Endomorphins exit the brain by a saturable efflux system at the basolateral surface of cerebral endothelial cells

Vı́gh, József; Kastin, Abba J.; Liao, Jie; Zadina, James E.; Pan, Weihong

doi:10.1007/s00221-003-1774-0

Cited by 18 publications

(11 citation statements)

References 33 publications

(30 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to the necessity for enzymic stability, it is widely accepted that peptides must cross the BBB to reach the CNS in an amount sufficient to act on appropriate receptors to exert the desired pharmacological effects (Gentry et al, 1999;Habgood et al, 2000). Recently, EM-1 and EM-2 have been demonstrated to have a saturable efflux system at the BBB (Kastin et al, 2001;Somogyvari-Vigh et al, 2004), which removes the peptides from the CNS, thus limiting brain uptake. Therefore, peptides need to find alternative transcellular pathways to increase their entry into the CNS for their potent biological activity, for example, by passive diffusion.…”

Section: Discussionmentioning

confidence: 99%

Utilization of Combined Chemical Modifications to Enhance the Blood-Brain Barrier Permeability and Pharmacological Activity of Endomorphin-1

Liu²,

Yao³

et al. 2006

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The endogenous -opioid receptor agonist, endomorphin (EM)-1, cannot be delivered into the central nervous system (CNS) in sufficient quantity to elicit analgesia when given systemically because it is severely restricted by the blood-brain barrier (BBB). To improve the physicochemical characteristics of EM-1 and subsequently achieve greater BBB permeation, we synthesized a series of EM-1 analogs by combining successful chemical modifications, including N-terminal cationization, Cterminal chloro-halogenation, and unnatural amino acid (D-Ala, Sar, and D-Pro-Gly) substitutions in position 2. Presently, their binding and bioassay activity, lipophilicity, stability, and antinociceptive activity were determined and compared. Guanidinoaddition and chloro-halogenation attenuated the -receptor affinity to some extent, but they demonstrated differences in the influence on stability. It appeared that guanidino-addition contributed to brain stability enhancement for the greater part, whereas chloro-halogenation together with amino acid substitutions in position 2 was of more importance for the stability enhancement in serum than in brain. Determination of the octanol/buffer coefficient revealed that chloro-halogenation did compromise the decreased lipophilicity caused by guanidinoaddition, and introduction of D-Ala as well as D-Pro-Gly, but not Sar, in place of L-Pro 2 , also increased the overall lipophilicity to some extent. Among the peptides tested, intracerebroventricular injection of guanidino-[D-Ala 2 , p-Cl-Phe 4 ]EM-1 showed the strongest analgesia, being 3 times more potent than the parent peptide. We also found that in comparison with EM-1, the four D-Ala-containing tetrapeptides and the chloro-halogenated DPro-Gly-containing pentapeptide elicited significant and prolonged central-mediated analgesia upon subcutaneous administration, indicating that more peptides reached the CNS, eliciting greater analgesic effect.

show abstract

Section: Discussionmentioning

confidence: 99%

Utilization of Combined Chemical Modifications to Enhance the Blood-Brain Barrier Permeability and Pharmacological Activity of Endomorphin-1

Liu²,

Yao³

et al. 2006

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Moreover, leucocytes have been also demonstrated to express MaRs, thus allowing to hypothesize that EM-1 could exert multiple analgesic/anti-inflammatory effects in both an autocrine and paracrine fashion (22)(23)(24). Notably, recent evidence demonstrated that EM-1 can actively cross the blood-brain barrier (BBB), thus diffusing into the blood and possibly reaching distant inflamed tissues (4)(5), also affecting the functions of circulating MaR-expressing cells.…”

Section: Discussionmentioning

confidence: 99%

“…from the central nervous system (4)(5). Coherently, EM-l presence has been traced in many peripheral inflamed tissues, where it has proven to significantly decrease sensory neuron firing rate (6)(7) and, most notably, to significantly suppress the release of inflammatory factors from macrophages, which mainly accounts for the development of any algesic reaction occurring in peripheral tissues (6).…”

mentioning

confidence: 99%

Endomorphin-1 Inhibits the Activation and the Development of a Hyporesponsive-like Phenotype in Lipopolysaccharide-Stimulated THP-1 Monocytes

