Search

Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory nervous system. It is accompanied by neuronal and non-neuronal alterations, including alterations in intracellular second messenger pathways. Cellular levels of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) are regulated by phosphodiesterase (PDE) enzymes. Here, we studied the impact of PDE inhibitors (PDEi) in a mouse model of peripheral nerve injury induced by placing a cuff around the main branch of the sciatic nerve. Mechanical hypersensitivity, evaluated using von Frey filaments, was relieved by sustained treatment with the non-selective PDEi theophylline and ibudilast (AV-411), with PDE4i rolipram, etazolate and YM-976, and with PDE5i sildenafil, zaprinast and MY-5445, but not by treatments with PDE1i vinpocetine, PDE2i EHNA or PDE3i milrinone. Using pharmacological and knock-out approaches, we show a preferential implication of delta opioid receptors in the action of the PDE4i rolipram and of both mu and delta opioid receptors in the action of the PDE5i sildenafil. Calcium imaging highlighted a preferential action of rolipram on dorsal root ganglia non-neuronal cells, through PDE4B and PDE4D inhibition. Rolipram had anti-neuroimmune action, as shown by its impact on levels of the pro-inflammatory cytokine tumor necrosis factor-α (TNFα) in the dorsal root ganglia of mice with peripheral nerve injury, as well as in human peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharides. This study suggests that PDEs, especially PDE4 and 5, may be targets of interest in the treatment of neuropathic pain., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background and Objective: Neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system. A number of preclinical studies have provided evidence for the involvement of cytokines, predominantly secreted by a variety of immune cells and by glial cells from the nervous system, in neuropathic pain conditions. Clinical trials and the use of anti-cytokine drugs in different neuropathic aetiologies support the relevance of cytokines as treatment targets. However, the use of such drugs, in particularly biotherapies, can provoke notable adverse effects. Moreover, it is challenging to select one given cytokine as a target, among the various neuropathic pain conditions. It could thus be of interest to target other proteins, such as growth factors, in order to act more widely on the neuroinflammation network. Thus, platelet-rich plasma (PRP), an autologous blood concentrate, is known to contain a natural concentration of growth factors and immune system messengers and is widely used in the clinical setting for tissue regeneration and repair., Database and Data Treatment: In the present review, we critically assess the current knowledge on cytokines in neuropathic pain by taking into consideration both human studies and animal models., Results: This analysis of the literature highlights the pathophysiological importance of cytokines. We particularly highlight the concept of time- and tissue-dependent cytokine activation during neuropathic pain conditions., Conclusion: Thus, direct or indirect cytokines modulation with biotherapies or growth factors appears relevant. In addition, we discuss the therapeutic potential of localized injection of PRP as neuropathic pain treatment by pointing out the possible link between cytokines and the action of PRP., Significance: Preclinical and clinical studies highlight the idea of a cytokine imbalance in the development and maintenance of neuropathic pain. Clinical trials with anticytokine drugs are encouraging but are limited by a 'cytokine candidate approach' and adverse effect of biotherapies. PRP, containing various growth factors, is a new therapeutic used in regenerative medicine. Growth factors can be also considered as modulators of cytokine balance. Here, we emphasize a potential therapeutic effect of PRP on cytokine imbalance in neuropathic pain. We also underline the clinical interest of the use of PRP, not only for its therapeutic effect but also for its safety of use., (© 2021 European Pain Federation - EFIC®.)

