Intrathecal injection of an alpha seven nicotinic acetylcholine receptor agonist attenuates gp120-induced mechanical allodynia and spinal pro-inflammatory cytokine profiles in rats.
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.
Loram
Lisa C
LC
Department of Psychology & Neuroscience, University of Colorado, Boulder, CO 80309, USA. Lisa.Loram@colorado.edu
Harrison
Jacqueline A
JA
Chao
Lindsey
L
Taylor
Frederick R
FR
Reddy
Anireddy
A
Travis
Carissa L
CL
Giffard
Rona
R
Al-Abed
Yousef
Y
Tracey
Kevin
K
Maier
Steven F
SF
Watkins
Linda R
LR
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
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