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How Antidepressants Ease Neuropathic Pain

A new study identifies a dual noradrenergic mechanism to explain the anti-allodynic effect of acute versus chronic antidepressant treatment

by Kayt Sukel


28 January 2019


PRF News

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DDMechanismFeatured

A new study identifies a dual noradrenergic mechanism to explain the anti-allodynic effect of acute versus chronic antidepressant treatment

For decades, antidepressants have been a first-line treatment for neuropathic pain. Yet how these drugs function at the cellular and molecular level to produce analgesia is not well understood, with many studies reporting contradictory results. Now, Michel Barrot, French National Center for Scientific Research (CNRS) and University of Strasbourg, France, and his colleagues identify two independent pathways by which the antidepressants duloxetine, a selective serotonin and noradrenaline reuptake inhibitor (SSNRI), and amitriptyline, a tricyclic antidepressant, relieve neuropathic allodynia.

 

Using a mouse model of neuropathic pain, the group shows that one pathway mediates the acute effects of the antidepressants on pain via descending modulation from the brain to the spinal cord and depends on α2A adrenoceptors, as well as mu and delta opioid receptors. The second pathway, which acts peripherally and involves anti-neuroimmune activity, regulates the chronic anti-allodynic effects of antidepressants via β2 adrenoceptors and delta opioid receptors.

 

Juan Antonio Micó, University of Cádiz, Spain, who studies the neurobiological underpinnings of antidepressant effects on pain, says the new work provides a convincing explanation for how these drugs affect the pain system, which should help both doctors and patients.

 

“You must bear in mind that when clinicians try to prescribe an antidepressant to a patient with chronic pain, they are often asked, ‘Why are you giving me a drug for depression? I’m not depressed. I don’t need this,’ ” he said. “This work shows that the effects are real and can be explained by these different mechanisms.”

 

The research was published November 14, 2018, in the Journal of Neuroscience.

 

A confusing picture

That antidepressants could ease neuropathic pain was first seen in the 1960s based on the use of tricyclic drugs in psychiatric settings. Studies since then confirmed that observation, and showed the analgesic efficacy of newer antidepressants such as duloxetine, but Barrot says it was unclear how these drugs controlled pain.

 

“These studies showed us that the mechanism was separate from the action on depression itself—something was different—but we were not sure what was different,” Barrot said (Micó et al., 2006). “One hypothesis was that antidepressants affected the neuronal pathways from the brain to the spinal cord and blocked the uptake of neurotransmitters like noradrenaline and serotonin. But the results were highly contradictory, mainly because researchers used different protocols in their studies.”

 

Another limitation of past studies is that they mostly examined the acute effects of antidepressants on pain.

 

“We also wanted to explore the long-term effects and see whether they were driven by similar or different mechanisms. We wanted to approach this question in a way that we could really discriminate between long- and short-term effects in terms of substrates and receptors so we could finally understand how these drugs work to relieve neuropathic pain,” Barrot said.

 

Acute versus central sources of noradrenaline

To do so, Barrot, first author Mélanie Kremer, also at CNRS and the University of Strasbourg, and their co-authors investigated how duloxetine acts on the central and peripheral nervous system to relieve neuropathic allodynia, both during acute and chronic administration. They used a sciatic nerve compression model of neuropathic pain in mice, with sham-operated animals serving as controls.

 

In dose-response experiments, the team first determined the oral dose of acute or chronic duloxetine that would produce a full anti-allodynic effect in the nerve-injured mice. Beginning antidepressant treatment at least two weeks after the surgical procedure, the animals displayed full relief within 120 minutes of acute administration, according to von Frey testing of paw withdrawal thresholds. Injured animals treated chronically displayed allodynia relief after a few days.

 

Since previous studies suggested a role for the noradrenergic system in antidepressant-related analgesia, the group looked at both central descending pathways and peripheral nerve fibers, each being sources of noradrenaline (Arsenault and Sawynok, 2009). Selective lesion of descending noradrenergic fibers in nerve-injured animals using a chemical toxin, administered intrathecally, decreased the number of tyrosine hydroxylase (TH)-positive fibers in the spinal cord dorsal horn; TH is a marker of noradrenergic fibers. After lesioning the fibers, the group saw that acute duloxetine no longer relieved neuropathic allodynia in the animals, whereas chronic treatment still did.

 

But when they used a different chemical toxin to selectively lesion peripheral noradrenergic fibers in the dorsal root ganglia (DRG), the opposite occurred: Acute duloxetine remained effective, while chronic treatment did not.

