Distribution and targeting of a mu-opioid receptor (MOR1) in brain and spinal cord

Arvidsson, Ulf; Riedl, Maureen; Chakrabarti, Swapan; Lee, Jang Hern; Nakano, Albert H.; Dado, Robert J.; Loh, Horace H.; Law, Ping Yee; Wessendorf, Martin W.; Elde, Robert

doi:10.1523/jneurosci.15-05-03328.1995

Cited by 588 publications

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“…The Mr's of the MORs in the mouse and rat CPu detected with anti-μC are similar to those detected by [ 3 H]β-funaltrexamine labeling [18] or an antiserum against a 15-aa peptide corresponding to amino acid 384-398 predicted from cloned rat MOR-1 [5], for which the whole brains were used. In addition, the Mr of the MOR in the rat thalamus in this study is consistent with that detected by receptor phosphorylation [23].…”

Section: Affinity-purified Rabbit Polyclonal Anti-mor Antibody Anti-mentioning

confidence: 53%

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Brain region-specific N-glycosylation and lipid rafts association of the rat mu opioid receptor

Huang

Chen

et al. 2008

Biochemical and Biophysical Research Communications

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The mu opioid receptor (MOR) in the rat and mouse caudate putamen (CPu) and thalamus was demonstrated as diffuse and broad bands by western blot with polyclonal antibodies against a Cterminal peptide of MOR, which were absent in the cerebellum and brains of MOR-knockout mice. The electrophoretic mobility of MOR differed in the two brain regions with median relative molecular masses (Mr's) of 75 kDa (CPu) vs. 66 kDa (thalamus) for the rat, and 74 kDa (CPu) vs. 63 kDa (thalamus) for the mouse, which was due to its differential N-glycosylation. Rat MOR in CPu was found mainly associated with low-density cholesterol-and ganglioside M1 (GM1)-enriched fractions (lipid rafts), while the MOR in the thalamus was present in rafts and non-rafts without preference. Cholesterol reduction by methyl-β-cyclodextrin decreased DAGMO-induced [ 35 S]GTPγS binding in rat CPu membranes to a greater extent than in the thalamus membranes.

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Section: Affinity-purified Rabbit Polyclonal Anti-mor Antibody Anti-mentioning

confidence: 53%

“…Morphine acts primarily on the MOR [3] and are among the most widely abused drugs. MOR is widely distributed in neurons throughout the brain and spinal cord [4,5].…”

Section: Introductionmentioning

confidence: 99%

Brain region-specific N-glycosylation and lipid rafts association of the rat mu opioid receptor

Huang

Chen

et al. 2008

Biochemical and Biophysical Research Communications

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“…The small population of neurons coexpressing SPR and MORs also makes the formation of heterodimers between these two receptors less likely (37). Anatomical studies illustrate that SPRs are located primarily on the somato-dendritic surfaces of neurons (i.e., postsynaptically), whereas MORs are found both postsynaptically and on axonal components (i.e., presynaptically) (38). ESP7 may, by causing release of chemical mediators from SPR-expressing neurons, be indirectly activating secondary messengers systems within MORexpressing neurons to alter the development of tolerance.…”

