Malika Benbouzid

β2-adrenoceptors are critical for antidepressant treatment of neuropathic pain†

Tricyclic antidepressants (TCAs) are one of the first‐line pharmacological treatments against neuropathic pain. TCAs increase the extracellular concentrations of noradrenaline and serotonin by blocking the reuptake transporters of these amines. However, the precise downstream mechanism leading to the therapeutic action remains identified. In this work, we evaluated the role of adrenergic receptors (ARs) in the action of TCAs.

Sciatic nerve cuffing in mice: a model of sustained neuropathic pain.

Because of its severity, chronicity, resistance to usual therapy and its consequences on quality of life, neuropathic pain represents a real clinical challenge. Fundamental research on this pathology uses metabolic, pharmacological or traumatic models in rodents that reproduce the characteristic human pain symptoms. In 1996, Mosconi and Kruger morphologically described a model of peripheral neuropathy in which a cuff of polyethylene tubing was placed around the sciatic nerve in rats. In the present study, we evaluated the behavioral consequences of this neuropathic pain model in C57Bl/6J mice which is the main genetic background used for studies in transgenic mice. A short cuff of polyethylene tubing was unilaterally placed around the main branch of the sciatic nerve. It induced an ipsilateral heat thermal hyperalgesia lasting around 3 weeks, and a sustained ipsilateral mechanical allodynia lasting at least 2 months. We showed that this neuropathic pain model is insensitive to ketoprofen, a non‐steroidal anti‐inflammatory drug. Morphine treatment acutely suppressed the mechanical allodynia, but tolerance to this effect rapidly developed. The analysis of video recordings revealed that most aspects of spontaneous behavior remained unaffected on the long term, excepted for a decrease in the time spent at social interaction for the neuropathic mice. Using the elevated plus‐maze and the marble‐burying test, we also showed that neuropathic mice develop an anxiety phenotype. Our data indicate that sciatic nerve cuffing in mice is a pertinent model for the study of nociceptive and emotional consequences of sustained neuropathic pain.

Delta-opioid receptors are critical for tricyclic antidepressant treatment of neuropathic allodynia.

BACKGROUND The therapeutic effect of antidepressant drugs against depression usually necessitates a chronic treatment. A large body of clinical evidence indicates that antidepressant drugs can also be highly effective against chronic neuropathic pain. However, the mechanism by which these drugs alleviate pain is still unclear. METHODS We used a murine model of neuropathic pain induced by sciatic nerve constriction to study the antiallodynic properties of a chronic treatment with the tricyclic antidepressants nortriptyline and amitriptyline. Using knockout and pharmacological approaches in mice, we determined the influence of delta-opioid receptors in the therapeutic action of chronic antidepressant treatment. RESULTS In our model, a chronic treatment by tricyclic antidepressant drugs totally suppresses the mechanical allodynia in neuropathic C57Bl/6J mice. This therapeutic effect can be acutely reversed by an injection of the delta-opioid receptor antagonist naltrindole. Moreover, the antiallodynic property of antidepressant treatment is absent in mice deficient for the delta-opioid receptor gene. CONCLUSIONS The antiallodynic effect of chronic antidepressant treatment is mediated by a recruitment of the endogenous opioid system acting through delta-opioid receptors.

Chronic, but not acute, tricyclic antidepressant treatment alleviates neuropathic allodynia after sciatic nerve cuffing in mice

Antidepressant drugs act mainly by blocking the noradrenaline and/or serotonin uptake sites and require a chronic treatment. Tricyclic antidepressants are among the first line treatments clinically recommended against neuropathic pain. As observed against depression, a chronic treatment is required for a therapeutic effect. However, both in depression‐related and pain‐related research in rodents, it is difficult to design models that reproduce the clinical conditions and are sensitive to chronic but not to acute treatment by antidepressant drugs. In this study, we used a murine neuropathic pain model induced by the unilateral insertion of a polyethylene cuff around the main branch of the sciatic nerve. This model induced a long‐lasting ipsilateral mechanical allodynia. We evidenced that chronic, but not acute, treatment with the tricyclic antidepressants nortriptyline or amitriptyline suppressed the cuff‐induced mechanical allodynia. On the contrary, fluoxetine, a selective serotonin reuptake inhibitor, remained ineffective. To understand which mechanism is recruited downstream in order to alleviate the allodynia, we tested the opioid receptor antagonist naloxone, the delta‐opioid receptor antagonist naltrindole and the kappa‐opioid receptor antagonist nor‐BNI. We show that the therapeutic effect of notriptyline implicates the endogenous opioid system, in particular the delta‐ and the kappa‐opioid receptors. For comparison, we tested the anticonvulsant gabapentin and showed that it alleviates neuropathic allodynia after 3 days of treatment. Naloxone had no effect on gabapentin therapeutic benefit, showing that antidepressants and anticonvulsants alleviate neuropathic allodynia through independent mechanisms. Our work provides a clinically relevant model to understand the mechanism by which chronic antidepressant treatment can alleviate neuropathic pain.

From antidepressant drugs to beta-mimetics: preclinical insights on potential new treatments for neuropathic pain.

The market for pain treatment is a major segment of nervous system pathologies. Despite this dynamism, the management of some pain conditions remains a clinical challenge. Neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system. It is generally a chronic and disabling condition which is difficult to treat. Antidepressant drugs are recommended as one of the first line treatments, but they display noticeable side effects and are not effective on all patients. Using a murine model of neuropathy, we demonstrated that the stimulation of beta2-adrenergic receptors (beta2-AR) is not only necessary for antidepressant drugs to exert their antiallodynic action but that it is in fact sufficient to alleviate neuropathic allodynia. Chronic, but not acute, treatment with beta-mimetics such as terbutaline, salbutamol, fenoterol, salmeterol, ritodrine, isoprenaline (isoproterenol), metaproterenol (orciprenaline), procaterol, formoterol, clenbuterol or bambuterol, relieves allodynia. Agonists of beta2-ARs, and more generally any molecule stimulating beta2-ARs such as beta-mimetics, are thus proposed as potential new treatments for neuropathic pain. Clinical studies are now in preparation to confirm this potential in patients with neuropathic pain. This article reviews the findings leading to propose beta-mimetics for neuropathic pain treatment and other recent patents on the topic.