Lactoferrin enhances opioid-mediated analgesia via nitric oxide in the  rat spinal cord

Lactoferrin (LF) is a multifunctional protein that is found in milk, neutrophils, and other biological fluids, and its receptors have also been identified in the central nervous system. Recently, we found that bovine milk-derived LF (BLF) produced analgesia via a μ-opioid receptor-mediated response in the spinal cord. However, the precise mechanism of this analgesic effect remains unclear. In this study, spinally applied BLF produced analgesia that was reversed by coadministration with a nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine methyl ester, during phases 1 and 2 in the formalin test. Spinal coadministration of a μ-opioid receptor agonist, morphine, with a subeffective dose of BLF produced a much more highly potentiated analgesia than that produced by morphine alone during phases 1 and 2 in the formalin test. This potentiated analgesia by morphine with BLF was reversed by a μ-opioid receptor antagonist, d-Phe-Cys-Tyr-d-Trp-Orn-Thr-NH2, or by NG-nitro-l-arginine methyl ester. In the tail-flick test, continuous spinal infusion of morphine via an osmotic minipump over 6 days resulted in development of tolerance by day 4, but no tolerance of BLF was observed throughout the experiment. These results suggest that BLF acts as an enhancer of the spinal opioidergic system via an NO-mediated mechanism.

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Novel function of bovine milk-derived lactoferrin on antinociception mediated by μ-opioid receptor in the rat spinal cord

Brain Research ◽

10.1016/s0006-8993(02)04207-5 ◽

2003 ◽

Vol 965 (1-2) ◽

pp. 239-245 ◽

Cited By ~ 29

Author(s):

Ken-ichiro Hayashida ◽

Takashi Takeuchi ◽

Hirohiko Shimizu ◽

Kunio Ando ◽

Etsumori Harada

Keyword(s):

Spinal Cord ◽

Opioid Receptor ◽

Bovine Milk ◽

Rat Spinal Cord ◽

Μ Opioid Receptor

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Evaluation of anti-nociceptive effect of methanolic extract of Sambucus nigra leaves using Formalin test and Tail-Flick test models

Planta Medica ◽

10.1055/s-2006-949895 ◽

2006 ◽

Vol 72 (11) ◽

Author(s):

M Faizi ◽

B Shafaghi ◽

M Kamalinejad

Keyword(s):

Formalin Test ◽

Methanolic Extract ◽

Tail Flick ◽

Sambucus Nigra ◽

Tail Flick Test ◽

Test Models

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C57BL/6J-bg J (beige) mice: Differential sensitivity in the tail flick test to centrally administered MU- and delta-opioid receptor agonists

Life Sciences ◽

10.1016/0024-3205(87)90288-8 ◽

1987 ◽

Vol 40 (20) ◽

pp. 1989-1994 ◽

Cited By ~ 34

Author(s):

Joanne R. Mathiasen ◽

Robert B. Raffa ◽

Jeffry L. Vaught

Keyword(s):

Opioid Receptor ◽

Differential Sensitivity ◽

Delta Opioid Receptor ◽

Tail Flick ◽

Tail Flick Test ◽

Receptor Agonists ◽

Opioid Receptor Agonists

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Absence of μ opioid receptor mRNA expression in astrocytes and microglia of rat spinal cord

Neuroreport ◽

10.1097/wnr.0b013e3283522e1b ◽

2012 ◽

Vol 23 (6) ◽

pp. 378-384 ◽

Cited By ~ 27

Author(s):

Sheng-Chin Kao ◽

Xiuli Zhao ◽

Chun-Yi Lee ◽

Fidelis E. Atianjoh ◽

Estelle B. Gauda ◽

...

Keyword(s):

Spinal Cord ◽

Mrna Expression ◽

Opioid Receptor ◽

Rat Spinal Cord ◽

Receptor Mrna ◽

Μ Opioid Receptor

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Inhibition of monoacylglycerol lipase: Another signalling pathway for potential therapeutic targets in migraine?

Cephalalgia ◽

10.1177/0333102417727537 ◽

2017 ◽

Vol 38 (6) ◽

pp. 1138-1147 ◽

Cited By ~ 5

Author(s):

Rosaria Greco ◽

Chiara Demartini ◽

Anna Maria Zanaboni ◽

Laura Berliocchi ◽

Daniele Piomelli ◽

...

Keyword(s):

