinity and extraordinary delta receptor selectivity include TIPP[Psi] (H-Tyr-TicPsi[CH(2)NH]Phe-Phe-OH] and TICP[Psi] (H-Tyr-TicPsi[CH(2)NH]Cha-Phe-OH); Cha: cyclohexylalanine), which are widely used in opioid research. Theoretical conformational analyses in conjunction with the pharmacological characterization of conformationally constrained TIPP analogues led to a definitive model of the receptor-bound conformation of H-Tyr-Tic-(Phe-Phe)-OH-related delta opioid antagonists, which is characterized by all-trans peptide bonds. Further structure-activity studies revealed that the delta antagonist vs delta agonist behavior of TIP(P)-derived compounds depended on very subtle structural differences in diverse locations of the molecule and suggested a delta receptor model involving a number of different inactive receptor conformations. A further outcome of these studies was the identification of a new class of potent and very selective dipeptide delta agonists of the general formula H-Tyr-Tic-NH-X (X = arylalkyl), which are of interest for drug development because of their low molecular weight and lipophilic character. Most interestingly, TIPP analogues containing a C-terminal carboxamide group displayed a mixed mu agonist/delta antagonist profile, and thus were expected to be analgesics with a low propensity to produce tolerance and physical dependence. This turned out to be the case with the TIPP-derived mu agonist/delta antagonist DIPP-NH(2)[Psi] (H-Dmt-TicPsi[CH(2)NH]Phe-Phe-NH(2)); Dmt: 2',6'- dimethyltyrosine).
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PMID:The TIPP opioid peptide family: development of delta antagonists, delta agonists, and mixed mu agonist/delta antagonists. 1079 30

Repeated exposure to mu-opioid analgesics produces unwanted side effects, including tolerance and physical dependence. delta-Opioid antagonists attenuate development of morphine tolerance and physical dependence. We recently reported that SoRI 9409, a mixed mu-agonist/delta-antagonist, produces antinociception with limited development of tolerance after repeated i.c.v. injections. The current studies report on a more complete characterization of the compound in male ICR mice. SoRI 9409 produced limited antinociceptive effects in the 55 degrees C tail-flick test and full agonist effects in the acetic acid writhing assay after i.c.v. or i.p. administration. Repeated i.p. administration of A(90) doses of SoRI 9409 did not produce tolerance. The agonist effects of the compound were preferentially blocked by the mu-selective antagonist beta-funaltrexamine. The kappa-antagonist nor-binaltorphimine produced partial antagonism, whereas the delta-antagonist naltrindole had no effect on SoRI 9409 antinociception. Intraperitoneal administration of SoRI 9409 preferentially antagonized the antinociceptive actions of the delta-2 agonist [D-Ala(2),Glu(4)]deltorphin over the delta-1 agonist cyclic[D-Pen(2),D-Pen(5)]-enkephalin and the mu-agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin. SoRI 9409 did not antagonize the antinociceptive effects of the kappa-agonist U69,593 (doses up to 60 mg/kg). SoRI 9409 (10 mg/kg i.p.) elicited much less vertical jumping than naloxone (10 mg/kg i.p.) in acute and chronic morphine dependence models. SoRI 9409 also suppressed withdrawal jumping when coadministered with naloxone. These studies indicate that SoRI 9409 acts primarily as a partial mu-agonist/delta-antagonist and supports the hypothesis that this type of compound may have a better therapeutic profile than currently available mu-agonists.
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PMID:In vivo pharmacological characterization of SoRI 9409, a nonpeptidic opioid mu-agonist/delta-antagonist that produces limited antinociceptive tolerance and attenuates morphine physical dependence. 1130 48

There is evidence to indicate that opioid compounds with mixed mu agonist/delta antagonist properties are analgesics with low propensity to produce tolerance and physical dependence. A chimeric peptide containing the potent and selective mu agonist H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA) (Dmt=2',6'-dimethyltyrosine) and the potent and selective delta antagonist H-Tyr-TicPsi[CH2-NH]Cha-Phe-OH (TICP[Psi]) (Cha=cyclohexylalanine), connected 'tail-to-tail' via a short linker, was synthesized using a combination of solid-phase and solution techniques. The resulting peptide, H-Dmt-->D-Arg-->Phe-->Lys-NH-CH2-CH2-NH-Phe<--Cha[NH-CH2]PsiTic<--Tyr-H, showed the expected mu agonist/delta antagonist profile in the guinea-pig ileum and mouse vas deferens assays. Its mu and delta receptor binding affinities were in the low nanomolar range, as determined in rat brain membrane binding assays.
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PMID:A chimeric opioid peptide with mixed mu agonist/delta antagonist properties. 1500 27