Abstract: Tricyclic antidepressants that inhibit serotonin and noradrenaline reuptake, such as amitriptyline, are among the first-line treatments for neuropathic pain, which is caused by a lesion or disease affecting the somatosensory nervous system. These treatments are, however, partially efficient to alleviate neuropathic pain symptoms, and better treatments are still highly required. Interactions between neurons and glial cells participate in neuropathic pain processes, and importantly, connexins-transmembrane proteins involved in cell-cell communication-contribute to these interactions. In a neuropathic pain model in rats, mefloquine, a connexin inhibitor, has been shown to potentiate the antihyperalgesic effect of amitriptyline, a widely used antidepressant. In this study, we further investigated this improvement of amitriptyline action by mefloquine, using the cuff model of neuropathic pain in mice. We first observed that oral mefloquine co-treatment prolonged the effect of amitriptyline on mechanical hypersensitivity by 12 hours after administration. In addition, we showed that this potentiation was not due to pharmacokinetic interactions between the 2 drugs. Besides, lesional and pharmacological approaches showed that the prolonged effect was induced through noradrenergic descending pathways and the recruitment of α2 adrenoceptors. Another connexin blocker, carbenoxolone, also improved amitriptyline action. Additional in vitro studies suggested that mefloquine may also directly act on serotonin transporters and on adenosine A1 and A2A receptors, but drugs acting on these other targets failed to amplify amitriptyline action. Together, our data indicate that pharmacological blockade of connexins potentiates the therapeutic effect of amitriptyline in neuropathic pain., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Neuropathic pain is a chronic pain caused by a lesion or disease affecting the somatosensory nervous system. To date, no specific treatment has been developed to cure this pain. Antidepressants and anticonvulsant drugs are used, but they do not demonstrate universal efficacy, and they often cause detrimental adverse effects. Some studies highlighted the efficacy of sildenafil, a well-known inhibitor of phosphodiesterase 5 (PDE5, (IC 50  = 3.3 nM)), in models of pain. Based on these results, we focused our attention on MY 5445, another known PDE5 inhibitor. Homologues, isosteres and structural analogues of MY 5445 were designed and all synthesized compounds were evaluated for their inhibitory activity toward PDE5. Selectivity profiles towards other PDE1-4 isoenzymes, water solubility and stability in acidic medium of the most potent PDE5 inhibitors were determined and the aminophthalazine 16h and its mimetic 41n (3-aminoindazole) were evaluated in comparison to MY 5445 (4b) in vivo in a model of neuropathic pain induced by sciatic nerve cuffing in mice (3 and 0.5 mg/kg, ip twice a day). Both compounds showed the same efficacy on neuropathic allodynia as MY 5445, and thus produced a significant relief of mechanical hypersensitivity after 12 days of treatment., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. Despite the widespread use of these drugs, the mechanism underlying their therapeutic action in this pain context remains partly elusive. The present study combined data collected in male and female mice from a model of neuropathic pain and data from the clinical setting to understand how antidepressant drugs act. We show two distinct mechanisms by which the selective inhibitor of serotonin and noradrenaline reuptake duloxetine and the tricyclic antidepressant amitriptyline relieve neuropathic allodynia. One of these mechanisms is acute, central, and requires descending noradrenergic inhibitory controls and α 2A adrenoceptors, as well as the mu and delta opioid receptors. The second mechanism is delayed, peripheral, and requires noradrenaline from peripheral sympathetic endings and β 2 adrenoceptors, as well as the delta opioid receptors. We then conducted a transcriptomic analysis in dorsal root ganglia, which suggested that the peripheral component of duloxetine action involves the inhibition of neuroimmune mechanisms accompanying nerve injury, including the downregulation of the TNF-α-NF-κB signaling pathway. Accordingly, immunotherapies against either TNF-α or Toll-like receptor 2 (TLR2) provided allodynia relief. We also compared duloxetine plasma levels in the animal model and in patients and we observed that patients' drug concentrations were compatible with those measured in animals under chronic treatment involving the peripheral mechanism. Our study highlights a peripheral neuroimmune component of antidepressant drugs that is relevant to their delayed therapeutic action against neuropathic pain. SIGNIFICANCE STATEMENT In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. However, the mechanism by which antidepressant drugs can relieve neuropathic pain remained in part elusive. Indeed, preclinical studies led to contradictions concerning the anatomical and molecular substrates of this action. In the present work, we overcame these apparent contradictions by highlighting the existence of two independent mechanisms. One is rapid and centrally mediated by descending controls from the brain to the spinal cord and the other is delayed, peripheral, and relies on the anti-neuroimmune action of chronic antidepressant treatment., (Copyright © 2018 the authors 0270-6474/18/389935-21$15.00/0.)

