Imagine waking up every day with a “pins and needles” feeling on the hands and feet. Situations that were ordinary before — such as snuggling under a blanket or hair brushing — are suddenly uncomfortable after someone becomes extremely sensitive to touch. These are some common symptoms that individuals who suffer from neuropathic pain experience (1). This condition affects ten percent of the global population, and it can arise from injury, surgery, or a variety of health conditions such as diabetes, HIV/AIDS, alcoholism, and Parkinson’s disease (2). 

Current neuropathic pain treatments such as anti-seizure medications or antidepressants commonly cause adverse side effects or take a long time to produce pain relief (3). Pain medication such as opioids provide short-term pain relief but pose addiction risks (4). Venetia Zachariou, a neuroscientist now at Boston University, and her colleagues at the Icahn School of Medicine at Mount Sinai set out to test whether a unique antidepressant known as tianeptine might offer the best of both worlds to treat neuropathic pain. Tianeptine is a non-FDA-approved atypical tricyclic antidepressant that not only targets monoamine signaling like typical antidepressants do, but also targets the mu-opioid receptor — making it a drug that interacts with the two major signaling systems targeted by common neuropathic pain treatments.

In a study published in Neuropsychopharmacology, Zachariou’s team discovered that tianeptine produced faster alleviation of heightened pain sensitivity in an animal model of neuropathic pain compared to desipramine, an antidepressant commonly prescribed for neuropathic pain (5). They also found that tianeptine more directly reversed transcriptomic changes observed in the animal models of neuropathic pain. Their findings suggest that tianeptine could be a potential new therapeutic option for treating neuropathic pain, and also highlight new molecular pathways to target for pain management.

“With this new approach, the understanding that drugs with broader site of action, such as antidepressants, may be triggering some interesting signal transduction intracellular pathways can guide us a little bit better about the next generation of drugs,” said Zachariou.

With this new approach, the understanding that drugs with broader side of action, such as antidepressants, may be triggering some interesting signal transduction intracellular pathways can guide us a little bit better about the next generation of drugs. 
– Venetia Zachariou, Boston University

To test the analgesic properties of tianeptine, Zachariou and her team tested the drug’s effects on the sensory hypersensitivity — the increased awareness and reaction to touch — of an animal model of neuropathic pain. They used the spared nerve injury (SNI) model that produces long-term nerve pain due to a sciatic nerve injury. For three weeks, the researchers injected male SNI mice with either tianeptine, desipramine, or saline. Throughout that treatment, they tested the mice’s mechanical pain threshold, which is a way to determine the minimum amount of pressure applied to the body necessary to produce a sensation of pain. Injured mice tend to sense pain with less force and thus have lower pain thresholds due to their sensory hypersensitivity. 

The team found that SNI mice treated with tianeptine had higher pain thresholds than mice that received desipramine or saline. The effect lasted for days, showing that tianeptine treatment could alleviate the sensory hypersensitivity caused by injury and last longer than other treatment methods.  

“One thing that is unique about this study in particular, is that a lot of groups will tend to look at the effects of the drug after maybe an hour or two of administering it,” said Randal Serafini, a coauthor on the study. The issue with only looking at drug treatments shortly after administration, Serafini explained, is the uncertainty of whether the treatment will continue to produce pain relief over longer periods of time. 

After uncovering the fast-acting and long-lasting analgesic effects of tianeptine, the team explored its molecular mechanisms. Regulator of G protein-signaling (RGS) proteins, which help aid in cell signaling between the inside and outside of cells, commonly modulate antidepressants like desipramine (6). By studying RGS protein knockout mice, Zachariou’s team found that while some RGS proteins blunt the early analgesic effects of tianeptine, others prevent its long-lasting pain-relieving effects, and some delay its analgesic efficacy. This meant that while tianeptine clearly produces different therapeutic results than desipramine, it is still vulnerable to RGS protein modulation. To uncover the potential reason for this therapeutic difference, the researchers turned to transcriptomics. 

