Antihyperalgesic Activity of Atomoxetine on Diabetes-Induced Neuropathic Pain: Contribution of Noradrenergic and Dopaminergic Systems

Atomoxetine is a selective noradrenaline reuptake inhibitor drug. Based on the knowledge that agents increasing monoamine levels in the central nervous system have therapeutic potential for neuropathic pain, it is planned to investigate the possible efficacy of atomoxetine on diabetes-induced hyperalgesia, in this study. Randall-Selitto (mechanical noxious stimuli) and Hargreaves (thermal noxious stimuli) tests were used to evaluate nociceptive perception of rats. Obtained data indicated that streptozotocin-induced diabetes causes significant decreases in the paw withdrawal threshold and paw withdrawal latency values of the animals, respectively. However, atomoxetine administered at 3 mg/kg/day for 7 and 14 days improved these diabetes-induced hyperalgesia responses. Furthermore, antihyperalgesic activity was antagonized with α-methyl-para-tyrosine methyl ester, phentolamine, propranolol, and sulpiride pre-treatments. The same effect was not reversed, however, by SCH 23390. These findings demonstrated, for the first time, that atomoxetine possesses significant antihyperalgesic activity on diabetes-induced neuropathic pain and this effect seems to be mediated by α- and β-adrenergic and D2/D3 dopaminergic receptors. Results of this present study seem to offer a new indication for an old drug; atomoxetine, but these preclinical data should first be confirmed with further well-designed clinical trials.

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Function and Mechanisms of Truncated BDNF Receptor TrkB.T1 in Neuropathic Pain

Cells ◽

10.3390/cells9051194 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1194 ◽

Cited By ~ 3

Author(s):

Tuoxin Cao ◽

Jessica J. Matyas ◽

Cynthia L. Renn ◽

Alan I. Faden ◽

Susan G. Dorsey ◽

...

Keyword(s):

Neuropathic Pain ◽

Therapeutic Potential ◽

Recovery Of Function ◽

Kinase Domain ◽

Cns Injury ◽

Trkb Receptor ◽

Receptor Isoforms ◽

The Central Nervous System ◽

Injury Models

Brain-derived neurotrophic factor (BDNF), a major focus for regenerative therapeutics, has been lauded for its pro-survival characteristics and involvement in both development and recovery of function within the central nervous system (CNS). However, studies of tyrosine receptor kinase B (TrkB), a major receptor for BDNF, indicate that certain effects of the TrkB receptor in response to disease or injury may be maladaptive. More specifically, imbalance among TrkB receptor isoforms appears to contribute to aberrant signaling and hyperpathic pain. A truncated isoform of the receptor, TrkB.T1, lacks the intracellular kinase domain of the full length receptor and is up-regulated in multiple CNS injury models. Such up-regulation is associated with hyperpathic pain, and TrkB.T1 inhibition reduces neuropathic pain in various experimental paradigms. Deletion of TrkB.T1 also limits astrocyte changes in vitro, including proliferation, migration, and activation. Mechanistically, TrkB.T1 is believed to act through release of intracellular calcium in astrocytes, as well as through interactions with neurotrophins, leading to cell cycle activation. Together, these studies support a potential role for astrocytic TrkB.T1 in hyperpathic pain and suggest that targeted strategies directed at this receptor may have therapeutic potential.

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RAS in the Central Nervous System: Potential Role in Neuropsychiatric Disorders

Current Medicinal Chemistry ◽

10.2174/0929867325666180226102358 ◽

2018 ◽

Vol 25 (28) ◽

pp. 3333-3352 ◽

Cited By ~ 21

Author(s):

Natalia Pessoa Rocha ◽

Ana Cristina Simoes e Silva ◽

Thiago Ruiz Rodrigues Prestes ◽

Victor Feracin ◽

Caroline Amaral Machado ◽

...

