ALIAmides Update: Palmitoylethanolamide and Its Formulations on Management of Peripheral Neuropathic Pain

Neuropathic pain results from lesions or diseases of the somatosensory nervous system and it remains largely difficult to treat. Peripheral neuropathic pain originates from injury to the peripheral nervous system (PNS) and manifests as a series of symptoms and complications, including allodynia and hyperalgesia. The aim of this review is to discuss a novel approach on neuropathic pain management, which is based on the knowledge of processes that underlie the development of peripheral neuropathic pain; in particular highlights the role of glia and mast cells in pain and neuroinflammation. ALIAmides (autacoid local injury antagonist amides) represent a group of endogenous bioactive lipids, including palmitoylethanolamide (PEA), which play a central role in numerous biological processes, including pain, inflammation, and lipid metabolism. These compounds are emerging thanks to their anti-inflammatory and anti-hyperalgesic effects, due to the down-regulation of activation of mast cells. Collectively, preclinical and clinical studies support the idea that ALIAmides merit further consideration as therapeutic approach for controlling inflammatory responses, pain, and related peripheral neuropathic pain.

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The Role of Mast Cells in Stroke

Cells ◽

10.3390/cells8050437 ◽

2019 ◽

Vol 8 (5) ◽

pp. 437 ◽

Cited By ~ 8

Author(s):

Edoardo Parrella ◽

Vanessa Porrini ◽

Marina Benarese ◽

Marina Pizzi

Keyword(s):

Central Nervous System ◽

Immune Response ◽

Nervous System ◽

Mast Cells ◽

Brain Edema ◽

Hemorrhagic Stroke ◽

Inflammatory Responses ◽

Adult Brain ◽

The Central Nervous System

Mast cells (MCs) are densely granulated perivascular resident cells of hematopoietic origin. Through the release of preformed mediators stored in their granules and newly synthesized molecules, they are able to initiate, modulate, and prolong the immune response upon activation. Their presence in the central nervous system (CNS) has been documented for more than a century. Over the years, MCs have been associated with various neuroinflammatory conditions of CNS, including stroke. They can exacerbate CNS damage in models of ischemic and hemorrhagic stroke by amplifying the inflammatory responses and promoting brain–blood barrier disruption, brain edema, extravasation, and hemorrhage. Here, we review the role of these peculiar cells in the pathophysiology of stroke, in both immature and adult brain. Further, we discuss the role of MCs as potential targets for the treatment of stroke and the compounds potentially active as MCs modulators.

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The attenuation of pain behaviour and serum interleukin-6 concentration by nimesulide in a rat model of neuropathic pain

Scandinavian Journal of Pain ◽

10.1016/j.sjpain.2010.08.003 ◽

2010 ◽

Vol 1 (4) ◽

pp. 229-234 ◽

Cited By ~ 5

Author(s):

Taraneh Moini Zanjani ◽

Masoumeh Sabetkasaei ◽

Behnaz Karimian ◽

Farzaneh Labibi ◽

Babak Farokhi ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neuropathic Pain ◽

Immune System ◽

Immune Cells ◽

Interleukin 6 ◽

Inflammatory Responses ◽

Pain Behaviour ◽

Behavioural Tests

AbstractBackgroundEvidence for a role of immune system in hyperalgesic pain states is increasing. Recent work in neuroimmunology suggests that the immune system does more than simply perform its well known functions of recognizing and removing invading pathogens and tumors. Interest in neuroinflammation and neuroimmune activation has grown rapidly in recent years with the recognition of the role of central nervous system inflammatiom and immune responses in the aetiology of pain states. Among various theories, the role of inflammatory responses of the injured nerve has recently received attention. Cytokines are heterogenous group of polypeptides that activate the immune system and mediate inflammatory responses, acting on a variety of tissue, including the peripheral and central nervous system. Interleukin-6 (IL-6) a pro-inflammatory cytokine, is potentially important in pain aetiology, have pronociceptive actions. Neuropathic pain may be due to a primary insult to the peripheral or central nervous system. Substances released during inflammation from immune cells play an important role in the development and maintenance of chronic pain. Nimesulide, a highly selective cox-2 inhibitor, effectively reduces hyperalgesia due to peripherally administration of inflammatory agents like formalin. The safety of nimesulide was reported for some conditions in which other NSAIDs are contraindicated. Here we have determined the effect of nimesulide on pain behaviour and serum IL-6 level in chronic constriction injury (CCI) model of neuropathic pain.MethodsExperiments were carried out on male Wistar rats, (weight 150–200 g, n = 8). Rats were divided into 3 different groups: 1-CCI + saline 0.9% 2Sham + saline 0.9% (control) 3CCI + drug. Nimesulide (1.25, 2.5, 5 mg/kg, i.p.) was injected 1h before surgery and continued daily to day 14 post-ligation. 42 °C water for thermal hyperalgesia, von Frey filaments for mechanical allodynia, acetone test for cool allodynia and 10 °C water for cold hyperalgesia were respectively used as pain behavioural tests. Behavioural tests were recorded before surgery and on postoperative days 1, 3, 5, 7, 10, 14 and the serum concentration of IL-6 was determined at the day 14.ResultsThe results of this study showed a decrease in hyperalgesia and allodynia following nimesulide administration.ConclusionsIt appears that nimesulide was able to reduce pain behaviour due to nerve inflammation and a parallel decrease in the serum IL-6 concentration was observed.ImplicationsThe immune system is an important mediator in the cascade of events that ultimately results in hyperalgesia. Cytokines contribute to the patheogenesis of neuropathic pain, therefore drugs that inhibit cytokine release from immune cells may reduce inflammatory pain states.

