Abstract
Sensory neuron nicotinic acetylcholine receptors (nAChRs) contribute to pain associated
with tissue injury. However, there are marked differences between rats and mice with
respect to both the properties and distribution of nAChR currents in sensory neurons.
Because both species are used to understand pain signaling in humans, we sought to
determine whether the currents present in either species was reflective of those present
in human sensory neurons. Neurons from the L4/L5 dorsal root ganglia were obtained
from adult male and female organ donors. Nicotine evoked currents were detected in
40 of 47 neurons (85%). In contrast with the naïve mouse, in which almost all nAChR
currents are transient, or the rat, in which both mouse-like transient and more slowly
activating and inactivating currents are detected, all the currents in human DRG neurons
were slow, but slower than those in the rat. Currents were blocked by the nAChR antagonists
mecamylamine (30 µmol/L), but not by the TRPA1 selective antagonist HC-030031 (10
µmol/L). Single cell polymerase chain reaction analysis of nicotinic receptor subunit
expression in human DRG neurons are consistent with functional data indicating that
receptor expression is detected 85 ± 2.1% of neurons assessed (n = 48, from 4 donors).
The most prevalent coexpression pattern was α3/β2 (95 ± 4% of neurons with subunits),
but α7 subunits were detected in 70 ± 3.4% of neurons. These results suggest that
there are not only species differences in the sensory neuron distribution of nAChR
currents between rodent and human, but that the subunit composition of the channel
underlying human nAChR currents may be different from those in the mouse or rat.
Perspective
The properties and distribution of nicotine evoked currents in human sensory neurons
were markedly different from those previously observed in mice and rats. These observations
add additional support to the suggestion that human sensory neurons may be an essential
screening tool for those considering moving novel therapeutics targeting primary afferents
into clinical trials.
Key Words
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Article info
Publication history
Published online: January 16, 2019
Accepted:
January 3,
2019
Received in revised form:
December 18,
2018
Received:
August 27,
2018
Footnotes
This study was supported by the National Institutes of Health (R01NS083347 and R01 DK107966), the National Natural Science Funds of China (81670686), Shandong Natural Science Funds (ZR2015HM001), and Eli Lilly Co. None of the authors have any conflicts of interest with respect to the work described in this article. Dr. Belfer contributed to this article in her personal capacity. The views expressed are her own and do not necessarily represent the views of the National Institutes of Health or the United States Government.
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© 2019 by the American Pain Society
