μ Opioid Receptor/MOR

DAMGO (1–10 μM) TFA does not suppress CXCR4 protein expression, but it dramatically lowers the activation of neuronal Akt and ERK1/2 by CXCL12 and inhibits CXCL12-promoted neuronal survival[2].
DAMGO (1 μM) TFA efficiently suppresses the prostaglandin E 2 (PGE 2)-induced rise in a tetrodotoxin-resistant voltage-gated Na⁺ current (TTX-R I _Na). In other words, PGE 2 (1 μM) can raise the TTX-R I _Na peak by 103% as opposed to 24.9% when DAMGO is added[3].

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The structural basis of mu-opioid receptor (OPR) for the specificity in its ligand binding was investigated using chimeric mu/delta-OPRs. Replacement of the region around the first extracellular loop of delta-OPR with the corresponding region of mu-OPR gave the resultant chimeric receptor the similar affinity to DAMGO compared with the native mu-OPR. The reciprocal replacement deprived the high affinity to DAMGO from mu-OPR. These results indicate that the difference(s) in the structure around the first extracellular loop is critical for DAMGO to distinguish between mu- and delta-OPRs. Furthermore, displacement studies revealed that this region is partly involved in the discrimination between mu- and delta-OPRs by other peptidic mu-selective ligands, such as dermorphin, morphiceptin and CTOP, but not by non-peptidic ligands, such as morphine and naloxone[1].

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The chemokine receptor CXCR4 regulates neuronal survival and differentiation and is involved in a number of pathologies, including cancer and human immunodeficiency virus (HIV). Recent data suggest that chemokines act in concert with neurotransmitters and neuropeptides, such as opioids. This study aimed to determine whether mu-opioid agonists alter the effect of CXCL12 (the specific CXCR4 ligand) on central neurons. Neuronal expression of CXCR4 and micro-opioid receptors (MORs) was analyzed by Western blot, immunostaining, and flow cytometry. Single-cell studies showed that all CXCR4-positive neurons coexpress MORs. Treatment of neuronal cultures with the selective MOR agonist DAMGO or the endogenous peptide endomorphin-1 inhibited intracellular signaling pathways (ERK1/2 and Akt) activated by CXCL12. Furthermore, DAMGO abolished the neuroprotective effect of CXCL12 in N-methyl-d-aspartate (NMDA) neurotoxicity studies. The effects of DAMGO and endomorphin-1 were inhibited by a general or a micro-specific opioid receptor antagonist, and not caused by changes in neuronal CXCR4 levels. DAMGO did not affect CXCL12-induced internalization of CXCR4. The authors propose that interactions between MOR and CXCR4 signaling can modulate the action of CXCL12 on neuronal survival-which may have important implications to neuroAIDS as well as other neuroinflammatory disorders.[2]

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We have tested the hypothesis that the mu-opioid agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO), inhibits prostaglandin E2 (PGE2)-induced modulation of a tetrodotoxin-resistant voltage-gated Na+ current (TTX-R INa) in putative nociceptors in vitro. Patch-clamp electrophysiological techniques were used on cultured dorsal root ganglion neurons from the adult rat. PGE2 (1 microM) induced a 103 +/- 22.8% increase in peak TTX-R INa. The PGE2-induced increase in TTX-R INa in the presence of 1 microM DAMGO (24.9 +/- 7.7%), was significantly less than that induced by PGE2 alone. In contrast, when DAMGO was applied after PGE2, PGE2-induced increase in TTX-R INa (85.3 +/- 19.6%) was not significantly different than the increase in the current induced by PGE2 alone. Preapplication of naloxone (10 microM) blocked DAMGO-induced inhibition of the PGE2-induced increase in TTX-R INa. DAMGO, alone, had no effect on peak TTX-R INa (1.4 +/- 1.5% of baseline). Our observation that DAMGO prevents PGE2-induced potentiation of TTX-R INa is consistent with the suggestion that modulation of TTX-R INa underlies the hyperalgesic agent-induced increase in the excitability of nociceptors associated with sensitization and hyperalgesia. Furthermore, our data suggest that inhibition of hyperalgesic agent induced modulation of TTX-R INa may be a novel mechanism underlying opioid-induced antinociception[3].

DAMGO (i.v., 0.5-2 mg/kg) TFA can effectively and durably reduce pain in injured paws of male Sprague-Dawley rats weighing 200-225 g in a dose-dependent manner[4].