Peripheral delta opioid (DOP) receptors are essential for the antiallodynic effect of the tricyclic antidepressant nortriptyline. However, the population of DOP-expressing cells affected in neuropathic conditions or underlying the antiallodynic activity of antidepressants remains unknown. Using a mouse line in which DOP receptors were selectively ablated in cells expressing Nav1.8 sodium channels (DOP cKO), we established that these DOP peripheral receptors were mandatory for duloxetine to alleviate mechanical allodynia in a neuropathic pain model based on sciatic nerve cuffing. We then examined the impact of nerve cuffing and duloxetine treatment on DOP-positive populations using a knock-in mouse line expressing a fluorescent version of the DOP receptor fused with the enhanced green fluorescent protein (DOPeGFP). Eight weeks postsurgery, we observed a reduced proportion of DOPeGFP-positive small peptidergic sensory neurons (calcitonin gene-related peptide (CGRP) positive) in dorsal root ganglia and a lower density of DOPeGFP-positive free nerve endings in the skin. These changes were not present in nerve-injured mice chronically treated with oral duloxetine. In addition, increased DOPeGFP translocation to the plasma membrane was observed in neuropathic conditions but not in duloxetine-treated neuropathic mice, which may represent an additional level of control of the neuronal activity by DOP receptors. Our results therefore established a parallel between changes in the expression profile of peripheral DOP receptors and mechanical allodynia induced by sciatic nerve cuffing., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Pain associates both sensory and emotional aversive components, and often leads to anxiety and depression when it becomes chronic. Here, we characterized, in a mouse model, the long-term development of these sensory and aversive components as well as anxiodepressive-like consequences of neuropathic pain and determined their electrophysiological impact on the anterior cingulate cortex (ACC, cortical areas 24a/24b). We show that these symptoms of neuropathic pain evolve and recover in different time courses following nerve injury in male mice. In vivo electrophysiological recordings evidence an increased firing rate and bursting activity within the ACC when anxiodepressive-like consequences developed, and this hyperactivity persists beyond the period of mechanical hypersensitivity. Whole-cell patch-clamp recordings also support ACC hyperactivity, as shown by increased excitatory postsynaptic transmission and contribution of NMDA receptors. Optogenetic inhibition of the ACC hyperactivity was sufficient to alleviate the aversive and anxiodepressive-like consequences of neuropathic pain, indicating that these consequences are underpinned by ACC hyperactivity. SIGNIFICANCE STATEMENT Chronic pain is frequently comorbid with mood disorders, such as anxiety and depression. It has been shown that it is possible to model this comorbidity in animal models by taking into consideration the time factor. In this study, we aimed at determining the dynamic of different components and consequences of chronic pain, and correlated them with electrophysiological alterations. By combining electrophysiological, optogenetic, and behavioral analyses in a mouse model of neuropathic pain, we show that the mechanical hypersensitivity, ongoing pain, anxiodepressive consequences, and their recoveries do not necessarily exhibit temporal synchrony during chronic pain processing, and that the hyperactivity of the anterior cingulate cortex is essential for driving the emotional impact of neuropathic pain., (Copyright © 2018 the authors 0270-6474/18/383102-14$15.00/0.)

