title: 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.affiliation: Department of Psychology & Neuroscience, University of Colorado, Boulder, CO 80309, USA. Lisa.Loram@colorado.edu
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Loram
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Harrison
authors.forename: Lindsey
authors.initials: L
authors.lastname: Chao
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Taylor
authors.forename: Anireddy
authors.initials: A
authors.lastname: Reddy
authors.forename: Carissa L
authors.initials: CL
authors.lastname: Travis
authors.forename: Rona
authors.initials: R
authors.lastname: Giffard
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.forename: Kevin
authors.initials: K
authors.lastname: Tracey
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
mesh_terms: D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis*; D017931:DNA Primers; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors*; D007278:Injections, Spinal; D053583:Interleukin-1beta / Q000096:biosynthesis; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control*; D010812:Physical Stimulation; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001597:Benzylidene Compounds; C579165:Chrna7 protein, rat; D016207:Cytokines; D017931:DNA Primers; D018076:DNA, Complementary; D015699:HIV Envelope Protein gp120; D053583:Interleukin-1beta; D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D011725:Pyridines; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; C088936:3-(2,4-dimethoxybenzylidene)anabaseine