Formalin Test ◽

Endocannabinoid System ◽

Tail Flick ◽

Monoacylglycerol Lipase ◽

Neuronal Activation ◽

Nociceptive Behavior ◽

Tail Flick Test ◽

Area Of Interest ◽

Key Enzyme ◽

Hydrolysis Of

Background Drugs that modulate endocannabinoid signalling are effective in reducing nociception in animal models of pain and may be of value in the treatment of migraine. Methods We investigated the anti-nociceptive effects of inhibition of monoacylglycerol lipase (MGL), a key enzyme in the hydrolysis of the 2-arachidonoylglycerol, in a rat model of migraine based on nitroglycerin (NTG) administration. We evaluated c-fos expression in specific brain areas and nociceptive behavior in trigeminal and extra-trigeminal body areas. Results URB602, a reversible MGL inhibitor, did not show any analgesic effect in the tail flick test, but it inhibited NTG-induced hyperalgesia in both the tail flick test and the formalin test applied to the hind paw or to the orofacial area. Quite unexpectedly, URB602 potentiated formalin-induced hyperalgesia in the trigeminal area when used alone. The latter result was also confirmed using a structurally distinct, irreversible MGL inhibitor, JZL184. URB602 did not induce neuronal activation in the area of interest, but significantly reduced the NTG-induced neuronal activation in the ventrolateral column of the periaqueductal grey and the nucleus trigeminalis caudalis. Conclusions These findings support the hypothesis that modulation of the endocannabinoid system may be a valuable approach for the treatment of migraine. The topographically segregated effect of MGL inhibition in trigeminal/extra-trigeminal areas calls for further mechanistic research.

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Effects of CGRP receptor antagonism in nitroglycerin-induced hyperalgesia

Cephalalgia ◽

10.1177/0333102413517776 ◽

2013 ◽

Vol 34 (8) ◽

pp. 594-604 ◽

Cited By ~ 27

Author(s):

R Greco ◽

AS Mangione ◽

F Siani ◽

F Blandini ◽

M Vairetti ◽

...

Keyword(s):

Clinical Evidence ◽

Formalin Test ◽

Tail Flick ◽

Cgrp Receptor ◽

Tail Flick Test ◽

Nociceptive Transmission ◽

Calcitonin Gene ◽

Cgrp Receptor Antagonists ◽

Cgrp Receptor Antagonist ◽

Trigeminal Nerves

Background The release of calcitonin gene-related peptide (CGRP) from trigeminal nerves plays a central role in the pathophysiology of migraine and clinical evidence shows an antimigraine effect for CGRP receptor antagonists. Systemic administration of nitroglycerin (NTG), a nitrovasodilator, consistently provokes spontaneous-like migraine attacks in migraine sufferers; in the rat, systemic NTG induces a condition of hyperalgesia, probably through the activation of cerebral/spinal structures involved in nociceptive transmission. Aim The aim of this article is to test the analgesic effect of the CGRP receptor antagonist MK-8825 in two animal models of pain that may be relevant for migraine: the tail flick test and the formalin test performed during NTG-induced hyperalgesia. Results MK-8825 showed analgesic activity when administered alone at both the tail flick test and the formalin test. Furthermore, the CGRP antagonist proved effective in counteracting NTG-induced hyperalgesia in both tests. MK-8825 indeed reduced the nociceptive behavior when administered either simultaneously or prior to (30–60 minutes before) NTG. Conclusion These data suggest that MK-8825 may represent a potential therapeutic tool for the treatment of migraine.

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Sensation of Abdominal Pain Induced by Peritoneal Carcinomatosis Is Accompanied by Changes in the Expression of Substance P and μ-Opioid Receptors in the Spinal Cord of Mice

Anesthesiology ◽

10.1097/aln.0b013e31826a4ac8 ◽

2012 ◽

Vol 117 (4) ◽

pp. 847-856 ◽

Cited By ~ 16

Author(s):

Masami Suzuki ◽

Minoru Narita ◽

Minami Hasegawa ◽

Sadayoshi Furuta ◽

Tomoyuki Kawamata ◽

...

Keyword(s):

Spinal Cord ◽

Abdominal Pain ◽

Substance P ◽

Peritoneal Carcinomatosis ◽

Opioid Receptor ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Receptor Expression ◽

Tumor Bearing ◽

Μ Opioid Receptor

Background Patients with peritoneal carcinomatosis often report abdominal pain, which is relatively refractory to morphine. It has been considered that a new animal model is required to investigate the mechanism of abdominal pain for the development of optimal treatments for this type of pain. Methods To prepare a peritoneal carcinomatosis model, highly peritoneal-seeding gastric cancer cells, 60As6, were implanted into the abdominal cavity. The nociceptive modality for pain-related behavior was assessed in terms of withdrawal behavior in response to mechanical stimuli and hunching behavior. Tissue samples from mouse dorsal root ganglia and spinal cord were subject to immunohistochemistry and real-time reverse transcription polymerase chain reaction. Results Mice with peritoneal dissemination showed significant hypersensitivity of the abdomen to mechanical stimulation and spontaneous visceral pain-related behavior. There was a significant increase in c-Fos-positive cells in the spinal cord in tumor-bearing mice. Those mice exhibited a remarkable increase in substance P-positive neurons in the dorsal root ganglia (control vs. tumor, 15.4 ± 1.1 vs. 24.2 ± 3.6, P < 0.05, n = 3). A significant decreases in μ-opioid receptor expression mainly in substance P-positive neurons was observed in tumor-bearing mice (69.3 ± 4.9 vs. 38.7 ± 0.9, P < 0.05, n = 3), and a relatively higher dose of morphine was required to significantly reverse the abdominal hypersensitivity. Conclusion Both the up-regulation of substance P and down-regulation of μ-opioid receptor seen in the dorsal root ganglia may be, at least in part, responsible for the abdominal pain-like state associated with peritoneal carcinomatosis.

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