Intrathecal injection of an alpha seven nicotinic acetylcholine receptor agonist attenuates gp120-induced mechanical allodynia and spinal pro-inflammatory cytokine profiles in rats.

Abstract	Nicotinic acetylcholine receptors (nAchRs) are not only key receptors in the autonomic nervous system, but also are present on immune cells. The alpha seven subunit of nAchR (alpha7nAchR) suppresses pro-inflammation in peripheral monocytes by decreasing pro-inflammatory cytokine production. In spinal cord, alpha7nAchRs are found on microglia, which are known to induce and maintain pain. We predicted that alpha7nAchR agonists might attenuate intrathecal HIV-1 gp120-induced, pro-inflammatory cytokine- and microglia-dependent mechanical allodynia. Choline, a precursor for acetylcholine and selective agonist for alpha7nAchR, was administered intrathecally either with, or 30 min after, intrathecal gp120. Choline significantly blocked and reversed gp120-induced mechanical allodynia for at least 4 h after drug administration. In addition, intrathecal choline, delivered either with or 30 min after gp120, reduced gp120-induced IL-1beta protein and pro-inflammatory cytokine mRNAs within the lumbar spinal cord. A second alpha7nAchR agonist, GTS-21, also significantly reversed gp120-induced mechanical allodynia and lumbar spinal cord levels of pro-inflammatory cytokine mRNAs and IL-1beta protein. A role of microglia is suggested by the observation that intrathecal choline suppressed the gp120-induced expression of, cd11b, a macrophage/microglial activation marker. Taken together, the data support that alpha7nAchR may be a novel target for treating pain where microglia maintain the pro-inflammatory state within the spinal cord.
Authors	Lisa C Loram, Jacqueline A Harrison, Lindsey Chao, Frederick R Taylor, Anireddy Reddy, Carissa L Travis, Rona Giffard, Yousef Al-Abed, Kevin Tracey, Steven F Maier, Linda R Watkins
Journal	Brain, behavior, and immunity (Brain Behav Immun) Vol. 24 Issue 6 Pg. 959-67 (Aug 2010) ISSN: 1090-2139 [Electronic] Netherlands
PMID	20353818 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Copyright	Published by Elsevier Inc.
Chemical References	Benzylidene Compounds Chrna7 protein, rat Cytokines DNA Primers DNA, Complementary HIV Envelope Protein gp120 Interleukin-1beta Nerve Tissue Proteins Nicotinic Agonists Pyridines RNA, Messenger Receptors, Nicotinic Tumor Necrosis Factor-alpha alpha7 Nicotinic Acetylcholine Receptor 3-(2,4-dimethoxybenzylidene)anabaseine
Topics	Animals Benzylidene Compounds (pharmacology) Cytokines (biosynthesis) DNA Primers DNA, Complementary (biosynthesis, genetics) HIV Envelope Protein gp120 (antagonists & inhibitors) Injections, Spinal Interleukin-1beta (biosynthesis) Male Nerve Tissue Proteins (biosynthesis) Nicotinic Agonists (administration & dosage, pharmacology) Pain (chemically induced, prevention & control) Physical Stimulation Pyridines (pharmacology) RNA, Messenger (biosynthesis, genetics) Rats Rats, Sprague-Dawley Receptors, Nicotinic (drug effects) Reverse Transcriptase Polymerase Chain Reaction Spinal Cord (drug effects, metabolism) Tumor Necrosis Factor-alpha (biosynthesis) alpha7 Nicotinic Acetylcholine Receptor

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