4-phenylpyridin-2-yl-guanidine (5b): a new inhibitor of the overproduction of pro-inflammatory cytokines (TNFα and Il1β) was identified from a high-throughput screening of a chemical library on human peripheral blood mononuclear cells (PBMCs) after LPS stimulation. Derivatives, homologues and rigid mimetics of 5b were designed and synthesized, and their cytotoxicity and ability to inhibit TNFα overproduction were evaluated. Among them, compound 5b and its mimetic 12 (2-aminodihydroquinazoline) showed similar inhibitory activities, and were evaluated in vivo in models of lung inflammation and neuropathic pain in mice. In particular, compound 12 proved to be active (5 mg/kg, ip) in both models., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background Surgeries causing nerve injury can result in chronic neuropathic pain, which is clinically managed by using antidepressant or anticonvulsant drugs. Currently, there is a growing interest for investigating preemptive treatments that would prevent this long-term development of neuropathic pain. Our aim was to compare analgesic drugs using two distinct treatment modalities: either treatment onset at surgery time or following a couple of weeks of neuropathic pain. Methods In male C57BL/6J mice, neuropathic pain was induced by cuffing the sciatic nerve, and allodynia was assessed using von Frey filaments. We tested the effect of anticonvulsants (gabapentin 10 mg/kg and carbamazepine 40 mg/kg), antidepressants (desipramine 5 mg/kg, duloxetine 10 mg/kg, and fluoxetine 10 mg/kg), dexamethasone (2 mg/kg), and ketamine (15 mg/kg). Drugs were injected daily or twice a day, starting either at surgery time or on day 25 postsurgery (15 days of treatment for antidepressants and 10 days for other drugs). Results Ketamine was the only effective treatment during the early postsurgical period. Although early anticonvulsant treatment was not immediately effective, it prevented chronification of allodynia. When treatments started at day 25 postsurgery, desipramine, duloxetine, and anticonvulsants suppressed the mechanical allodynia. Conclusions Our data show that allodynia measured in experimental neuropathic pain model likely results from a combination of different processes (early vs. late allodynia) that display different sensitivity to treatments. We also propose that early anticonvulsant treatment with gabapentin or carbamazepine may have a prophylactic effect on the chronification of allodynia following nerve injury.

Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory system. It is generally chronic and challenging to treat. The recommended pharmacotherapy for neuropathic pain includes the use of some antidepressants, such as tricyclic antidepressants (TCAs) (amitriptyline…) or serotonin and noradrenaline re-uptake inhibitors (duloxetine…), and/or anticonvulsants such as the gabapentinoids gabapentin or pregabalin. Antidepressant drugs are not acute analgesics but require a chronic treatment to relieve neuropathic pain, which suggests the recruitment of secondary downstream mechanisms as well as long-term molecular and neuronal plasticity. Noradrenaline is a major actor for the action of antidepressant drugs in a neuropathic pain context. Mechanistic hypotheses have implied the recruitment of noradrenergic descending pathways as well as the peripheral recruitment of noradrenaline from sympathetic fibers sprouting into dorsal root ganglia; and importance of both α2 and β2 adrenoceptors have been reported. These monoamine re-uptake inhibitors may also indirectly act as anti-proinflammatory cytokine drugs; and their therapeutic action requires the opioid system, particularly the mu (MOP) and/or delta (DOP) opioid receptors. Gabapentinoids, which target the voltage-dependent calcium channels α2δ-1 subunit, inhibit calcium currents, thus decreasing the excitatory transmitter release and spinal sensitization. Gabapentinoids also activate the descending noradrenergic pain inhibitory system coupled to spinal α2 adrenoceptors. Gabapentinoid treatment may also indirectly impact on neuroimmune actors, like proinflammatory cytokines. These drugs are effective against neuropathic pain both with acute administration at high dose and with repeated administration. This review focuses on mechanistic knowledge concerning chronic antidepressant treatment and gabapentinoid treatment in a neuropathic pain context., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Clinical management of neuropathic pain, which is pain arising as a consequence of a lesion or a disease affecting the somatosensory system, partly relies on the use of anticonvulsant drugs such as gabapentinoids. Therapeutic action of gabapentinoids such as gabapentin and pregabalin, which act by the inhibition of calcium currents through interaction with the α2δ-1 subunit of voltage-dependent calcium channels, is well documented. However, some aspects of the downstream mechanisms are still to be uncovered. Using behavioral, genetic, and