Two recent developments of opioid peptide-based analgesics are reviewed. The first part of the review discusses the dermorphin-derived, cationic-aromatic tetrapeptide H-Dmt-D-Arg-Phe-Lys-NH(2) ([Dmt(1)]DALDA, where Dmt indicates 2',6'-dimethyltyrosine), which showed subnanomolar mu receptor binding affinity, extraordinary mu receptor selectivity, and high mu agonist potency in vitro. In vivo, [Dmt(1)]DALDA looked promising as a spinal analgesic because of its extraordinary antinociceptive effect (3000 times more potent than morphine) in the mouse tail-flick assay, long duration of action (4 times longer than morphine), and lack of effect on respiration. Unexpectedly, [Dmt(1)]DALDA also turned out to be a potent and long-acting analgesic in the tail-flick test when given subcutaneously (s.c.), indicating that it is capable of crossing the blood-brain barrier. Furthermore, little or no cross-tolerance was observed with s.c. [Dmt(1)]DALDA in morphine-tolerant mice. The second part of the review concerns the development of mixed mu agonist/delta antagonists that, on the basis of much evidence, are expected to be analgesics with a low propensity to produce tolerance and physical dependence. The prototype pseudopeptide H-Dmt-TicPsi[CH(2)NH]Phe-Phe-NH(2) (DIPP-NH(2)[Psi], where Tic indicates 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) showed subnanomolar mu and delta receptor binding affinities and the desired mu agonist/delta antagonist profile in vitro. DIPP-NH(2)[Psi] produced a potent analgesic effect after intracerebroventricular administration in the rat tail-flick assay, no physical dependence, and less tolerance than morphine. The results obtained with DIPP-NH(2)[Psi] indicate that mixed mu agonist/delta antagonists look promising as analgesic drug candidates, but compounds with this profile that are systemically active still need to be developed.
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PMID:Opioid peptide-derived analgesics. 1635 33

The development of the prototype synthetic delta-opioid receptor antagonist peptides TIPP [(H-Tyr-Tic-Phe- Phe-OH); Tic: tetrahydroisoquinoline-3-carboxylic acid] and TIPPpsi (H-Tyr-psiTic-Phe-Phe-OH) by Schiller and coworkers was followed by extensive structure-activity relationship studies, leading to the emergence of numerous analogs that are of pharmacological interest. Eight novel diastereomeric compounds in this peptide family were designed, prepared, and tested biologically to gain structure-activity relationship information. The new multisubstituted tetrapeptide analogs contain both a 2',6'-dimethyltyrosine residue at the N-terminus and beta-methyl-cyclohexylalanine at the third position as replacements for the original first tyrosine and the third phenylalanine, respectively. These derivatives wear either free acidic (-COOH) or amidated (-CONH2) C-terminal. The potency and delta- versus mu-opioid receptor selectivity were evaluated by in vitro radioreceptor-binding assays, while the intrinsic G-protein-activating efficacy of these analogs was tested in [35S]GTPgammaS-binding assays using rat brain membranes or Chinese hamster ovary cells stably expressing mu- or delta-opioid receptors. The analogs showed delta-antagonist selectivity with differences regarding their isomeric forms, and these analogs containing a C-terminal carboxamide group displayed a mixed mu-agonist/delta-antagonist profile, thus they are expected to be safer analgesics with a low propensity to produce tolerance and physical dependence. These results constitute further examples of the influence of beta-methyl substitution and C-terminal amidation on potency, selectivity, and signal transduction properties of TIPP-related peptides as well as they represent valuable pharmacological tools for opioid research.
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PMID:Opioid receptor binding characteristics and structure-activity studies of novel tetrapeptides in the TIPP (Tyr-Tic-Phe-Phe) series. 1677 34

The broad applicability of receptor theory to diverse species, from invertebrates to mammals, provides evidence for the evolution in complexity of pharmacologic receptor diversification and of receptor-effector signal transduction mechanisms. However, pre-mammalian species have less receptor subtype differentiation, and thus, might share signal transduction pathways to a greater extent than do mammals, a phenomenon that we term 'pharmacologic congruence'. We have demonstrated previously that the lowest species considered to have a centralized nervous system, planarians, display both abstinence-induced and antagonist-precipitated withdrawal signs, indicative of the development of physical dependence. We report here: (1) amphetamine abstinence-induced withdrawal, and (2) the attenuation of cocaine and amphetamine, but not cannabinoid agonist (WIN 52212-2), abstinence-induced withdrawal by the opioid receptor antagonist naloxone and by the selective kappa-opioid receptor subtype antagonist nor-BNI (nor-Binaltorphimine), but not by the selective mu-opioid or the delta-opioid receptor subtype antagonists CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)) and naltrindole. These results provide evidence that the withdrawal from cocaine and amphetamine, but not cannabinoids, in planarians is mediated through a common nor-BNI-sensitive (kappa-opioid receptor-like) pathway.
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PMID:The kappa-opioid receptor antagonist nor-BNI inhibits cocaine and amphetamine, but not cannabinoid (WIN 52212-2), abstinence-induced withdrawal in planarians: an instance of 'pharmacologic congruence'. 1817 75

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