Keyword(s):

Blood Pressure ◽

Central Nervous System ◽

Nervous System ◽

Therapeutic Potential ◽

Neuropsychiatric Disorders ◽

Extensive Literature ◽

Ang Ii ◽

Mas Receptor ◽

The Central Nervous System ◽

The Brain

Background: The Renin-Angiotensin System (RAS) is a key regulator of cardiovascular and renal homeostasis, but also plays important roles in mediating physiological functions in the central nervous system (CNS). The effects of the RAS were classically described as mediated by angiotensin (Ang) II via angiotensin type 1 (AT1) receptors. However, another arm of the RAS formed by the angiotensin converting enzyme 2 (ACE2), Ang-(1-7) and the Mas receptor has been a matter of investigation due to its important physiological roles, usually counterbalancing the classical effects exerted by Ang II. Objective: We aim to provide an overview of effects elicited by the RAS, especially Ang-(1-7), in the brain. We also aim to discuss the therapeutic potential for neuropsychiatric disorders for the modulation of RAS. Method: We carried out an extensive literature search in PubMed central. Results: Within the brain, Ang-(1-7) contributes to the regulation of blood pressure by acting at regions that control cardiovascular functions. In contrast with Ang II, Ang-(1-7) improves baroreflex sensitivity and plays an inhibitory role in hypothalamic noradrenergic neurotransmission. Ang-(1-7) not only exerts effects related to blood pressure regulation, but also acts as a neuroprotective component of the RAS, for instance, by reducing cerebral infarct size, inflammation, oxidative stress and neuronal apoptosis. Conclusion: Pre-clinical evidence supports a relevant role for ACE2/Ang-(1-7)/Mas receptor axis in several neuropsychiatric conditions, including stress-related and mood disorders, cerebrovascular ischemic and hemorrhagic lesions and neurodegenerative diseases. However, very few data are available regarding the ACE2/Ang-(1-7)/Mas receptor axis in human CNS.

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The Therapeutic Potential of Chemokines in the Treatment of Chemotherapy- Induced Peripheral Neuropathy

Current Drug Targets ◽

10.2174/1389450120666190906153652 ◽

2020 ◽

Vol 21 (3) ◽

pp. 288-301 ◽

Cited By ~ 5

Author(s):

Lin Zhou ◽

Luyao Ao ◽

Yunyi Yan ◽

Wanting Li ◽

Anqi Ye ◽

...

Keyword(s):

Nervous System ◽

Neuropathic Pain ◽

Immune System ◽

Peripheral Neuropathy ◽

Immune Cell ◽

Therapeutic Potential ◽

Chemotherapeutic Agents ◽

Cell Trafficking ◽

Mediated Communication ◽

Novel Therapeutic Strategies

Background: Some of the current challenges and complications of cancer therapy are chemotherapy- induced peripheral neuropathy (CIPN) and the neuropathic pain that are associated with this condition. Many major chemotherapeutic agents can cause neurotoxicity, significantly modulate the immune system and are always accompanied by various adverse effects. Recent evidence suggests that cross-talk occurs between the nervous system and the immune system during treatment with chemotherapeutic agents; thus, an emerging concept is that neuroinflammation is one of the major mechanisms underlying CIPN, as demonstrated by the upregulation of chemokines. Chemokines were originally identified as regulators of peripheral immune cell trafficking, and chemokines are also expressed on neurons and glial cells in the central nervous system. Objective: In this review, we collected evidence demonstrating that chemokines are potential mediators and contributors to pain signalling in CIPN. The expression of chemokines and their receptors, such as CX3CL1/CX3CR1, CCL2/CCR2, CXCL1/CXCR2, CXCL12/CXCR4 and CCL3/CCR5, is altered in the pathological conditions of CIPN, and chemokine receptor antagonists attenuate neuropathic pain behaviour. Conclusion: By understanding the mechanisms of chemokine-mediated communication, we may reveal chemokine targets that can be used as novel therapeutic strategies for the treatment of CIPN.

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The activation of galanin receptor 2 plays an antinociceptive effect in nucleus accumbens of rats with neuropathic pain

The Journal of Physiological Sciences ◽

10.1186/s12576-021-00790-5 ◽

2021 ◽

Vol 71 (1) ◽

Author(s):

Yan Dong ◽

Chong-Yang Li ◽

Xiao-Min Zhang ◽

Ya-Nan Liu ◽

Shuang Yang ◽

...

