Role of hyperpolarization-activated cyclic nucleotide-gated ion channels in neuropathic pain: a proof-of-concept study of ivabradine in patients with chronic peripheral neuropathic pain

Neuropathic pain results from lesions or diseases of the somatosensory nervous system and it remains largely difficult to treat. Peripheral neuropathic pain originates from injury to the peripheral nervous system (PNS) and manifests as a series of symptoms and complications, including allodynia and hyperalgesia. The aim of this review is to discuss a novel approach on neuropathic pain management, which is based on the knowledge of processes that underlie the development of peripheral neuropathic pain; in particular highlights the role of glia and mast cells in pain and neuroinflammation. ALIAmides (autacoid local injury antagonist amides) represent a group of endogenous bioactive lipids, including palmitoylethanolamide (PEA), which play a central role in numerous biological processes, including pain, inflammation, and lipid metabolism. These compounds are emerging thanks to their anti-inflammatory and anti-hyperalgesic effects, due to the down-regulation of activation of mast cells. Collectively, preclinical and clinical studies support the idea that ALIAmides merit further consideration as therapeutic approach for controlling inflammatory responses, pain, and related peripheral neuropathic pain.

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Cyclic nucleotide-gated ion channels

Ion ChannelsFrom Structure to Function ◽

10.1093/acprof:oso/9780199296750.003.0012 ◽

2009 ◽

pp. 392-402

Author(s):

Zhengchao Wan ◽

Fangxiong Shi

Keyword(s):

Ion Channels ◽

Cyclic Nucleotide ◽

Gated Ion Channels

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Empirically founded genotype–phenotype maps from mammalian cyclic nucleotide-gated ion channels

Journal of Theoretical Biology ◽

10.1016/j.jtbi.2014.08.038 ◽

2014 ◽

Vol 363 ◽

pp. 205-215

Author(s):

Andrea Becchetti

Keyword(s):

Ion Channels ◽

Cyclic Nucleotide ◽

Gated Ion Channels

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Role of Receptor-Gated Ion Channels in Alcohol Actions and Alcohol Dependence.

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)35816-0 ◽

1994 ◽

Vol 64 ◽

pp. 7

Author(s):

R. Adron Harris ◽

Paula Hoffman ◽

Boris Tabakoff

Keyword(s):

Ion Channels ◽

Alcohol Dependence ◽

Gated Ion Channels

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Modification of Cyclic Nucleotide–Gated Ion Channels by Ultraviolet Light

The Journal of General Physiology ◽

10.1085/jgp.116.2.227 ◽

2000 ◽

Vol 116 (2) ◽

pp. 227-252 ◽

Cited By ~ 12

Author(s):

Thomas R. Middendorf ◽

Richard W. Aldrich ◽

Denis A. Baylor

Keyword(s):

Absorption Spectrum ◽

Ion Channels ◽

Ultraviolet Light ◽

Cyclic Nucleotide ◽

Uv Light ◽

Action Spectrum ◽

Light Sensitivity ◽

Current Reduction ◽

Photochemical Modification ◽

Gated Ion Channels

We irradiated cyclic nucleotide–gated ion channels in situ with ultraviolet light to probe the role of aromatic residues in ion channel function. UV light reduced the current through excised membrane patches from Xenopus oocytes expressing the α subunit of bovine retinal cyclic nucleotide–gated channels irreversibly, a result consistent with permanent covalent modification of channel amino acids by UV light. The magnitude of the current reduction depended only on the total photon dose delivered to the patches, and not on the intensity of the exciting light, indicating that the functionally important photochemical modification(s) occurred from an excited state reached by a one-photon absorption process. The wavelength dependence of the channels' UV light sensitivity (the action spectrum) was quantitatively consistent with the absorption spectrum of tryptophan, with a small component at long wavelengths, possibly due to cystine absorption. This spectral analysis suggests that UV light reduced the currents at most wavelengths studied by modifying one or more “target” tryptophans in the channels. Comparison of the channels' action spectrum to the absorption spectrum of tryptophan in various solvents suggests that the UV light targets are in a water-like chemical environment. Experiments on mutant channels indicated that the UV light sensitivity of wild-type channels was not conferred exclusively by any one of the 10 tryptophan residues in a subunit. The similarity in the dose dependences of channel current reduction and tryptophan photolysis in solution suggests that photochemical modification of a small number of tryptophan targets in the channels is sufficient to decrease the currents.

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