The team chose to sequence the cells in the nucleus accumbens (NAc) because of the area’s role in modulating antidepressant drug efficacy (7). They found that while tianeptine regulated fewer genes than desipramine in SNI mice, tianeptine reversed more injury-related gene expression changes in the NAc than desipramine. 

“The really unique aspects of this study are the RNA analysis and looking at the different transcriptomic endpoints,” said Laura Bohn, a G protein-coupled receptor function researcher at the University of Florida who was not involved in the study. “This transcriptomic approach, I like it, because [Zachariou is] getting a holistic view of what changed, in addition to confirming efficacy and potency in some of the neuropathic pain models that she's used.”

Although tianeptine shows promise in treating neuropathic pain, one concern is its lack of FDA approval in the United States. Doctors can prescribe tianeptine in some European, Asian, and Latin American countries, and in most U.S. states people can purchase it over the counter (8). However, nine states have banned it due to its abuse potential (9). While some research indicates that tianeptine can produce drug tolerance, which lowers a drug’s effectiveness after long-time use, other studies suggest it does not (10,11). Consequently, more research is required before people can use tianeptine as a prescribed neuropathic pain treatment. 

In future experiments, Zachariou and her team hope to expand their RNA sequencing approach to other pain-modulating brain areas, such as the periaqueductal gray and basal ganglia. They’ve also been repeating these experiments in female mice to see if there are any mechanisms in their pain processing that differ compared to male mice. 

To further drug development in this space, Zachariou emphasized the importance of screening through G protein pathways, including the RGS proteins that influence tianeptine’s effectiveness. “Instead of coming up with a new drug, you can come up with interventions in this G protein pathway to make these drugs better tolerated and more appropriate for use of chronic pain,” she said.

References 

1. Cavalli, E., Mammana, S., Nicoletti, F., Bramanti, P., & Mazzon, E. The neuropathic pain: An overview of the current treatment and future therapeutic approaches. Int J Immunopathol Pharmacol   33, 2058738419838383 (2019).
2. Peripheral neuropathy - Symptoms and causes. Mayo Clinic https://www.mayoclinic.org/diseases-conditions/peripheral-neuropathy/symptoms-causes/syc-20352061.  
3. Kelly, K., Posternak, M., & Alpert, J.E. Toward achieving optimal response: understanding and managing antidepressant side effects. Dialogues Clin Neurosci  10, 409–418 (2008).
4. Benyamin, R. et al. Opioid complications and side effects. Pain Physician  11, S105–20 (2008).
5. Serafini, R.A., Estill, M., Pekarskaya, E.A. et al. Tianeptine promotes lasting antiallodynic effects in a mouse model of neuropathic pain. Neuropsychopharmacol  48, 1680–1689 (2023). 
6. Stewart, A. & Fisher, R.A. Introduction: G Protein-coupled Receptors and RGS Proteins. Prog Mol Biol Transl Sci   133, 1–11 (2015). 
7. Mitsi, V. et al. RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states. Proc Natl Acad Sci USA  112, E5088–97 (2015).
8. FDA. Tianeptine Products Linked to Serious Harm, Overdoses, Death. (2022). https://www.fda.gov/consumers/consumer-updates/tianeptine-products-linked-serious-harm-overdoses-death 
9. Edinoff, A.N. et al. Tianeptine, an Antidepressant with Opioid Agonist Effects: Pharmacology and Abuse Potential, a Narrative Review. Pain Ther   12, 1121–1134 (2023). 
10. Allain, F. et al. Chronic tianeptine induces tolerance in analgesia and hyperlocomotion via mu-opioid receptor activation in mice. Front Psychiatry   14, 1186397 (2023). 
11. Heo, B.H. et al. Effects of tianeptine on the development and maintenance of mechanical allodynia in a rat model of neuropathic pain. Neurosci Lett  633, 82–6 (2016).