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This study evaluated the antinociceptive effects of systemically administered selective opioid agonists of mu (DAMGO), delta (BUBU) and kappa (U 69593) receptors on the vocalization threshold to paw pressure in a rat model of peripheral unilateral mononeuropathy produced by loose ligatures around the common sciatic nerve. DAMGO (0.5-2 mg/kg), BUBU (1.5-6 mg/kg) and U 69593 (0.75-3 mg/kg) injected intravenously (i.v.) produced a potent long-lasting antinociceptive effect on both hind paws. The effects on the lesioned paw were clearly and statistically more potent than for the non-lesioned paw. The selective antinociceptive effect of 2 mg/kg DAMGO, 3 mg/kg BUBU and 1.5 mg/kg U 69593 were completely prevented by prior administration of the appropriate antagonists: 0.1 mg/kg naloxone, 1 mg/kg naltrindole and 0.4 mg/kg MR 2266. The present data clearly show that an acute i.v. injection of these selective opioid agonists induces potent antinociceptive effects in a rat model of peripheral neuropathy. These data are discussed with regard to the classical view that there is opioid resistance in neuropathic pain [4].

For nine days in vitro, neurons are cultured in their original dish with DAMGO (10 μM) for twenty-four hours. The neurons are then moved to a dish with Mg2+-free saline containing glycine (15 μM) and exposed to either NMDA (100 μM) or CXCL12 (20 nM) in the absence of glia. Neurons are returned to the original glia-containing culture dishes following treatment. A 24-hour period is used to assess neural death. To distinguish between normal and apoptotic cells, use cleaved caspase-3 (1:100) staining in conjunction with Hoechst 33342 (3 μg/mL)[2].

[1]. DAMGO, a mu-opioid receptor selective agonist, distinguishes between mu- and delta-opioid receptors around their first extracellular loops.

[2]. Modulation of neuronal CXCR4 by the micro-opioid agonist DAMGO. J Neurovirol. 2006 Dec;12(6):492-500.

[3]. DAMGO inhibits prostaglandin E2-induced potentiation of a TTX-resistant Na+ current in rat sensory neurons in vitro. Neurosci Lett. 1996 Jul 12;212(2):83-6.

[4]. Selective opioid receptor agonists modulate mechanical allodynia in an animal model of neuropathic pain. Pain. 1993 Jun;53(3):277-285.

(D-Ala(2)-mephe(4)-gly-ol(5))enkephalin is a peptide.
An enkephalin analog that selectively binds to the MU OPIOID RECEPTOR. It is used as a model for drug permeability experiments.

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Under the experimental conditions reported here, DAMGO increases gp120 neurotoxicity in vitro (Patel et al, unpublished data); morphine exerts similar effects in human fetal brain cultures (Hu et al, 2005). Opiates in general are potential cofactors in AIDS progression (Bell et al, 1998; Donahoe and Vlahov, 1998; Bell et al, 2002; Nath et al, 2002). In conclusion, this study reports the first example of a functional crosstalk between CXCL12 and μ-opioids in cultures of central neurons. Though these findings will have to be validated in vivo, they suggest a novel mechanism of CXCR4 regulation in the CNS and indicate that levels of endogenous or exogenous neuropeptides in the brain can affect the actions of CXCL12 on neurons. Such regulation could take place in healthy as well as pathological conditions, including neuroAIDS.[2]

C28H36F3N5O8

627.609357833862

513.26

950492-85-0

DAMGO; 78123-71-4

5462471

White to off-white solid powder

0.2

6

7

13

37

752

3

C(F)(F)(F)C(=O)O.[C@H](C(=O)NCCO)(N(C)C(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](N)CC1C=CC(O)=CC=1)CC1C=CC=CC=1

HPZJMUBDEAMBFI-UHFFFAOYSA-N

InChI=1S/C26H35N5O6/c1-17(30-25(36)21(27)14-19-8-10-20(33)11-9-19)24(35)29-16-23(34)31(2)22(26(37)28-12-13-32)15-18-6-4-3-5-7-18/h3-11,17,21-22,32-33H,12-16,27H2,1-2H3,(H,28,37)(H,29,35)(H,30,36)

2-amino-N-[1-[[2-[[1-(2-hydroxyethylamino)-1-oxo-3-phenylpropan-2-yl]-methylamino]-2-oxoethyl]amino]-1-oxopropan-2-yl]-3-(4-hydroxyphenyl)propanamide

DAMGO TFA; DAMGO (TFA); 950492-85-0; damgo; trifluoroacetic acid;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O: ~125 mg/mL (~199.12 mM)

Solubility in Formulation 1: 100 mg/mL (159.33 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)