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Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain.

Guasti L, Richardson D, Jhaveri M, Eldeeb K, Barrett D, Elphick MR, Alexander SP, Kendall D, Michael GJ, Chapman V - Mol Pain (2009)

Bottom Line: Endocannabinoids (ECs) are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro.Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG), and the related compound N-palmitoylethanolamine (PEA), in neuropathic spinal cord.Minocycline treatment significantly (P < 0.01) decreased levels of 2-AG and significantly (P < 0.01) increased levels of PEA in the ipsilateral spinal cord of SNL rats, compared to the contralateral spinal cord.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Biological and Chemical Sciences, Queen Mary University of London, UK. l.guasti@qmul.ac.uk

ABSTRACT
Activation of spinal microglia contributes to aberrant pain responses associated with neuropathic pain states. Endocannabinoids (ECs) are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro. Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG), and the related compound N-palmitoylethanolamine (PEA), in neuropathic spinal cord. Selective spinal nerve ligation (SNL) in rats resulted in mechanical allodynia and the presence of activated microglia in the ipsilateral spinal cord. Chronic daily treatment with minocycline (30 mg/kg, ip for 14 days) significantly reduced the development of mechanical allodynia at days 5, 10 and 14 post-SNL surgery, compared to vehicle-treated SNL rats (P < 0.001). Minocycline treatment also significantly attenuated OX-42 immunoreactivity, a marker of activated microglia, in the ipsilateral (P < 0.001) and contralateral (P < 0.01) spinal cord of SNL rats, compared to vehicle controls. Minocycline treatment significantly (P < 0.01) decreased levels of 2-AG and significantly (P < 0.01) increased levels of PEA in the ipsilateral spinal cord of SNL rats, compared to the contralateral spinal cord. Thus, activation of microglia affects spinal levels of endocannabinoids and related compounds in neuropathic pain states.

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Time course of hydrolysis of AEA (anandamide) and PEA (N-palmitoylethanolamine) in BV2 microglial cells. Data are means ± SEM of six independent experiments conducted in triplicate.
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Figure 4: Time course of hydrolysis of AEA (anandamide) and PEA (N-palmitoylethanolamine) in BV2 microglial cells. Data are means ± SEM of six independent experiments conducted in triplicate.

Mentions: Our in vivo data demonstrate that neuropathic pain has a differential effect on the levels of AEA and PEA in the spinal cord, which may reflect the presence of microglia in the spinal cord. Here, we investigated the hypothesis that microglia have a differential effect on the hydrolysis of AEA and PEA, which may account for our in vivo observations in neuropathic rats. We report marked differences in the time courses for PEA and AEA hydrolysis in intact BV-2 microglial cells (Fig 4.) Specifically, the capacity for hydrolysis of AEA by the BV-2 cells was limited, in that, after 10 minutes, there was no further metabolism of AEA, as shown by the plateau in accumulation of water-soluble product. In marked contrast, the hydrolysis of PEA continued for at least 30 minutes (Fig 4).


Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain.

Guasti L, Richardson D, Jhaveri M, Eldeeb K, Barrett D, Elphick MR, Alexander SP, Kendall D, Michael GJ, Chapman V - Mol Pain (2009)

Time course of hydrolysis of AEA (anandamide) and PEA (N-palmitoylethanolamine) in BV2 microglial cells. Data are means ± SEM of six independent experiments conducted in triplicate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2719614&req=5

Figure 4: Time course of hydrolysis of AEA (anandamide) and PEA (N-palmitoylethanolamine) in BV2 microglial cells. Data are means ± SEM of six independent experiments conducted in triplicate.
Mentions: Our in vivo data demonstrate that neuropathic pain has a differential effect on the levels of AEA and PEA in the spinal cord, which may reflect the presence of microglia in the spinal cord. Here, we investigated the hypothesis that microglia have a differential effect on the hydrolysis of AEA and PEA, which may account for our in vivo observations in neuropathic rats. We report marked differences in the time courses for PEA and AEA hydrolysis in intact BV-2 microglial cells (Fig 4.) Specifically, the capacity for hydrolysis of AEA by the BV-2 cells was limited, in that, after 10 minutes, there was no further metabolism of AEA, as shown by the plateau in accumulation of water-soluble product. In marked contrast, the hydrolysis of PEA continued for at least 30 minutes (Fig 4).

Bottom Line: Endocannabinoids (ECs) are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro.Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG), and the related compound N-palmitoylethanolamine (PEA), in neuropathic spinal cord.Minocycline treatment significantly (P < 0.01) decreased levels of 2-AG and significantly (P < 0.01) increased levels of PEA in the ipsilateral spinal cord of SNL rats, compared to the contralateral spinal cord.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Biological and Chemical Sciences, Queen Mary University of London, UK. l.guasti@qmul.ac.uk

ABSTRACT
Activation of spinal microglia contributes to aberrant pain responses associated with neuropathic pain states. Endocannabinoids (ECs) are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro. Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG), and the related compound N-palmitoylethanolamine (PEA), in neuropathic spinal cord. Selective spinal nerve ligation (SNL) in rats resulted in mechanical allodynia and the presence of activated microglia in the ipsilateral spinal cord. Chronic daily treatment with minocycline (30 mg/kg, ip for 14 days) significantly reduced the development of mechanical allodynia at days 5, 10 and 14 post-SNL surgery, compared to vehicle-treated SNL rats (P < 0.001). Minocycline treatment also significantly attenuated OX-42 immunoreactivity, a marker of activated microglia, in the ipsilateral (P < 0.001) and contralateral (P < 0.01) spinal cord of SNL rats, compared to vehicle controls. Minocycline treatment significantly (P < 0.01) decreased levels of 2-AG and significantly (P < 0.01) increased levels of PEA in the ipsilateral spinal cord of SNL rats, compared to the contralateral spinal cord. Thus, activation of microglia affects spinal levels of endocannabinoids and related compounds in neuropathic pain states.

Show MeSH
Related in: MedlinePlus