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Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia.
Eur J Neurosci. 2005 Nov; 22(10):2431-40.EJ

Abstract

Activation of p38 mitogen-activated protein kinase (p38) in spinal microglia is implicated in spinal nociceptive processing. Minocycline, a tetracycline derivative, displays selective inhibition of microglial activation, a function that is distinct from its antibiotic activity. In the present study we examined antinociceptive effects of intrathecal (IT) administration of minocycline in experimental models of inflammation-evoked hyperalgesia in addition to the effect of minocycline on stimulation-induced activation of p38 in spinal microglia. Intrathecal minocycline produced a dose-dependent reduction of formalin-evoked second-phase flinching behaviour in rats, and prevented thermal hyperalgesia induced by carrageenan injection into the paw. In contrast, systemic delivery (intraperitoneally) of minocycline inhibited the first but not the second phase of formalin-induced flinching, and it had no effect on carrageenan-induced hyperalgesia. Centrally mediated hyperalgesia induced by IT delivery of N-methyl-d-aspartate was completely blocked by IT minocycline. An increase in phosphorylation (activation) of p38 (P-p38) was observed in the dorsal spinal cord after carrageenan paw injection, assessed by both Western blotting and immunohistochemistry. The increased P-p38 immunoreactivity was seen primarily in microglia but also in a small population of neurons. Minocycline, at the IT dose that blocked carrageenan-induced hyperalgesia, also attenuated the increased P-p38 in microglia. In addition, minocycline suppressed lipopolysaccharide-evoked P-p38 in cultured spinal microglial cells. Taken together, these findings show that minocycline given IT produces a potent and consistent antinociception in models of tissue injury and inflammation-evoked pain, and they provide strong support for the idea that this effect is mediated by direct inhibition of spinal microglia and subsequent activation of p38 in these cells.

Authors+Show Affiliations

Department of Anaesthesiology, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0818, USA. xyhua@ucsd.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16307586

Citation

Hua, Xiao-Ying, et al. "Intrathecal Minocycline Attenuates Peripheral Inflammation-induced Hyperalgesia By Inhibiting P38 MAPK in Spinal Microglia." The European Journal of Neuroscience, vol. 22, no. 10, 2005, pp. 2431-40.
Hua XY, Svensson CI, Matsui T, et al. Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur J Neurosci. 2005;22(10):2431-40.
Hua, X. Y., Svensson, C. I., Matsui, T., Fitzsimmons, B., Yaksh, T. L., & Webb, M. (2005). Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. The European Journal of Neuroscience, 22(10), 2431-40.
Hua XY, et al. Intrathecal Minocycline Attenuates Peripheral Inflammation-induced Hyperalgesia By Inhibiting P38 MAPK in Spinal Microglia. Eur J Neurosci. 2005;22(10):2431-40. PubMed PMID: 16307586.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. AU - Hua,Xiao-Ying, AU - Svensson,Camilla I, AU - Matsui,Tomohiro, AU - Fitzsimmons,Bethany, AU - Yaksh,Tony L, AU - Webb,Michael, PY - 2005/11/26/pubmed PY - 2006/1/18/medline PY - 2005/11/26/entrez SP - 2431 EP - 40 JF - The European journal of neuroscience JO - Eur. J. Neurosci. VL - 22 IS - 10 N2 - Activation of p38 mitogen-activated protein kinase (p38) in spinal microglia is implicated in spinal nociceptive processing. Minocycline, a tetracycline derivative, displays selective inhibition of microglial activation, a function that is distinct from its antibiotic activity. In the present study we examined antinociceptive effects of intrathecal (IT) administration of minocycline in experimental models of inflammation-evoked hyperalgesia in addition to the effect of minocycline on stimulation-induced activation of p38 in spinal microglia. Intrathecal minocycline produced a dose-dependent reduction of formalin-evoked second-phase flinching behaviour in rats, and prevented thermal hyperalgesia induced by carrageenan injection into the paw. In contrast, systemic delivery (intraperitoneally) of minocycline inhibited the first but not the second phase of formalin-induced flinching, and it had no effect on carrageenan-induced hyperalgesia. Centrally mediated hyperalgesia induced by IT delivery of N-methyl-d-aspartate was completely blocked by IT minocycline. An increase in phosphorylation (activation) of p38 (P-p38) was observed in the dorsal spinal cord after carrageenan paw injection, assessed by both Western blotting and immunohistochemistry. The increased P-p38 immunoreactivity was seen primarily in microglia but also in a small population of neurons. Minocycline, at the IT dose that blocked carrageenan-induced hyperalgesia, also attenuated the increased P-p38 in microglia. In addition, minocycline suppressed lipopolysaccharide-evoked P-p38 in cultured spinal microglial cells. Taken together, these findings show that minocycline given IT produces a potent and consistent antinociception in models of tissue injury and inflammation-evoked pain, and they provide strong support for the idea that this effect is mediated by direct inhibition of spinal microglia and subsequent activation of p38 in these cells. SN - 0953-816X UR - https://www.unboundmedicine.com/medline/citation/16307586/Intrathecal_minocycline_attenuates_peripheral_inflammation_induced_hyperalgesia_by_inhibiting_p38_MAPK_in_spinal_microglia_ L2 - https://doi.org/10.1111/j.1460-9568.2005.04451.x DB - PRIME DP - Unbound Medicine ER -