pharmacological approaches, we tested whether opioid receptors are necessary for the antiallodynic action of acute and/or long-term pregabalin treatment in the specific context of neuropathic pain., Results: Using the cuff model of neuropathic pain in mice, we show that acute pregabalin administration at high dose has a transitory antiallodynic action, while prolonged oral pregabalin treatment leads to sustained antiallodynic action, consistent with clinical observations. We show that pregabalin remains fully effective in μ-opioid receptor, in δ-opioid receptor and in κ-opioid receptor deficient mice, either female or male, and its antiallodynic action is not affected by acute naloxone. Our work also shows that long-term pregabalin treatment suppresses tumor necrosis factor-α overproduction induced by sciatic nerve constriction in the lumbar dorsal root ganglia., Conclusions: We demonstrate that neither acute nor long-term antiallodynic effect of pregabalin in a context of neuropathic pain is mediated by the endogenous opioid system, which differs from opioid treatment of pain and antidepressant treatment of neuropathic pain. Our data are also supportive of an impact of gabapentinoid treatment on the neuroimmune aspect of neuropathic pain., (© The Author(s) 2016.)

Background: Pre-clinical research has shown β2 -adrenoceptors to be essential for the antiallodynic action of antidepressant drugs in murine models of neuropathic pain and that sustained treatment with β2 -agonists has an antiallodynic action. Here, we clinically investigated whether chronic β2 -agonist treatments may influence the incidence of post-thoracotomy chronic pain, defined as pain that recurs or persists along a thoracotomy scar more than 2 months after surgery, either neuropathic or non-neuropathic., Methods: We conducted an epidemiological study on patients operated by thoracotomy. Demographic data, medical history and treatments concomitant to the surgery were recorded at a follow-up visit. Information on perioperative treatments was collected from the anaesthesia records and confirmed by the patients. In patients with pain at the surgery level, post-thoracotomy chronic pain was assessed by clinical examination and numeric scale. Physical examination and DN4 questionnaire were used to discriminate neuropathic and non-neuropathic chronic pain at scar level., Results: One hundred and eighty-nine patients were included. Eighty-one patients reported persisting thoracic pain, with neuropathic characteristics in 58 of them (30% of the 189 patients). The most common chronic drugs during the perioperative period were inhaled β2 -agonists (28.6%). The chronic use of β2 -agonists was an independent predictor of thoracic neuropathic pain (but not of non-neuropathic pain) and was associated with a five-fold decrease in the relative incidence of neuropathic pain [OR = 0.19 (0.06-0.45)]., Conclusions: These data suggest a possible influence of chronic β2 -agonist treatments on neuropathic pain secondary to thoracotomy. This apparent preventive effect of β2 -agonist treatments should warrant controlled clinical trials., (© 2015 European Pain Federation - EFIC®)

Background and Purpose: Tricyclic antidepressants are used clinically as first-line treatments for neuropathic pain. Opioid receptors participate in this pain-relieving action, and preclinical studies in receptor-deficient mice have highlighted a critical role for δ-, but not μ-opioid receptors. In this study, we investigated whether κ-opioid (KOP) receptors have a role in the antiallodynic action of tricyclic antidepressants., Experimental Approach: We used a model of neuropathic pain induced by unilateral sciatic nerve cuffing. In this model, the mechanical allodynia was evaluated using von Frey filaments. Experiments were conducted in C57BL/6J mice, and in KOP receptor-deficient mice and their wild-type littermates. The tricyclic antidepressant nortriptyline (5 mg · kg(-1)) was delivered twice a day for over 2 weeks. Agonists and antagonists of opioid receptors were used to test the selectivity of the KOP receptor antagonist norbinaltorphimine (nor-BNI) in mice with neuropathic pain., Key Results: After 12 days of treatment, nortriptyline relieved neuropathic allodynia in both wild-type and KOP receptor-deficient mice. Surprisingly, acute nor-BNI reversed the effect of nortriptyline in both wild-type and KOP receptor-deficient mice. Further experiments showed that nor-BNI action was selective for KOP receptors at a late time-point after its administration (8 h), but not at an early time-point, when it may also interact with δ-opioid (DOP) receptors., Conclusions and Implications: KOP receptors are not necessary for the effect of a tricyclic antidepressant against neuropathic allodynia. These findings together with previous data indicate that the DOP receptor is the only opioid receptor that is necessary for the antiallodynic action of antidepressants., (© 2014 The British Pharmacological Society.)

