Very few discoveries in the neurosciences have triggered clinical speculation and experimentation regarding the etiology of psychiatric illness to the same extent as that following identification of the opiate receptor(s) and subsequent isolation of endogenous morphine-like peptides. There is overwhelming evidence in animals and in human that opioids are involved in behaviorally relevant issues such as the modulation of pain, the response to stress, motivation, addiction, sexuality, food intake, etc., but our knowledge on the possible relation between opioids and mental illness is still very limited.These responses could be explored eitheir by using higlhy selective delta agonist or by emphasizing the effects of phasically secreted endogenous opioid peptides, enkephalin. Both approaches were investigated in particular through protection of enkephalin degradation by dual enkephalinase ihibitors DENKIs such as RB101, PL37 or PL265.

2014-04-09·The Journal of Neuroscience1区 · 医学

TGF-β and Opioid Receptor Signaling Crosstalk Results in Improvement of Endogenous and Exogenous Opioid Analgesia under Pathological Pain Conditions

1区 · 医学

Article

作者: Bernard P. Roques ; Mónica Tramullas ; Aquilino Lantero ; María A. Hurlé ; Fuencisla Pilar-Cuéllar ; Elsa M. Valdizán ; Rosa Santillán

Transforming growth factor-β1 (TGF-β1) protects against neuroinflammatory events underlying neuropathic pain. TGF-β signaling enhancement is a phenotypic characteristic of mice lacking the TGF-β pseudoreceptor BAMBI (BMP and activin membrane-bound inhibitor), which leads to an increased synaptic release of opioid peptides and to a naloxone-reversible hypoalgesic/antiallodynic phenotype. Herein, we investigated the following: (1) the effects ofBAMBIdeficiency on opioid receptor expression, functional efficacy, and analgesic responses to endogenous and exogenous opioids; and (2) the involvement of the opioid system in the antiallodynic effect of TGF-β1.BAMBI-KO mice were subjected to neuropathic pain by sciatic nerve crash injury (SNI). Gene (PCR) and protein (Western blot) expressions of μ- and δ-opioid receptors were determined in the spinal cord. The inhibitory effects of agonists on the adenylyl cyclase pathway were investigated. Two weeks after SNI, wild-type mice developed mechanical allodynia and the functionality of μ-opioid receptors was reduced. By this time,BAMBI-KO mice were protected against allodynia and exhibited increased expression and function of opioid receptors. Four weeks after SNI, when mice of both genotypes had developed neuropathic pain, the analgesic responses induced by morphine and RB101 (an inhibitor of enkephalin-degrading enzymes, which increases the synaptic levels of enkephalins) were enhanced inBAMBI-KO mice. Similar results were obtained in the formalin-induced chemical-inflammatory pain model. Subcutaneous TGF-β1 infusion prevented pain development after SNI. The antiallodynic effect of TGF-β1 was naloxone-sensitive. In conclusion, modulation of the endogenous opioid system by TGF-β signaling improves the analgesic effectiveness of exogenous and endogenous opioids under pathological pain conditions.

2012-01-01·Neuropsychopharmacology1区 · 医学

Endogenous Opioids as Physiological Antidepressants: Complementary Role of Delta Receptors and Dopamine

1区 · 医学

Article

作者: Emily M Jutkiewicz ; Bernard P Roques

A review.μ- And δ-Opioid receptors have been investigated for potential antidepressant activity, using exogenous agonists and antagonists for both receptors and enkephalin (ENKs) protected from their inactivating enzymes by dual inhibitors such as RB101 (N-(R,S)-2-benzyl-3- ((S)(2-amino-4-methyl-thio)-butyldithio)- 1-oxopropyl)-1-phenylalanine benzyl ester), which induced a synaptic enhancement of phasically released ENKs, to develop fast-acting therapeutics for severe depression, particularly in adolescents.In animal models, exogenous delta agonists such as SNC80 (( + )- 4-(aR)-a-((2S,5R)-2,5-dimethyl-4-(2- propenyl)-1-piperazinyl)-(3-methoxyphenyl) methyl)-N,N-diethylbenzamide induce highly significant antidepressant effects whereas mu agonists do not.This is associated with an increase in brain-derived neurotrophic factor mRNA, which has been suggested to have a role in antidepressant effects, as well as an indirect increase in DA efflux into the striatum.Dtimulation of opioid receptors by RB101 protected ENKs does not induce the undesirable side effects of morphine.The key role of interconnected endogenous opioid and dopaminergic systems in mood control is demonstrated by the facilitation of antidepressant-like effects of RB101 after deafferentation of the dopaminergic mesolimbic pathway, which increases the concentrations of PENK and ENKs.Taken together, these results suggest a phasic control of the dopaminergic mesolimbic pathway by ENKs, which may be impaired in depressive-like syndromes, and clin. studies are starting to investigate this endogenous opioid-DA interaction in human depression.

100 项与 RB-101 相关的药物交易

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