Keyword(s):

Neuropathic Pain ◽

Nucleus Accumbens ◽

Pain Threshold ◽

Antinociceptive Effect ◽

Galanin Receptor ◽

Pain Model ◽

Withdrawal Threshold ◽

Neuropathic Pain Model ◽

Galanin Receptors ◽

Intact Rats

AbstractOur previous research has shown that galanin plays an antinociceptive effect via binding to galanin receptors (GalRs) in nucleus accumbens (NAc). This study focused on the involvement of GalR2 in galanin-induced antinociceptive effect in NAc of neuropathic pain rats. The chronic constriction injury of sciatic nerve (CCI) was used to mimic neuropathic pain model. The hind paw withdrawal latency (HWL) to thermal stimulation and hind paw withdrawal threshold (HWT) to mechanical stimulation were measured as the indicators of pain threshold. The results showed that 14 and 28 days after CCI, the expression of GalR2 was up-regulated in bilateral NAc of rats, and intra-NAc injection of GalR2 antagonist M871 reversed galanin-induced increases in HWL and HWT of CCI rats. Furthermore, intra-NAc injection of GalR2 agonist M1145 induced increases in HWL and HWT at day 14 and day 28 after CCI, which could also be reversed by M871. Finally, we found that M1145-induced antinociceptive effect in NAc of CCI rats was stronger than that in intact rats. These results imply that the GalR2 is activated in the NAc from day 14 to day 28 after CCI and GalR2 is involved in the galanin-induced antinociceptive effect in NAc of CCI rats.

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New Inhibitory Effects of Cilnidipine on Microglial P2X7 Receptors and IL-1β Release: An Involvement in its Alleviating Effect on Neuropathic Pain

Cells ◽

10.3390/cells10020434 ◽

2021 ◽

Vol 10 (2) ◽

pp. 434

Author(s):

Tomohiro Yamashita ◽

Sawako Kamikaseda ◽

Aya Tanaka ◽

Hidetoshi Tozaki-Saitoh ◽

Jose M. M. Caaveiro ◽

...

Keyword(s):

Neuropathic Pain ◽

High Throughput Screening ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Inhibitory Effect ◽

Intrathecal Administration ◽

Chemical Library ◽

P2x7 Receptors ◽

Approved Drugs ◽

Cardinal Symptom

P2X7 receptors (P2X7Rs) belong to a family of ATP-gated non-selective cation channels. Microglia represent a major cell type expressing P2X7Rs. The activation of microglial P2X7Rs causes the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β). This response has been implicated in neuroinflammatory states in the central nervous system and in various diseases, including neuropathic pain. Thus, P2X7R may represent a potential therapeutic target. In the present study, we screened a chemical library of clinically approved drugs (1979 compounds) by high-throughput screening and showed that the Ca2+ channel blocker cilnidipine has an inhibitory effect on rodent and human P2X7R. In primary cultured rat microglial cells, cilnidipine inhibited P2X7R-mediated Ca2+ responses and IL-1β release. Moreover, in a rat model of neuropathic pain, the intrathecal administration of cilnidipine produced a reversal of nerve injury-induced mechanical hypersensitivity, a cardinal symptom of neuropathic pain. These results point to a new inhibitory effect of cilnidipine on microglial P2X7R-mediated inflammatory responses and neuropathic pain, proposing its therapeutic potential.

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Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs’ World

Cells ◽

10.3390/cells9010075 ◽

2019 ◽

Vol 9 (1) ◽

pp. 75 ◽

Cited By ~ 3

Author(s):

Nicoletta Nuzziello ◽

Loredana Ciaccia ◽

Maria Liguori

Keyword(s):