Background: Besides chronic stress, chronic pain is a prevalent determinant for depression. Changes induced in specific brain regions by sustained pain may alter the processing of affective information, thus resulting in anxiodepressive disorders. Here, we compared the role of the anterior cingulate cortex (ACC) and the posterior insular cortex in the anxiodepressive, sensory, and affective aspects of chronic pain., Methods: Neuropathic pain was induced by cuffing the right sciatic nerve of C57BL/6J mice. Lesions were performed by local injection of ibotenic acid and chronic activation of the ACC by optogenetic stimulation. Anxiodepressive-related behaviors were evaluated through the novelty suppressed feeding, marble burying, splash, and forced swimming tests. Mechanical thresholds were determined using von Frey filaments, and the relief of spontaneous pain was determined by using place conditioning., Results: The ACC lesion prevented the anxiodepressive consequences of chronic pain without affecting the sensory mechanical allodynia. Conversely, the tonic or spontaneous pain and the anxiodepressive consequences of pain remained present after posterior insular cortex lesion, even though the mechanical allodynia was suppressed. Furthermore, optogenetic stimulation of the ACC was sufficient to induce anxiety and depressive-like behaviors in naïve animals., Conclusions: Our results show that, at cortical level, the sensory component of chronic pain remains functionally segregated from its affective and anxiodepressive components. Spontaneous tonic pain and evoked allodynia can be experimentally dissociated. Furthermore, the ACC appears as a critical hub for mood disorders, including for the anxiodepressive consequences of chronic pain, and thus constitutes an important target for divulging the underlying mechanism., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Mood disorders such as depression and anxiety are frequently observed in patients suffering from chronic pain, including neuropathic pain. While this comorbidity is clinically well established, the underlying mechanism(s) remained unclear. The recent development of animal models now allows addressing the consequences of neuropathic pain. In this review, we report the preclinical evidences from anatomical, neuroimaging, behavioral, pharmacological and biochemical studies that address the anxiodepressive consequences of neuropathic pain. We present an overview of rodent models of these consequences and we discuss the challenges and parameters to consider for generating these models. We then discuss the possible mechanism(s) underlying anxiodepressive consequences by describing morphological and functional changes. Information is provided concerning neuroanatomical changes and plasticity, including LTP and LTD, in the anterior cingulate cortex, the insula, the hippocampus, the amygdala and the mesolimbic system, neuroendocrine parameters concerning the hypothalamo-pituitary-adrenal axis, neuroimmune response including the role of glial cells and cytokines, monoamine systems and changes in locus coeruleus noradrenergic system, and neurotrophic factors such as BDNF., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Neuropathic pain arises as a consequence of a lesion or a disease affecting the somatosensory system. This syndrome results from maladaptive changes in injured sensory neurons and along the entire nociceptive pathway within the central nervous system. It is usually chronic and challenging to treat. In order to study neuropathic pain and its treatments, different models have been developed in rodents. These models derive from known etiologies, thus reproducing peripheral nerve injuries, central injuries, and metabolic-, infectious- or chemotherapy-related neuropathies. Murine models of peripheral nerve injury often target the sciatic nerve which is easy to access and allows nociceptive tests on the hind paw. These models rely on a compression and/or a section. Here, the detailed surgery procedure for the "cuff model" of neuropathic pain in mice is described. In this model, a cuff of PE-20 polyethylene tubing of standardized length (2 mm) is unilaterally implanted around the main branch of the sciatic nerve. It induces a long-lasting mechanical allodynia, i.e., a nociceptive response to a normally non-nociceptive stimulus that can be evaluated by using von Frey filaments. Besides the detailed surgery and testing procedures, the interest of this model for the study of neuropathic pain mechanism, for the study of neuropathic pain sensory and anxiodepressive aspects, and for the study of neuropathic pain treatments are also discussed.