Izzi

Chiurchiù

D'Aquilio

et al. 2008

Int J Immunopathol Pharmacol

View full text Add to dashboard Cite

Endomorphin-l (EM-I) is an endogenous opioid peptide selectively binding to J1 opioid receptors (MORs). Besides its analgesic effects on the central nervous system (CNS), it has been recently reported that EM-l can cross the blood-brain barrier (BBB) and diffuse into the blood, behaving as an analgesic/ anti-inflammatory molecule on peripheral tissues, thus leading to the hypothesis that it could represent a soluble modulator of immune cell functions. Interestingly, nothing is known about its possible effects on monocytes, the main circulating cell-type involved in those systemic responses, such as fever and septic states, involving the release of high amounts of pyrogenic inflammatory factors. The aim of this work is to evaluate possible EM-leffects on Iipopolisaccharide (LPS)-stimulated THP-I monocytes in terms of the production of inflammatory mediators and the instauration of a hyporesponsive-Iike phenotype which is a main feature of systemic inflammatory responses, and on the development of peripheral monocytes to DC. Our data demonstrate for the first time that EM-I is able to inhibit both LPS-stimulated monocyte activation, in terms of arachidonic acid, PGE 2 , ROI and NO z production and instauration of a hypo responsive phenotype without any macroscopic effect on DC development. These data support the hypothesis that EM-I could be involved in modulating monocyte functions during systemic inflammatory reactions, also providing new evidence for its eventual clinical application in endotoxic states.Endomorphin-I (EM-I) is an ammidated tetrapeptide discovered by Zadina et aL in human tissues mostly belonging to the nervous and the immune system (1-2). To date, EM-l is thought to be a powerful endogenous analgesic molecule, 'as its presence in the nervous system has been traced in those areas involved in pain perception (nociception) and in the spinal antinociceptive descending pathways (2-3). Notably, it has also been recently demonstrated that EM-l can cross the blood-brain barrier (BBB), thus entering the blood flow and possibly reaching areas of the body far

show abstract

“…These transport systems, known as peptide transport system (PTS)-1, PTS-2, PTS-3, and PTS-4, are Na ϩ -independent and show no involvement of metabolic energy. Another transport system that is specific for endomorphins has also been described in the blood-brain barrier (Kastin et al, 2001;Somogyvari-Vigh et al, 2004). A distinct transport system specific for deltorphins, which shows partial Na ϩ dependence but with no evidence of concentrative uptake, has been described in brain microvessels (Fiori et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Differential Modulation of Sodium- and Chloride-Dependent Opioid Peptide Transport System by Small Nonopioid Peptides and Free Amino Acids

Miyauchi¹,

Gopal²,

Thakkar³

et al. 2007

J Pharmacol Exp Ther

View full text Add to dashboard Cite

We recently identified a novel opioid peptide transport system in the retinal pigment epithelium that transports opioid peptides by a Na ϩ /Cl Ϫ -dependent process. Here we describe a similar transport system expressed in SK-N-SH cells (a human neuronal cell line) and show for the first time that the activity of the transport system is modulated differentially by lysine and small nonopioid peptides. The transport process in SK-N-SH cells, monitored with deltorphin II as the substrate, is Na ϩ /Cl Ϫ -dependent and interacts with several opioid peptides, consisting of 5 to 13 amino acids. The activity of this transport system is markedly stimulated by specific dipeptides and tripeptides, with significant stimulation observable at low micromolar concentrations. The ion dependence, Na ϩ /Cl Ϫ -activation kinetics, and opioid peptide selectivity of the transport system, however, remain unchanged. The stimulation by the modulatory peptides is associated with an increase in maximal velocity with no change in substrate affinity of the system. Amino acids have no or little effect on the transport system, with the exception of lysine. This cationic amino acid inhibits the transport system, with significant inhibition occurring at physiologic concentrations of the amino acid. The inhibitory effect is primarily associated with a decrease in the maximal velocity of the transport system with little change in substrate affinity. Methyl and ethyl esters of lysine retain the inhibitory potency, but most other structural analogs have no effect. The differential modulation of the transport system by lysine and specific small peptides has important implications in the biology and pharmacology of opioid peptides.

show abstract

Endomorphins exit the brain by a saturable efflux system at the basolateral surface of cerebral endothelial cells

Cited by 18 publications

References 33 publications

Utilization of Combined Chemical Modifications to Enhance the Blood-Brain Barrier Permeability and Pharmacological Activity of Endomorphin-1

Utilization of Combined Chemical Modifications to Enhance the Blood-Brain Barrier Permeability and Pharmacological Activity of Endomorphin-1

Endomorphin-1 Inhibits the Activation and the Development of a Hyporesponsive-like Phenotype in Lipopolysaccharide-Stimulated THP-1 Monocytes

Differential Modulation of Sodium- and Chloride-Dependent Opioid Peptide Transport System by Small Nonopioid Peptides and Free Amino Acids

Contact Info

Product

Resources

About