Neurodegenerative Diseases ◽

Precision Medicine ◽

Target Genes ◽

Drug Disposition ◽

Therapeutic Potential ◽

Response To Treatment ◽

Therapeutic Effects ◽

Exciting Potential ◽

The Central Nervous System ◽

Effective Use

Novel insights in the development of a precision medicine approach for treating the neurodegenerative diseases (NDDs) are provided by emerging advances in the field of pharmacoepigenomics. In this context, microRNAs (miRNAs) have been extensively studied because of their implication in several disorders related to the central nervous system, as well as for their potential role as biomarkers of diagnosis, prognosis, and response to treatment. Recent studies in the field of neurodegeneration reported evidence that drug response and efficacy can be modulated by miRNA-mediated mechanisms. In fact, miRNAs seem to regulate the expression of pharmacology target genes, while approved (conventional and non-conventional) therapies can restore altered miRNAs observed in NDDs. The knowledge of miRNA pharmacoepigenomics may offers new clues to develop more effective treatments by providing novel insights into interindividual variability in drug disposition and response. Recently, the therapeutic potential of miRNAs is gaining increasing attention, and miRNA-based drugs (for cancer) have been under observation in clinical trials. However, the effective use of miRNAs as therapeutic target still needs to be investigated. Here, we report a brief review of representative studies in which miRNAs related to therapeutic effects have been investigated in NDDs, providing exciting potential prospects of miRNAs in pharmacoepigenomics and translational medicine.

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Understanding Neuropathic Pain

CNS Spectrums ◽

10.1017/s1092852900022628 ◽

2005 ◽

Vol 10 (4) ◽

pp. 298-308 ◽

Cited By ~ 38

Author(s):

Walter Zieglgänsberger ◽

Achim Berthele ◽

Thomas R. Tölle

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neuropathic Pain ◽

Neuronal Excitability ◽

Traumatic Injury ◽

Nerve Fibers ◽

Cellular Events ◽

Excitatory Neurotransmitters ◽

The Central Nervous System ◽

Activity Dependent

AbstractNeuropathic pain is defined as a chronic pain condition that occurs or persists after a primary lesion or dysfunction of the peripheral or central nervous system. Traumatic injury of peripheral nerves also increases the excitability of nociceptors in and around nerve trunks and involves components released from nerve terminals (neurogenic inflammation) and immunological and vascular components from cells resident within or recruited into the affected area. Action potentials generated in nociceptors and injured nerve fibers release excitatory neurotransmitters at their synaptic terminals such as L-glutamate and substance P and trigger cellular events in the central nervous system that extend over different time frames. Short-term alterations of neuronal excitability, reflected for example in rapid changes of neuronal discharge activity, are sensitive to conventional analgesics, and do not commonly involve alterations in activity-dependent gene expression. Novel compounds and new regimens for drug treatment to influence activity-dependent long-term changes in pain transducing and suppressive systems (pain matrix) are emerging.

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Repeated Dosing with Oral Allosteric Modulator of Adenosine A1 Receptor Produces Tolerance in Rats with Neuropathic Pain

Anesthesiology ◽

10.1097/00000542-200404000-00028 ◽

2004 ◽

Vol 100 (4) ◽

pp. 956-961 ◽

Cited By ~ 12

Author(s):

Xinhui Li ◽

Carsten Bantel ◽

Dawn Conklin ◽

Steven R. Childers ◽

James C. Eisenach

Keyword(s):

Neuropathic Pain ◽

Radioligand Binding ◽

Spinal Nerve ◽

Pain Model ◽

Withdrawal Threshold ◽

Receptor Modulator ◽

A1 Receptor ◽

Receptor Number ◽

Repeated Dosing ◽

Motor Effects

Background The positive allosteric adenosine receptor modulator, T62 (2-amino-3-(4-chlorobenzoyl)-5,6,7,8-tetrahydrobenzothiophene), has been shown to reduce mechanical allodynia in a rat model of neuropathic pain. However, whether chronic oral T62 retains efficacy in this pain model has not been examined. Therefore, the authors studied antiallodynic effects of chronic oral T62 in spinal nerved-ligated rats, as well as motor and sedative behavioral effects. Methods Oral T62, 100 mg/kg, or oral oil was applied daily to spinal nerve-ligated rats for 4 weeks, with rat weights examined daily. Sedation, placing and ambulation scores, and withdrawal threshold were observed for 3 h daily for the first 2 weeks and then once a week. At the end of observation, the animals were killed, and the spinal tissues were collected for radioligand binding. In addition, withdrawal thresholds were also observed in rats with 5 days of treatment with 50 mg/kg oral T62. Furthermore, the effects of intrathecal adenosine on rats with oral T62 or oil treatment were compared. Results Chronic oral T62, at 100 mg/kg, initially returned the withdrawal threshold to mechanical testing to preinjury levels, with minor or no sedative or motor effects. Tolerance was observed, with a 60% loss of most possible effects in antiallodynia within 5 days of daily administration. Similarly, tolerance also occurred with chronic oral T62 at 50 mg/kg but did not alter the effect of intrathecal adenosine. Furthermore, 4 weeks of exposure to 100 mg/kg T62 resulted in a small reduction in spinal cord A1 receptor number. Conclusion The results imply that chronically administered A1 adenosine modulators lose efficacy over time, partly as a result of receptor down-regulation.

