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)

A new met-enkephalin analogue (compound 82/205) was evaluated for its opioidergic activity in mice. The compound showed antinociception (warm water tail-flick test), tolerance, cross tolerance to morphine and physical dependence. The time course of antinociceptive effect of the compound was comparable to morphine. The antinociceptive ED50 (mumol kg-1, i.p.) values for the compound and morphine base were 5.31 and 7.59, respectively. Its antinociceptive effect was blocked by naloxone, beta-FNA (mu antagonist) and naloxonazine (mu1 antagonist) but not by ICI 174,864 (delta antagonist). Naloxone precipitated withdrawal jumpings were 2.6 times less in compound 82/205 treated mice than the morphine treated group. The new analogue compound 82/205 is a potent mu agonist antinociceptive with a possible weak dependence liability.
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PMID:Novel met-enkephalin analogue: a potent systemic mu agonist antinociceptive agent. 747 23

1. In previous studies, we have demonstrated that delta-opioid receptors are involved both in the acute control of hypothalamus-pituitary-adrenocortical (HPA) axis activity and in the development of neuroendocrine opioid tolerance. In the present work we studied whether central delta-opioid receptors play a role in the development of neuroendocrine physical dependence to opioids in the rat. 2. Intracerebroventricular (i.c.v.) administration of the delta-selective agonist DPDPE ([D-Pen2,D-Pen2]enkephalin) produced stimulation of HPA activity, as shown by an increase in corticosterone release. This effect was antagonized by i.c.v. co-administration of ICI 174,864, a selective delta-receptor antagonist, which provide direct evidence that the activation of the HPA axis produced by DPDPE is mediated by central delta-opioid receptor. 3. Chronic pretreatment with i.c.v. DPDPE resulted in tolerance to its neuroendocrine effect. Intracerebroventricular injection of ICI 174,864 to DPDPE-tolerant rats produced neither alteration in corticosterone release nor behaviour signs of dependence. 4. It was concluded that delta-opioid receptors do not play a role in the development of opioid neuroendocrine physical dependence at the HPA axis.
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PMID:Lack of involvement of delta-opioid receptor in mediating physical dependence at the hypothalamus-pituitary-adrenocortical (HPA) axis in the rat. 795 33

Morphine was administered intracerebroventricularly to normal or recombinant inbred CXBK (mu-opioid receptor deficient) mice and antinociception was determined against two different stimuli. Morphine-induced antinociception against acetylcholine was strain-dependent, whereas against endothelin-1 it was not. The antinociception was mediated via opioid mu receptors (blocked by beta-FNA, but not naltrindole, ICI 174,864 or nor-BNI) through separate pathways, one naloxonazine-sensitive and the other naloxonazine-insensitive. Taken together, these results appear to demonstrate supraspinal morphine-induced antinociception through distinct subtypes of the mu opioid receptor, supporting the possibility of novel subtype-selective therapeutic agents with greater separation between analgesia and side-effects or physical dependence. Furthermore, the methodology described herein provides model systems for the in vivo screening of such agents.
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PMID:Opioid mu receptor subtypes (possibly mu 1 and mu 2) revealed by morphine-induced antinociception vs endothelin-1 in recombinant inbred CXBK mice. 828 81

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

Analgesics such as morphine cause many side effects including addiction, but kappa-opioid receptor agonist can produce antinociception without morphine-like side effects. With the aim of developing new and potent analgesics with lower abuse potential, we studied the antinociceptive and physical dependent properties of a derivate of ICI-199441, an analogue of (-)U50,488H, named (2-(3,4-dichloro)-phenyl)-N-methyl-N-[(1S)-1-(2-isopropyl)-2-(1-(3-pyrrolinyl))ethyl] acetamides (LPK-26). LPK-26 showed a high affinity to kappa-opioid receptor with the Ki value of 0.64 nM and the low affinities to micro-opioid receptor and delta-opioid receptor with the Ki values of 1170 nM and >10,000 nM, respectively. It stimulated [(35)S]GTPgammaS binding to G-proteins with an EC50 value of 0.0094 nM. In vivo, LPK-26 was more potent than (-)U50,488H and morphine in analgesia, with the ED50 values of 0.049 mg/kg and 0.0084 mg/kg in hot plat and acetic acid writhing tests, respectively. Moreover, LPK-26 failed to induce physical dependence, but it could suppress naloxone-precipitated jumping in mice when given simultaneously with morphine. Taken together, our results show that LPK-26 is a novel selective kappa-opioid receptor agonist with highly potent antinociception effects and low physical dependence potential. It may be valuable for the development of analgesic and drug that can be used to reduce morphine-induced physical dependence.
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PMID:LPK-26, a novel kappa-opioid receptor agonist with potent antinociceptive effects and low dependence potential. 1835 7