Peripheral polyneuropathy is a frequent complication of diabetes. One of its consequences is neuropathic pain which is often chronic and difficult to treat. This pain management classically involves anticonvulsant drugs or tricyclic antidepressant drugs (TCA). We have previously shown that β2 adrenoceptors and δ opioid receptors are critical for TCA action in a traumatic model of neuropathic pain. In the present work, we used the obese leptin deficient mice (ob/ob) which are a genetic model of type 2 diabetes in order to study the treatment of diabetic polyneuropathy. ob/ob mice with hyperglycemia develop tactile bilateral allodynia. We investigated the action of the TCA nortriptyline and the β2 adrenoceptor agonist terbutaline on this neuropathic allodynia. The consequences of acute and chronic treatments were tested, and mechanical allodynia was assessed by using von Frey hairs. Chronic but not acute treatment with nortriptyline alleviates allodynia caused by the diabetic neuropathy. This effect depends on β2 adrenoceptors but not on α2 adrenoceptors, as shown by the blockade with repeated co-administration of the β2 adrenoceptor antagonist ICI118551 but not with repeated co-administration of the α2 adrenoceptor antagonist yohimbine. Direct stimulation of β2 adrenoceptors appears sufficient to relieve allodynia, as shown with chronic terbutaline treatment. δ but not mu opioid receptors seem important to these action since acute naltrindole, but not acute naloxonazine, reverses the effect of chronic nortriptyline or terbutaline treatment., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. It is usually chronic and challenging to treat. Some antidepressants are first-line pharmacological treatments for neuropathic pain. The noradrenaline that is recruited by the action of the antidepressants on reuptake transporters has been proposed to act through β2-adrenoceptors (β2-ARs) to lead to the observed therapeutic effect. However, the complex downstream mechanism mediating this action remained to be identified. In this study, we demonstrate in a mouse model of neuropathic pain that an antidepressant's effect on neuropathic allodynia involves the peripheral nervous system and the inhibition of cytokine tumor necrosis factor α (TNFα) production. The antiallodynic action of nortriptyline is indeed lost after peripheral sympathectomy, but not after lesion of central descending noradrenergic pathways. More particularly, we report that antidepressant-recruited noradrenaline acts, within dorsal root ganglia, on β2-ARs expressed by non-neuronal satellite cells. This stimulation of β2-ARs decreases the neuropathy-induced production of membrane-bound TNFα, resulting in relief of neuropathic allodynia. This indirect anti-TNFα action was observed with the tricyclic antidepressant nortriptyline, the selective serotonin and noradrenaline reuptake inhibitor venlafaxine and the β2-AR agonist terbutaline. Our data revealed an original therapeutic mechanism that may open novel research avenues for the management of painful peripheral neuropathies., (© 2013.)

