Understanding Mechanisms of Neuropathic Pain to Design Effective Treatments
Dysregulation of multiple ion channels leads to hyperexcitability of pain-producing neurons
A review article recently published in Neuron1 by the groups of Yves de Koninck, PhD and Steven Prescott, MD, PhD at the Laval University, Quebec, Canada and the Hospital for Sick Children, Toronto, Canada, respectively, highlights the need to better target treatments for chronic neuropathic pain. Individuals experiencing chronic pain with neuropathic characteristics account for 7-8% of adults2 and report higher pain levels than patients with non-neuropathic chronic pain.
Altered potassium-chloride co-transporter (KCC2) function leads to dysregulation of intracellular chloride (Cl-) levels, which severely affects inhibitory signals normally blocking pain transmission. This results in hyperexcitability of spinal neurons transmitting pain signals, causing neuropathic pain3. A recent study from the Prescott laboratory shows that alterations in KCC2 function, although impacting inhibition of both excitatory pain-producing and inhibitory pain-reducing neurons, results in low levels of excitation, which, through spatial summation results in supra-threshold excitation, thus producing allodynia4.
Disrupted inhibition of excitatory vs inhibitory spinal neurons causes much more dramatic effects, as the former neurons themselves receive excitatory signals, which are unmasked in the absence of inhibition. This phenomenon underlies nociceptive sensations elicited by normally painless touch.
A number of other ion channels have also been implicated in hyperexcitability of pain-producing neurons5. Current pharmacologic interventions for neuropathic pain aim at reducing hyperexcitability of pain-producing neurons. However, these target single ion channels, and have therefore proved ineffective. Studies like those conducted in the laboratories of Drs Prescott and De Koninck, investigating precise mechanisms of spinal neuronal excitability, will contribute to designing adequate treatments for neuropathic pain target all implicated ion channels, dysregulation of which affects pain signal transmission.
1. Doyon N, Vinay L, Prescott SA, De koninck Y. Chloride Regulation: A Dynamic Equilibrium Crucial for Synaptic Inhibition. Neuron. 2016;89(6):1157-72.
2. Epidemiology of neuropathic pain: http://iasp.files.cms-plus.com/AM/Images/GYAP/Epidemiology%20of%20Neuropathic%20Pain.pdf
3. Price TJ, Cervero F, Gold MS, Hammond DL, Prescott SA. Chloride regulation in the pain pathway. Brain Res Rev. 2009;60(1):149-70.
4. Lee KY, Prescott SA. Chloride dysregulation and inhibitory receptor blockade yield equivalent disinhibition of spinal neurons yet are differentially reversed by carbonic anhydrase blockade. Pain. 2015;156(12):2431-7.
5. Waxman SG, Zamponi GW. Regulating excitability of peripheral afferents: emerging ion channel targets. Nat Neurosci. 2014;17(2):153-63.