Dissociation of analgesic and rewarding effects of endomorphin-1 in rats

Wilson, Aimee M; Soignier, R. Denis; Zadina, James E.; Kastin, Abba J.; Nores, William L.; Olson, Richard D.; Olson, Gayle A.

doi:10.1016/s0196-9781(00)00340-5

Cited by 74 publications

(57 citation statements)

References 14 publications

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“…The discrepancy between the results obtained in rats and mice might be explained by the pharmacogenetic differences between animals, that is, the differential expression of target sites, as well as species differences in the endomorphin-modulated rewarding. As suggested by Wilson et al (2000), the length of conditioning trials in the conditioned place preference test might also have been a critical factor for the absence of the rewarding effect in rats.…”

Section: A Biological Effects Of Endomorphinsmentioning

confidence: 99%

The Endomorphin System and Its Evolving Neurophysiological Role

Fichna

Janecka²,

Costentin³

et al. 2007

Pharmacol Rev

222

171

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Section: A Biological Effects Of Endomorphinsmentioning

confidence: 99%

The Endomorphin System and Its Evolving Neurophysiological Role

Fichna

Janecka²,

Costentin³

et al. 2007

Pharmacol Rev

222

171

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“…They are thought to inhibit pain without some of the undesirable side effects of morphine. Particularly, the rewarding effect of EM-1 can be separated from analgesia (Wilson et al, 2000), and it is less prone to induce respiratory depression and cardiovascular effects at effective antinociceptive doses (Czapla et al, 2000). However, EM-1 still suffers from serious limitations including short dura-tion of action, lack of oral activity, relative inability to cross the BBB into the CNS, and poor metabolic stability (Tö mbö ly et al, 2002).…”

mentioning

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

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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.

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“…Another study showed a dissociation of analgesic and rewarding effects of endomorphin-1 in rats (24). If corroborated by further studies at different doses, this could indicate that the potent effects of endomorphin-1 on pain might not be associated with the addictive properties of reward.…”

Section: Bodymentioning

confidence: 83%

Facilitated Delivery of Endomorphins and Morphine into the CNS

Kastin¹

2001

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Public reporting burden for this collection of information Is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget, Paperwork Reduction Project (0704-0188), Washington, DC 20503 AGENCY USE ONLY (Leave blank) 2. REPORT DATEMarch 2 001 REPORT TYPE AND DATES COVEREDAnnual (1 Mar 00 -28 Feb 01) TITLE AND SUBTITLE Facilitated Delivery of Endomorphins and Morphine Into the CNS AUTHOR(S)Abba J. Kastin, M, D. FUNDING NUMBERSDAMD17-00-1-0113 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Veteran Affairs Medical Center New Orleans, Louisiana 70112-1262PERFORMING ORGANIZATION REPORT NUMBER Endomorphins, endogenous brain opiates with the highest affinity and specifity for the mu opiate receptor, potently produce analgesia. A rapid brain-to-blood efflux system could give misleading results when entry rates are determined. Preliminary results show that endomorphin-1 and endomorphin-2 are saturably transported from brain to blood, as shown by self-inhibition by an excess ofthat peptide. There also was cross-inhibition of each endomorphin by the other, indicating shared components for the efflux system. CGRP, substance P, or constriction of the sciatic nerve did not decrease efflux. Furthermore, chronic pain induced by sciatic nerve constriction caused a striking decrease in endomorphin-2 immunoreactivity on the nerve-injured side in the spinal cord. Preliminary results also indicate that immunoreactive substance P, but not CGRP, was modestly reduced on the injured side, showing that immunoreactive endomorphin-2 in the spinal cord is decreased during the development of chronic pain. We also found a dissociation of analgesic and rewarding effects of endomorphin-1 in rats. This could indicate that the potent effects of endomorphin-1 on pain might not always be associated with the addictive properties of reward. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)U14. SUBJECT TERMS pain, endomorphins, peptides, blood-brain barrier, INTRODUCTION:The main purpose of this research is to examine the crossing of the blood-brain barrier (BBB) by the endomorphins. Endomorphin-1 and endomorphin-2 have been isolated by us from human and bovine brain (12,25). They represent the brain opiates with the highest affinity and specificity for the mu opiate receptor, which is the site of most of morphine's actions. They produce analgesia in mice with a potency similar to that of morphine. We are studying how their passage across the BBB is influenced by pain and its modulating peptides. BODY:Determination of the rate of entry of subs...

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Dissociation of analgesic and rewarding effects of endomorphin-1 in rats

Cited by 74 publications

References 14 publications

The Endomorphin System and Its Evolving Neurophysiological Role

The Endomorphin System and Its Evolving Neurophysiological Role

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

Facilitated Delivery of Endomorphins and Morphine into the CNS

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