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Oral Gabapentin Activates Spinal Cholinergic Circuits to Reduce Hypersensitivity after Peripheral Nerve Injury and Interacts Synergistically with Oral Donepezil

Anesthesiology ◽

10.1097/01.anes.0000267605.40258.98 ◽

2007 ◽

Vol 106 (6) ◽

pp. 1213-1219 ◽

Cited By ~ 45

Author(s):

Ken-ichiro Hayashida ◽

Renée Parker ◽

James C. Eisenach

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Intrathecal Injection ◽

Spinal Nerve ◽

Male Rats ◽

Additive Interaction ◽

Alzheimer Dementia ◽

Routes Of Administration ◽

Withdrawal Threshold ◽

The Brain

Background Gabapentin administration into the brain of mice reduces nerve injury-induced hypersensitivity and is blocked by intrathecal atropine and enhanced by intrathecal neostigmine. The authors tested the relevance of these findings to oral therapy by examining the efficacy of oral gabapentin to reduce hypersensitivity after nerve injury in rats and its interaction with the clinically used cholinesterase inhibitor, donepezil. Methods Male rats with hypersensitivity after spinal nerve ligation received gabapentin orally, intrathecally, and intracerebroventricularly with or without intrathecal atropine, and withdrawal threshold to paw pressure was determined. The effects of oral gabapentin and donepezil alone and in combination on withdrawal threshold were determined in an isobolographic design. Results Gabapentin reduced hypersensitivity to paw pressure by all routes of administration, and was more potent and with a quicker onset after intracerebroventricular than intrathecal injection. Intrathecal atropine reversed the effect of intracerebroventricular and oral gabapentin. Oral gabapentin and donepezil interacted in a strongly synergistic manner, with an observed efficacy at one tenth the predicted dose of an additive interaction. The gabapentin-donepezil combination was reversed by intrathecal atropine. Conclusions Although gabapentin may relieve neuropathic pain by actions at many sites, these results suggest that its actions in the brain to cause spinal cholinergic activation predominate after oral administration. Side effects, particularly nausea, cannot be accurately determined on rats. Nevertheless, oral donepezil is well tolerated by patients in the treatment of Alzheimer dementia, and the current study provides the rationale for clinical study of combination of gabapentin and donepezil to treat neuropathic pain.

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Src Family Kinases in the Central Nervous System：Their Emerging Role in Pathophysiology of Migraine and Neuropathic Pain

Current Neuropharmacology ◽

10.2174/1570159x18666200814180218 ◽

2020 ◽

Vol 18 ◽

Author(s):

Lingdi Nie ◽

Wen-Rui Ye ◽

Shangbin Chen ◽

Domenico Chirchiglia ◽

Minyan Wang

Keyword(s):

Neuropathic Pain ◽

Tyrosine Kinases ◽

Neurological Diseases ◽

Src Family Kinases ◽

Signalling Pathways ◽

Pain Mechanisms ◽

Promising Therapeutic Target ◽

The Central Nervous System ◽

The Relationship

: Src family kinases (SFK) are a group of non-receptor tyrosine kinases which play a pivotal role in cellular responses and oncogenesis. Accumulating evidence suggest that SFK also act as a key component in signalling pathways of the central nervous system (CNS) in both physiological and pathological conditions. Despite the crucial role of SFK in signal transduction of the CNS, the relationship between SFK and molecules implicated in pain has been relatively unexplored. This article briefly reviews the recent advances uncovering the interplay of SFK with diverse membrane proteins and intracellular proteins in the CNS and the importance of SFK in the pathophysiology of migraine and neuropathic pain. Mechanisms underlying the role of SFK in these conditions and potential clinical applications of SFK inhibitors in neurological diseases are also summarised. We propose that SFK are the convergent point of signalling pathways in migraine and neuropathic pain and may constitute a promising therapeutic target for these diseases.

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