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Neuropathic pain: mechanisms of development, principles of diagnostics and treatment

Pain medicine ◽

10.31636/pmjua.v4i2.1 ◽

2019 ◽

Vol 4 (2) ◽

pp. 4-32

Author(s):

Dmytro Dmytriiev ◽

Pylyp Prudius ◽

Olesia Zaletskaya ◽

Yevhen Lisak ◽

Yurii Rudnitsky ◽

...

Keyword(s):

Nervous System ◽

Neuropathic Pain ◽

Pain Syndrome ◽

Diabetic Polyneuropathy ◽

Pain Mechanisms ◽

Peripheral Neuropathic Pain ◽

Pain Pathways ◽

Mechanisms Of Development ◽

Somatosensory Nervous System ◽

Cause Of Pain

Neuropathic pain is a pain caused by a disease or focal damage to the somatosensory nervous system. The prevalence of chronic pain with neuropathic features in different countries is estimated at 7–10 %. Damages to the nervous system can occur at the level of peripheral nerves, plexus and dorsal roots (peripheral neuropathic pain) or spinal cord and brain (central neuropathic pain). Neuropathic pain is based on pathological activation of pain pathways. Neuropathic pain occurs with diabetic polyneuropathy more often than with all polyneuropathies of another etiology. Hyperglycemia is the major cause of chronic diabetes mellitus and its progression. Since the cause of pain can rarely be cured, treatment is usually symptomatic. Neuropathic pain is generally poorly controlled by analgesics. NB management is started with conservative pharmacotherapy before applying invasive analgesia. Although there are many drugs that can be used in patients with DPN, monotherapy can not always stop pain syndrome. In addition, the patient may not tolerate the full therapeutic dose of the drug. All this dictates the need for combination therapy.

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B12 as a Treatment for Peripheral Neuropathic Pain: A Systematic Review

Nutrients ◽

10.3390/nu12082221 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2221

Author(s):

Thomas Julian ◽

Rubiya Syeed ◽

Nicholas Glascow ◽

Efthalia Angelopoulou ◽

Panagiotis Zis

Keyword(s):

Quality Of Life ◽

Systematic Review ◽

Nervous System ◽

Neuropathic Pain ◽

Post Herpetic Neuralgia ◽

Peripheral Neuropathic Pain ◽

Treatment Regimens ◽

Level Ii ◽

Somatosensory Nervous System

Neuropathic pain describes a range of unpleasant sensations caused by a lesion or disease of the somatosensory nervous system. The sensations caused by neuropathic pain are debilitating and improved treatment regimens are sought in order to improve the quality of life of patients. One proposed treatment for neuropathic pain is vitamin B12, which is thought to alleviate pain by a number of mechanisms including promoting myelination, increasing nerve regeneration and decreasing ectopic nerve firing. In this paper, the evidence for B12 as a drug treatment for neuropathic pain is reviewed. Twenty four published articles were eligible for inclusion in this systematic review in which a range of treatment regimens were evaluated including both B12 monotherapy and B12 in combination with other vitamins or conventional treatments, such as gabapentinoids. Overall, this systematic review demonstrates that there is currently some evidence for the therapeutic effect of B12 in the treatment of post-herpetic neuralgia (level II evidence) and the treatment of painful peripheral neuropathy (level III evidence).