 

Taken together, the results showed that the acute anti-allodynic effects of duloxetine depended on a central source of noradrenaline, while the drug’s chronic effects relied on a peripheral supply.

 

Are different receptors involved?

Having shown a role for the noradrenergic system in the anti-allodynic effects of duloxetine, the researchers then turned to adrenoceptors, a class of G protein-coupled receptors at which noradrenaline acts. They sought to determine whether acute and chronic duloxetine relieved pain by working at different types of these receptors, which come in two main groups, α and β, each with a number of subtypes.

 

Yohimbine, an antagonist of α2 adrenoceptors, blocked the acute anti-allodynic effects of duloxetine in nerve-injured animals but had no effect on the long-term pain relief provided by chronic duloxetine. RNA interference studies more specifically implicated α2A adrenoceptors in these acute effects of the antidepressant drug.

 

The researchers saw the opposite with chronic propranolol, which blocks β2 adrenoceptors: Now the anti-allodynic effects of chronic duloxetine were impaired, leaving acute effects untouched. Similar results were observed in β2 adrenoceptor knockout mice.

 

Previous studies had suggested that opioid receptors (ORs) also play a role in pain relief from antidepressants (Kremer et al., 2016). So the researchers tested whether different types of ORs were recruited depending on whether duloxetine was administered acutely or chronically. Using genetically modified animals missing mu, delta, or kappa ORs, they found that acute duloxetine required mu and delta ORs but not kappa ORs, while chronic duloxetine required delta ORs. Experiments with OR antagonists revealed that acute duloxetine recruited ORs in the central nervous system, while chronic duloxetine recruited peripheral ORs.

 

Delving into the peripheral mechanism

To learn more about how duloxetine acted in the periphery, Barrot and colleagues then looked at how the antidepressant changed gene expression in the DRG using RNA sequencing. Five weeks after nerve injury, they still saw changes in the expression of 193 genes in the DRG, two-thirds of which were upregulated. But with chronic duloxetine, the investigators saw changes in only half that number of genes, with about two-thirds of those being downregulated.

 

Many of those downregulated genes were ones associated with immune responses. Further analysis showed that chronic duloxetine downregulated genes implicated in the pro-inflammatory tumor necrosis factor (TNF)-α pathway.

 

Additional work would show that chronic duloxetine, but not acute treatment, reduced the amount of membrane-bound TNF-α in the lumbar DRG. And, the researchers showed that blocking TNF-α eased allodynia in nerve-injured animals. It turned out that chronic duloxetine’s impact on TNF-α was indirect via effects on the pro-inflammatory nuclear factor (NF)-kappaB pathway, which is activated by TNF-α.

 

Together, the results suggest that chronic duloxetine may ease pain by reducing nerve injury-associated neuroinflammation.

 

“This is quite interesting to us,” said Barrot. “We’ve highlighted that antidepressants indirectly act on these neuroinflammatory mechanisms, and that could potentially offer us new targets for pain drug development beyond antidepressant drugs.”

 

Finally, the group did a new series of experiments using a second antidepressant drug, amitriptyline, identifying the same distinct mechanisms for acute versus chronic treatment that they saw with duloxetine.

 

What does it all mean for patients?

To determine whether the results from the neuropathic pain model in mice could have clinical relevance, the investigators compared plasma levels of duloxetine in eight neuropathic pain patients who reported partial relief from chronic administration of the drug to levels seen in the nerve-injured animals treated chronically. Mass spectrometry revealed comparable duloxetine levels between the patients and the animals, suggesting the peripheral mechanism observed in the mice may also be relevant to the human situation.

 

Speaking of which, Barrot says it would be important to identify those patients with neuropathic pain who are most likely to respond to antidepressant treatment.

 

“Right now, these drugs only work in one out of two neuropathic pain patients,” he said. “Clinically, we don’t yet know which patients will respond to antidepressants. But if biomarkers of susceptibility to treatment could be identified, such as neuroinflammatory ones, that may help in treatment choice.”

 

Meanwhile, Micó said that the new findings should strengthen the conviction amongst doctors that antidepressants are “a real analgesic” as well as a worthy alternative to opioids.

 

“This can help clinicians understand that there are other options,” according to Micó. “This could also help reduce consumption of opioids in chronic pain patients and, as a consequence, reduce tolerance and dependence. That’s a good thing.”

 

Kayt Sukel is a freelance writer based outside Houston, Texas.

 

Image credit: molekuul/123RF Stock Photo.

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