Why do tricyclic antidepressants relieve neuropathic pain?

Neuropathic pain results from damage of the somatosensory nerves as a result of direct lesions. The pain is usually described as a burning sensation and affected areas are often sensitive to touch. Symptoms of neuropathic pain may also include excruciating pain, the sensation of ‘pins and needles’, difficulty correctly sensing temperatures and numbness. Some people may even experience difficulty with wearing heavy clothes as even slight pressure can aggravate the pain. Common causes of neuropathic pain include nerve pressure or nerve damage resulting from surgery or trauma, viral infections, cancer, vascular malformations, alcoholism, neurological conditions such as multiple sclerosis and metabolic conditions such as diabetes. It may also be a side effect of certain medications. Neuropathy has a high disease burden, and therapeutic options are limited. Current treatments, like antiepileptics [such as gabapentin and pregabalin], tricylic antidepressants such as amitriptyline, and duloxetine, and topical capsaicin, are often unsatisfactory. There is a high unmet medical need for new analgesics, which requires not only a better understanding of how currently used analgesics work but also the design more efficacious analgesics.

Although the analgesic effect of tricyclic antidepressants (TCAs) is frequently attributed to the blocking of neuronal calcium ion channels, there is very little experimental or theoretical evidence to back up this claim. The N-type calcium ion channel (Cav2.2) is a well-established target for the treatment of neuropathic pain. Dr. Fernanda Cardoso, Matthieu Schmit, Dr. Michael Kuiper, Prof. Richard Lewis, Dr. Kellie Tuck and Prof. Peter Duggan from CSIRO, Monash University and The University of Queensland conducted a series of elegant experiments to support the notion that the blockade of neuronal calcium ion channels by TCAs is at least partially responsible for their analgesic effect. This research has been published in the journal RSC Medicinal Chemistry. For this purpose, they selected 13 different compounds, eleven TCAs and two closely related drugs. They performed biological assays and in silico studies like protein equilibration, compared equilibrated homology model and the Cryo-EM structure, docking, binding modes, molecular dynamics simulations of docked structures.

The research team evaluated a set of eleven TCAs and two related drugs for their ability to inhibit the human N-type or Ca_V2.2 channel endogenously expressed in the neuroblastoma cell line, SH-SY5Y. The Ca_V2.2 channel was chosen because, amongst the human neuronal calcium ion channels, it is one of the most thoroughly validated targets for the formulation of neuropathic pain drugs. The authors found that all of the test drugs showed moderate inhibition of the hCa_V2.2 channel, with those predominantly consisting of a carbon framework and bearing a flexible amine sidechain (2–6, 8, 10 and 12) eliciting slightly stronger responses. These compounds were found to be more than two-fold stronger inhibitors of the hCa_V2.2 channel than the positive control, cilnidipine, a N-type channel blocker. In order to gain insights into the mechanism of action of TCAs on the Ca_V2.2 channel, an in silico model of the pore forming α1 subunit of the Ca_V2.2 channel, previously constructed from a static rabbit Ca_V1.1 single-particle Cryo-EM map, was used as a starting point. The homology model was then embedded into a simulated cell membrane, and MD simulations, which incorporated a simulated calcium chloride solution, were used to model channel behavior. The transmembrane component of the model thus obtained compared favorably with a recently reported Cryo-EM structure of the human Ca_V2.2 channel. Rigid docking of the selected TCAs, followed by further MD simulations, revealed two plausible binding sites for TCAs in the human Ca_V2.2 channel.

In summary, this study by Professor Peter Duggan and colleagues provides the most comprehensive evidence to date that supports the notion that the blockade of neuronal calcium ion channels by TCAs is at least partially responsible for their analgesic effect. Moreover, it provides an opportunity to better understand the pharmacological blockade of Ca_V2.2 channels in human disease and their potential as drug targets.