Enhanced analgesic cholinergic tone in the spinal cord in a mouse model of neuropathic pain.
Neurobiology of Disease. 2021-07-01; 155: 105363
DOI: 10.1016/j.nbd.2021.105363
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Dhanasobhon D(1), Medrano MC(1), Becker LJ(1), Moreno-Lopez Y(1), Kavraal S(1), Bichara C(1), Schlichter R(1), Inquimbert P(1), Yalcin I(1), Cordero-Erausquin M(2).
Author information:
(1)Centre National de la Recherche Scientifique, Université de Strasbourg,
Institut des Neurosciences Cellulaires et Intégratives, 67000 Strasbourg, France.
(2)Centre National de la Recherche Scientifique, Université de Strasbourg,
Institut des Neurosciences Cellulaires et Intégratives, 67000 Strasbourg, France;
University of Strasbourg Institute for Advanced Study (USIAS), 67000 Strasbourg,
France. Electronic address: .
Endogenous acetylcholine (ACh) is an important modulator of nociceptive sensory
processing in the spinal cord. An increased level of spinal ACh induces analgesia
both in humans and rodents while interfering with cholinergic signaling is
allodynic, demonstrating that a basal tone of spinal ACh modulates nociceptive
responses in naïve animals. The plasticity undergone by this cholinergic system
in chronic pain situation is unknown, and the mere presence of this tone in
neuropathic animals is controversial. We have addressed these issues in mice
through behavioral experiments, histology, electrophysiology and molecular
biology, in the cuff model of peripheral neuropathy. Our behavior experiments
demonstrate the persistence, and even increased impact of the analgesic
cholinergic tone acting through nicotinic receptors in cuff animals. The
neuropathy does not affect the number or membrane properties of dorsal horn
cholinergic neurons, nor specifically the frequency of their synaptic inputs. The
alterations thus appear to be in the neurons receiving the cholinergic signaling,
which is confirmed by the fact that subthreshold doses of acetylcholinesterase
(AChE) inhibitors in sham animals become anti-allodynic in cuff mice and by the
altered expression of the β2 nicotinic receptor subunit. Our results demonstrate
that endogenous cholinergic signaling can be manipulated to relieve mechanical
allodynia in animal models of peripheral neuropathy. Until now, AChE inhibitors
have mainly been used in the clinics in situations of acute pain (parturition,
post-operative). The fact that lower doses (thus with fewer side effects) could
be efficient in chronic pain conditions opens new avenues for the treatment of
neuropathic pain.
SIGNIFICANCE STATEMENT: Chronic pain continues to be the most
common cause of disability that impairs the quality of life, accruing enormous
and escalating socio-economic costs. A better understanding of the plasticity of
spinal neuronal networks, crucially involved in nociceptive processing, could
help designing new therapeutic avenues. We here demonstrate that chronic pain
modifies the spinal nociceptive network in such a way that it becomes more
sensitive to cholinergic modulations. The spinal cholinergic system is
responsible for an analgesic tone that can be exacerbated by acetylcholinesterase
inhibitors, a property used in the clinic to relief acute pain (child birth,
post-op). Our results suggest that lower doses of acetylcholinesterases, with
even fewer side effects, could be efficient to relieve chronic pain.