Endomorphin-1 and endomorphin-2: pharmacology of the selective endogenous μ-opioid receptor agonists

Horváth, Gyöngyi

doi:10.1016/s0163-7258(00)00100-5

Cited by 117 publications

(72 citation statements)

References 91 publications

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“…The analgesic capacity of endomorphin 1 is generally equipotent with that of morphine but in some models is more effective than morphine and other -opioid receptor agonists (for review, see ref. 17). Endomorphin 1-like immunoreactivity has recently been identified in rat knee joints (18,19), where the peptide has the potential to act as an endogenous modulator of peripheral hyperalgesia, although this has yet to be tested.…”

mentioning

confidence: 99%

Chronic arthritis down‐regulates peripheral μ‐opioid receptor expression with concomitant loss of endomorphin 1 antinociception

Proud

Zhang

et al. 2005

Arthritis & Rheumatism

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Objective. To determine whether peripheral administration of the endogenous -opioid peptide endomorphin 1 could reduce knee joint pain, using animal models of acute and chronic arthritis.Methods. Extracellular electrophysiologic recordings were made of rat knee joint primary afferent nerve activity in response to noxious hyperrotation of the joint. Neuronal activity was assessed before and following local injection of endomorphin 1. Comparisons were made between normal knees and knees with adjuvantinduced monarthritis, tested at 48 hours and 1 week posttreatment. Expression of -opioid receptors in the dorsal root ganglia ipsilateral to the chronically inflamed joints was determined by real-time polymerase chain reaction (PCR) and immunohistochemical analysis.Results. In normal knees, endomorphin 1 caused up to a 75% reduction in joint afferent nerve activity, which was blocked by the -opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-amide. The inhibitory effect of endomorphin 1 was sustained in acutely inflamed knees. Conversely, in chronically inflamed joints, endomorphin 1 had no observable effect on the primary afferent nerve firing rate elicited by a noxious mechanical stimulus and, as such, was significantly different from the rate in normal joints. Immunohistochemical and real-time PCR analysis of the L3-L5 dorsal root ganglia ipsilateral to the chronic arthritis lesion revealed a reduction in -opioid receptor protein and gene expression compared with that in normal control animals.Conclusion. Taken together, these results provide the first electrophysiologic evidence that selective activation of peripheral -opioid receptors reduces normal knee joint mechanosensitivity to a noxious stimulus. Furthermore, the analgesic effect of endomorphin 1 is lost during chronic inflammation due to downregulation of -opioid receptor expression in afferent nerve cell bodies. These findings begin to explain the ambiguous efficacy of peripherally administered -opioid drugs in controlling chronic inflammatory joint pain.

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confidence: 99%

Chronic arthritis down‐regulates peripheral μ‐opioid receptor expression with concomitant loss of endomorphin 1 antinociception

Proud

Zhang

et al. 2005

Arthritis & Rheumatism

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“…This conclusion has been confirmed by many physiological and pharmacological studies (6, 11, 16, 27, 31, 37 -46) and has been reviewed (47,48). From the morphological point of view, endomorphin-like immunoreactivity has been found in many areas in the brain and the spinal cord that contain MOP-Rs (23 -27, 30, 36, 47).…”

Section: The Morphological Relationships Between Endomorphins and Mop-rmentioning

confidence: 77%

Recent Advances in the Search for the N-Opioidergic System: Morphological Studies of the Endomorphinergic Neurons in the Central Nervous System

Wang

Zadina

Guan

et al. 2002

Japanese Journal of Pharmacology

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ABSTRACT-Endomorphins (EMs) are newly found endogenous opioid peptides. Both endomorphin-1 (EM-1) and -2 (EM-2) are composed of four amino acids. Their high affinity and specificity for m-opioid receptors have been confirmed by many physiological and pharmacological studies. In the present minireview, we discuss the distribution and localization of these peptides. While EM-2 is more prevalent in the spinal cord and lower brainstem, EM-1 is more widely and densely distributed throughout the brain than EM-2. We also discuss the possible coexistence of EM with other neurotransmitters. Finally, we introduce some new results regarding the ultrastructure and synaptic relationships of EM-2 obtained by the immunoelectron microscopic method.Keywords: Endomorphin, Distribution, Coexistence, Ultrastructure, SynapseEndomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2) are endogenous agonists for the m-opioid receptors (MOP-R) first isolated from bovine (1) and then from human brain cortex (2). Endomorphins (EMs) activate G-proteins (3 -6) and inhibit calcium (7,8) and activate potassium (9) channels. The peptides have been reported to be involved in many physiological phenomena, including pain modulation (1, 10 -14), feeding responses (15), oxygen consumption (16), blood pressure regulation (17 -19) and modulation of endocrine function (20,21). EMs are the only endogenous peptides that exhibit high affinity and selectivity for MOP-R. In addition, EM-1 is the first agonist for MOP-R shown to produce profound potent analgesia in the absence of reward behavior, indicating significant clinical potential (22). For these reasons, the morphological study of the endomorphinergic neurons in the central nervous system is of extraordinary interest. EM-1 has been shown to be the predominant form in the brain, while EM-2 is predominant in the spinal cord (23). We discuss them separately and then discuss the relationship to MOP-R. We also report some recent findings concerning the ultrastructure and synaptic relationships of the EM-2-like immunoreactive (EM2-LI) neuronal processes in the dorsal horn of the spinal cord. The distribution of the EM2-LI neurons in the central nervous systemThe first paper on the distribution of the EM2-LI neurons was published in 1997 (24) soon after the discovery of this peptide (1). In the first paper, the EM2-LI varicose fibers were reported in a long, narrow region, extending from the open medulla oblongata to the lowest level of the sacral spinal cord. Most of these immunoreactive fibers were distributed in the superficial laminae of the spinal dorsal horn and the entire region of the spinal trigeminal tract. The nucleus of the solitary tract, the parasolitary nucleus, the lateral reticular nucleus, and the nucleus ambiguus were also reported as containing EM2-LI fibers (24). Subsequently, the distribution of the EM2-LI fibers in the spinal cord was confirmed many times and by different laboratories (23, 25 -30). Similarly, many studies contributed data concerning the a...

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“…The efficacies of endomorphins were found to be lower than that of DAMGO in [ CHO cells in mouse [103]. These investigations suggest that µ-opioid receptor gene products play a key role in G-protein activation by endomorphins, and µ-opioid receptor densities could be rate-limiting steps in the G-protein activation by the µ-receptor reserve [9].…”

Section: Function Of Endomorphinsmentioning

confidence: 83%

Design, synthesis and pharmacological evaluation of novel endomorphin analogues with multiple structural modifications

Mallareddy

Borics

Keresztes

et al. 2011

Pharmacological Reports

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Endomorphin-1 and endomorphin-2: pharmacology of the selective endogenous μ-opioid receptor agonists

Cited by 117 publications

References 91 publications

Chronic arthritis down‐regulates peripheral μ‐opioid receptor expression with concomitant loss of endomorphin 1 antinociception

Chronic arthritis down‐regulates peripheral μ‐opioid receptor expression with concomitant loss of endomorphin 1 antinociception

Recent Advances in the Search for the N-Opioidergic System: Morphological Studies of the Endomorphinergic Neurons in the Central Nervous System

Design, synthesis and pharmacological evaluation of novel endomorphin analogues with multiple structural modifications

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