01 September 2018
5-HT, Serotonin, Ach, acetylcholine, AchE, acetylcholinesterase, AChR, acetylcholine receptor, BLA, basolateral amygdala, CEA, central amygdala, ChAT, choline acetyltransferase, CNS, central nervous system, DRG, dorsal root ganglion, EPSC, excitatory postsynaptic current, GABA, γ-aminobutyric acid, GABAA, γ-aminobutyric acid receptor A, i.c.v., intracerebroventricular, LDTg, laterodorsal tegmental nucleus, mAchR, muscarinic AChR, mPFC, medial prefrontal cortex, nAchR, nicotinic AChR, SCS, spinal cord stimulation, VTA, ventral tegmental area, acetylcholine, pain, muscarinic, cholinergic analgesia, nicotinic, cholinergic–opioidergic interaction
Cholinergic mechanisms modulate multiple stations of the pain pathway.
Cholinomimetic drugs may provide a promising avenue in pain therapy.
Bilateral cholinergic–opioidergic interactions are therapeutically important.
Underlying circuits and mechanisms require further elucidation.
Plasticity of cholinergic neurons and pathways is important to study.
In addition to being a key component of the autonomic nervous system, acetylcholine acts as a prominent neurotransmitter and neuromodulator upon release from key groups of cholinergic projection neurons and interneurons distributed across the central nervous system. It has been more than forty years since it was discovered that cholinergic transmission profoundly modifies the perception of pain. Directly activating cholinergic receptors or extending the action of endogenous acetylcholine via pharmacological blockade of acetylcholine esterase reduces pain in rodents as well as humans; conversely, inhibition of muscarinic cholinergic receptors induces nociceptive hypersensitivity. Here, we aim to review the considerable progress in our understanding of peripheral, spinal and brain contributions to cholinergic modulation of pain.
We discuss the distribution of cholinergic neurons, muscarinic and nicotinic receptors over the central nervous system and the synaptic and circuit-level modulation by cholinergic signaling. AchRs profoundly regulate nociceptive transmission at the level of the spinal cord via pre- as well as postsynaptic mechanisms. Moreover, we attempt to provide an overview of how some of the salient regions in the pain network spanning the brain, such as the primary somatosensory cortex, insular cortex, anterior cingulate cortex, the medial prefrontal cortex and descending modulatory systems are influenced by cholinergic modulation.
Finally, we critically discuss the clinical relevance of cholinergic signaling to pain therapy. Cholinergic mechanisms contribute to several both conventional as well as unorthodox forms of pain treatments, and reciprocal interactions between cholinergic and opioidergic modulation impact on the function and efficacy of both opioids and cholinomimetic drugs.