Neuropathic pain is often a chronic condition, disabling and difficult to treat. Using a murine model of neuropathic pain induced by placing a polyethylene cuff around the main branch of the sciatic nerve, we have shown that chronic treatment with β-AR agonists is effective against neuropathic allodynia. β-mimetics are widely used against asthma and chronic obstructive pulmonary disease and may offer an interesting option for neuropathic pain management. The most prominent adverse effects of chronic treatment with β-mimetics are cardiovascular. In this study, we compared the action of low doses of the selective β(2)-AR agonist terbutaline and of a high dose of the mixed β(1)/β(2)-AR agonist isoproterenol on cardiovascular parameters in a neuropathic pain context. Isoproterenol was used as a positive control for some heart-related changes. Cardiac functions were studied by echocardiography, hemodynamic measurements, histological analysis of fibrosis and cardiac hypertrophy, and by quantitative real time PCR analysis of atrial natriuretic peptide (Nppa), periostin (Postn), connective tissue growth factor (Ctgf) and β-myosin heavy chain (Myh7). Our data show that a chronic treatment with the β(2)-AR agonist terbutaline at low antiallodynic dose does not affect cardiovascular parameters, whereas the mixed β(1)/β(2)-AR agonist isoproterenol induces cardiac hypertrophy. These data suggest that low doses of β(2)-AR agonists may provide a suitable treatment with rare side effects in neuropathic pain management. This study conducted in an animal model requires clinical confirmation in humans., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Tricyclic antidepressants (TCAs) are among the first line treatments clinically recommended against neuropathic pain. However, the mechanism by which they alleviate pain is still unclear. Pharmacological and genetic approaches evidenced a critical role of delta-opioid receptors (DORs) in the therapeutic action of chronic TCA treatment. It is however unclear whether mu-opioid receptors (MORs) are also necessary to the pain-relieving action of TCAs. The lack of highly selective MOR antagonists makes difficult to conclude based on pharmacological studies. In the present work, we thus used a genetic approach and compared mutant mice lacking MORs and their wild-type littermates. The neuropathy was induced by unilateral sciatic nerve cuffing. The threshold for mechanical response was evaluated using von Frey filaments. MOR-deficient mice displayed the same baseline for mechanical sensitivity as their wild-type littermates. After sciatic nerve cuffing, both wild-type and MOR-deficient mice displayed an ipsilateral mechanical allodynia. After about 10 days of treatment, nortriptyline suppressed this allodynia in both wild-type and MOR-deficient mice. MORs are thus not critical for nortriptyline action against neuropathic pain. An acute injection of the DOR antagonist naltrindole induced a relapse of neuropathic allodynia in both wild-type and MOR-deficient mice, thus confirming the critical role of DORs in nortriptyline action. Moreover, morphine induced an acute analgesia in control and in neuropathic wild-type mice, but was without effect in MOR-deficient mice. While MORs are crucial for morphine action, they are not critical for nortriptyline action. Our results highlight the functional difference between DORs and MORs in mechanisms of pain relief., (Copyright (c) 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: Antidepressants are a first-line treatment against neuropathic pain. We previously demonstrated that beta(2)-adrenoceptors are necessary for antidepressants to exert their anti-allodynic action. The aim of the present study was to assess whether beta(2)-adrenoceptor agonists could be sufficient to alleviate neuropathic allodynia., Experimental Approach: We used a murine model of neuropathy induced by unilateral sciatic nerve cuffing in C57BL/6J mice. We previously demonstrated that this animal model is sensitive to chronic, but not to acute, treatment with antidepressant drugs, which is clinically relevant. The mechanical allodynia was evaluated using the von Frey filaments., Key Results: We showed that chronic but not acute treatment with the beta-adrenoceptor agonists, bambuterol, isoprenaline, fenoterol, salbutamol, salmeterol, terbutaline or ritodrine suppressed mechanical allodynia. We confirmed that the action of these beta-adrenoceptor agonists was mediated through beta(2)-adrenoceptors by blocking it with intraperitoneal or intrathecal, but not intracerebroventricular or intraplantar, injections of the antagonist ICI118551. We also showed that chronic treatments with the beta-adrenoceptor antagonists, propranolol or ICI118551 did not suppress the allodynia., Conclusions and Implications: Our data show that chronic treatment with beta-adrenoceptor agonists has the same antiallodynic properties as treatments with antidepressant drugs. This study was, however, conducted in an animal model, and a clinical validation will be required to confirm the value of the present findings in patients.

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.

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.