Section: Discussionmentioning

confidence: 99%

A substance P-opioid chimeric peptide as a unique nontolerance-forming analgesic

Foran

Carr

Lipkowski

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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To elucidate mechanisms of acute and chronic pain, it is important to understand how spinal excitatory systems influence opioid analgesia. The tachykinin substance P (SP) represents the prototypic spinal excitatory peptide neurotransmitter͞neuromodulator, acting in concert with endogenous opioid systems to regulate analgesic responses to nociceptive stimuli. We have synthesized and pharmacologically characterized a chimeric peptide containing overlapping NH2-and COOH-terminal functional domains of the endogenous opioid endomorphin-2 (EM-2) and the tachykinin SP, respectively. Repeated administration of the chimeric molecule YPFFGLM-NH2, designated ESP7, into the rat spinal cord produces opioid-dependent analgesia without loss of potency over 5 days. In contrast, repeated administration of ESP7 with concurrent SP receptor (SPR) blockade results in a progressive loss of analgesic potency, consistent with the development of tolerance. Furthermore, tolerant animals completely regain opioid sensitivity after post hoc administration of ESP7 alone, suggesting that coactivation of SPRs is essential to maintaining opioid responsiveness. Radioligand binding and signaling assays, using recombinant receptors, confirm that ESP7 can coactivate -opioid receptors (MOR) and SPRs in vitro. We hypothesize that coincidental activation of the MOR-and SPR-expressing systems in the spinal cord mimics an ongoing state of reciprocal excitation and inhibition, which is normally encountered in nociceptive processing. Due to the ability of ESP7 to interact with both MOR and SPRs, it represents a unique prototypic, anti-tolerance-forming analgesic with future therapeutic potential.T he neuropeptide substance P (SP) and endogenous opioids are intimately involved in the regulation of acute and chronic pain transmission (1-6). Overlapping distributions of SP-and opioid-containing neurons, as well as their corresponding G protein-coupled receptors, within the superficial dorsal horn of the spinal cord suggest major SP͞opioid functional interactions (7-9). The superficial dorsal horn is an important site of functional integration and transmission of nociceptive input. Here neuronal signaling is mediated by both SP and excitatory amino acids released from primary afferent terminals with further modulation by opioid peptides originating from secondorder spinal cord neurons. In light of the established literature indicating that SP-and opioid-expressing neurons presumably mediate opposite physiological effects at the spinal level, investigators have tended to overlook the role of SP and SP receptors (SPRs) in the regulation of endogenous opioid systems (10-14), particularly in the area of analgesic responsiveness. Previous pharmacological data from our group strongly suggest that SP released in the dorsal horn plays an important role in antinociception by regulating analgesic activity of the postsynaptic opioid systems (15,16). In particular, we demonstrated that low doses of SP, when coadministered with marginally effective doses of morphine sulfa...

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“…The anti-MOR antibody was a rabbit antiserum raised against amino acids 384-398 of the cloned rat MOR-1 (DiaSorin, Stillwater, MN, catalog no. 24216), which has been characterized (Arvidsson et al, 1995) and shown to label dorsal horn neurons (Spike et al, 2002). Pre-absorption of the MOR antibody with its immunizing peptide (10 µg/ml) abolished the staining.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Noxious mechanical stimulation evokes the segmental release of opioid peptides that induce μ-opioid receptor internalization in the presence of peptidase inhibitors

et al. 2008

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The internalization of μ-opioid receptors (MORs) provides an ideal way to locate areas of opioid peptide release. We used this method to study opioid release in the spinal cord evoked by noxious stimuli in anesthetized rats. Previous studies have shown that opioids released in the spinal cord produce MOR internalization only when they are protected from peptidase degradation. Accordingly, rats were implanted with chronic intrathecal catheters that were used to inject a mixture of peptidase inhibitors (amastatin, captopril and phosphoramidon) onto the lumbar spinal cord. Five minutes later, a noxious stimulus was delivered to the paw. Lumbar spinal segments were double-stained with antibodies against MORs and neurokinin 1 receptors (NK1Rs) using immunofluorescence. Mechanical stimulation of the hindpaw consisted of repeated 10 sec clamps with a hemostat for 10 min. In the ipsilateral dorsal horn, the stimulus produced abundant NK1R internalization in segments L3-L6, and a more modest but significant MOR internalization in segments L5 and L6. In the contralateral dorsal horn, NK1R was substantially lower and MOR internalization was negligible. The same mechanical stimulus applied to a forepaw did not produce NK1R or MOR internalization in the lumbar spinal cord. Thermal stimulation consisted of immersing a hindpaw in water at 52 °C for 2 min. It produced substantial NK1R internalization ipsilaterally in segment L6, but no MOR internalization. These results show that mechanical stimulation induces segmental opioid release, i.e., in the dorsal horn receiving the noxious signals and not in other spinal segments.

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Distribution and targeting of a mu-opioid receptor (MOR1) in brain and spinal cord

Cited by 588 publications

References 0 publications

Brain region-specific N-glycosylation and lipid rafts association of the rat mu opioid receptor

Brain region-specific N-glycosylation and lipid rafts association of the rat mu opioid receptor

A substance P-opioid chimeric peptide as a unique nontolerance-forming analgesic

Noxious mechanical stimulation evokes the segmental release of opioid peptides that induce μ-opioid receptor internalization in the presence of peptidase inhibitors

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