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Effects of Curcumin and Its Different Formulations in Preclinical and Clinical Studies of Peripheral Neuropathic and Postoperative Pain: A Comprehensive Review

International Journal of Molecular Sciences ◽

10.3390/ijms22094666 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4666

Author(s):

Paramita Basu ◽

Camelia Maier ◽

Arpita Basu

Keyword(s):

Neuropathic Pain ◽

Postoperative Pain ◽

Clinical Studies ◽

Curcuma Longa ◽

Somatosensory System ◽

Positive Outcomes ◽

Negative Effects ◽

Acute Postoperative Pain ◽

Peripheral Neuropathic Pain ◽

Preclinical And Clinical Studies

Lesion or disease of the somatosensory system leads to the development of neuropathic pain. Peripheral neuropathic pain encompasses damage or injury of the peripheral nervous system. On the other hand, 10–15% of individuals suffer from acute postoperative pain followed by persistent pain after undergoing surgeries. Antidepressants, anticonvulsants, baclofen, and clonidine are used to treat peripheral neuropathy, whereas opioids are used to treat postoperative pain. The negative effects associated with these drugs emphasize the search for alternative therapeutics with better efficacy and fewer side effects. Curcumin, a polyphenol isolated from the roots of Curcuma longa, possesses antibacterial, antioxidant, and anti-inflammatory properties. Furthermore, the low bioavailability and fast metabolism of curcumin have led to the advent of various curcumin formulations. The present review provides a comprehensive analysis on the effects of curcumin and its formulations in preclinical and clinical studies of neuropathic and postoperative pain. Based on the positive outcomes from both preclinical and clinical studies, curcumin holds the promise of mitigating or preventing neuropathic and postoperative pain conditions. However, more clinical studies with improved curcumin formulations are required to involve its use as adjuvant to neuropathic and postoperative drugs.

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Therapeutically Targeting Neuroinflammation and Microglia after Acute Ischemic Stroke

BioMed Research International ◽

10.1155/2014/297241 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 40

Author(s):

Youngjeon Lee ◽

Sang-Rae Lee ◽

Sung S. Choi ◽

Hyeon-Gu Yeo ◽

Kyu-Tae Chang ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Inflammatory Responses ◽

Secondary Injury ◽

Initial Event ◽

Stroke Models ◽

Anti Inflammatory ◽

Preclinical And Clinical Studies ◽

Multiple Receptor

Inflammation has a pivotal role in the pathogenesis of ischemic stroke, and recent studies posit that inflammation acts as a double-edged sword, not only detrimentally augmenting secondary injury, but also potentially promoting recovery. An initial event of inflammation in ischemic stroke is the activation of microglia, leading to production of both pro- and anti-inflammatory mediators acting through multiple receptor signaling pathways. In this review, we discuss the role of microglial mediators in acute ischemic stroke and elaborate on preclinical and clinical studies focused on microglia in stroke models. Understanding how microglia can lead to both pro- and anti-inflammatory responses may be essential to implement therapeutic strategies using immunomodulatory interventions in ischemic stroke.

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Rationalized Approach for The Treatment of Neuropathic Pain

Research Journal of Pharmacy and Technology ◽

10.52711/0974-360x.2021.00507 ◽

2021 ◽

pp. 2887-2895

Author(s):

Srishti Chaudhary ◽

Pankaj Kumar Prashar ◽

Anamika Gautam ◽

Ankita Sood ◽

Sachin Kumar Singh ◽

...

Keyword(s):

Nervous System ◽

Neuropathic Pain ◽

Good Choice ◽

Opioid Agonist ◽

Painful Condition ◽

Inflammatory Drugs ◽

Topical Glyceryl Trinitrate ◽

Multiple Drugs ◽

Somatosensory Nervous System ◽

Global Population

Injury to the nerves causes alteration in normal neurobiological sequences lead to disease of somatosensory nervous system called as neuropathic pain (NP). It affects both central as well as peripheral nervous system. It is a chronic painful condition occurs due to various diseases like HIV, diabetes, lesions, infection, trauma, and metabolic insults. NP affects 7-10% of global population, hence subsequently is a major concern. Pharmacotherapy for NP remains a major clinical challenge due to its complex pathophysiology. Current treatments like Analgesics, anticonvulsants, non-steroidal anti-inflammatory drugs, tri-cyclic antidepressants, sodium channel blocker and opioid agonist administrated individually to patients of NP are providing only meager and partial relief. Furthermore, these drugs have limited efficacy as well as adverse effects. Hence instead of monotherapy, pathophysiology of NP suggests that administering multiple drugs (polypharmacy) show quick and sufficient effect in the treatment of NP. Recent updates indicate that combination of Morphine and gabapentin, Pregabalin and duloxetine, Gabapentin and nortriptyline, Amitriptyline and ketamine (topical), Doxepin and capsaicin (topical), Glyceryl trinitrate (topical) and valproate are also a good choice for the treatment of NP. Several clinical trials also established that combination pharmacotherapy showed greater efficacy than monotherapy in treating NP. Physicians, scientists working in the area of NP are not only looking for its treatment but also in resolving the issues of co-morbidities associated with it. Hence the present review focuses on rationalized approach of combination therapy for the treatment of various aspects of NP.

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