Endomorphin-2 is an endogenous opioid in primary sensory afferent fibers

Martin‐Schild, Sheryl; Gerall, Arnold A.; Kastin, Abba J.; Zadina, James E.

doi:10.1016/s0196-9781(98)00136-3

Cited by 102 publications

(78 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Endomorphins not only are potent analgesics but also can participate in immune modulation and behavioral changes (Bujdoso et al 2001), as do other ligands of mu-opiate receptors. The immunoreactivity of endomorphins in the brain and spinal cord under conditions of basal and neuropathic pain has been mapped in our laboratory and others (Martin-Schild et al 1998Pierce et al 1998;Smith et al 2001;Wang et al 2003a;b).…”

Section: Introductionmentioning

confidence: 93%

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

Vı́gh

Kastin

Liao

et al. 2004

Experimental Brain Research

Self Cite

View full text Add to dashboard Cite

Endomorphin-1 (EM-1) and endomorphin-2 (EM-2) are two highly selective mu-opiate receptor agonists. We recently demonstrated that EM-1 and EM-2 have a saturable transport system from brain-to-blood in vivo. Since the endothelial cells are the main component of the non-fenestrated microvessels of the blood-brain barrier (BBB), we examined whether these endogenous tetrapeptides have a saturable transport system in cultured cerebral endothelial cells. EM-1 and EM-2 binding and transport were studied in a transwell system in which primary mouse endothelial cells were co-cultured with rat glioma cells. We found that binding of both endomorphins was greater on the basolateral than the apical cell surface. Flux of EM-1 and EM-2 occurred predominantly in the basolateral to apical direction, each showing self-inhibition with an excess of the respective endomorphin. Transport was not influenced by the addition of the Pglycoprotein inhibitor, cyclosporin A. Neither the mu-opiate receptor agonist DAMGO nor the delta-opiate receptor agonist DPDPE had any effect on the transport. Thus, the results show that a saturable transport system for EM-1 and EM-2 occurs at the level of endothelial cells of the BBB, and unlike β-endorphin and morphine, P-glycoprotein is not needed for the brain-to-blood transport. Cross-inhibition of the transport of each endomorphin by the other suggests a shared transport system that is different from mu-or delta-opiate receptors. As endormorphins are mainly produced in the CNS, the presence of the efflux system at the BBB could play an important role in pain modulation and neuroendocrine control.

show abstract

Section: Introductionmentioning

confidence: 93%

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

Vı́gh

Kastin

Liao

et al. 2004

Experimental Brain Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the dorsal horn of the spinal cord, it has been reported that EM-2 existed in the same neuronal fibers that also showed MOP-R immunoreactivity by two-colored fluorescent immunohistochemistry (25). Because the EM2-LI found in this region was also proposed as originating from the dorsal root ganglions (25), the result suggested the possible presynaptic inhibition by EM-2 on the same primary afferent fiber through the MOP-R (47).…”

Section: The Morphological Relationships Between Endomorphins and Mop-rmentioning

confidence: 97%

“…Because the EM2-LI found in this region was also proposed as originating from the dorsal root ganglions (25), the result suggested the possible presynaptic inhibition by EM-2 on the same primary afferent fiber through the MOP-R (47). The same group has also reported the coexistence of EM-2 and substance P (SP) (24,25), and another group has reported the coexistence of EM-2 and calcitonin gene-related peptide (CGRP) (29).…”

Section: The Morphological Relationships Between Endomorphins and Mop-rmentioning

confidence: 99%

“…Although Martin-Schild et al (24) found so many EM2-LI neuronal perikarya in the dorsal root ganglia in all segments of the spinal cord in that report that they could not report these neurons as EM-2-producing because the immunostaining of those neurons could not be eliminated by preabsorption with excess EM-2 peptides. This question was addressed in the next year by the same group (25). A series of successful experiments showed that chemical disruption of primary sensory afferents by exposure to the primary afferent neurotoxin, capsaicin, virtually abolished EM-2 immunostaining in the spinal cord.…”

Section: The Distribution Of the Em2-li Neurons In The Central Nervoumentioning

confidence: 99%

“…Recent electron microscopic study of the EM2-LI neuronal fibers in the dorsal horn of the spinal cord Although it is suggested that EM-2 may act at both the presynaptic and postsynaptic MOP-R (25,47), there has been no direct anatomical evidence. For this reason, we tried to study the ultrastructure and synaptic relationships of the EM2-LI neuronal fibers (64).…”

Section: The Morphological Relationships Between Endomorphins and Mop-rmentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Differential distribution of endomorphin 1‐ and endomorphin 2‐like immunoreactivities in the CNS of the rodent

et al. 1999

Self Cite

View full text Add to dashboard Cite

Endomorphin-2 is an endogenous opioid in primary sensory afferent fibers

Cited by 102 publications

References 26 publications

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

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

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

Differential distribution of endomorphin 1‐ and endomorphin 2‐like immunoreactivities in the CNS of the rodent

Contact Info

Product

Resources

About