scholarly journals Shedding Light on the Pharmacological Interactions between μ-Opioid Analgesics and Angiotensin Receptor Modulators: A New Option for Treating Chronic Pain

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6168
Author(s):  
Kornél Király ◽  
Dávid Á. Karádi ◽  
Ferenc Zádor ◽  
Amir Mohammadzadeh ◽  
Anna Rita Galambos ◽  
...  

The current protocols for neuropathic pain management include µ-opioid receptor (MOR) analgesics alongside other drugs; however, there is debate on the effectiveness of opioids. Nevertheless, dose escalation is required to maintain their analgesia, which, in turn, contributes to a further increase in opioid side effects. Finding novel approaches to effectively control chronic pain, particularly neuropathic pain, is a great challenge clinically. Literature data related to pain transmission reveal that angiotensin and its receptors (the AT1R, AT2R, and MAS receptors) could affect the nociception both in the periphery and CNS. The MOR and angiotensin receptors or drugs interacting with these receptors have been independently investigated in relation to analgesia. However, the interaction between the MOR and angiotensin receptors has not been excessively studied in chronic pain, particularly neuropathy. This review aims to shed light on existing literature information in relation to the analgesic action of AT1R and AT2R or MASR ligands in neuropathic pain conditions. Finally, based on literature data, we can hypothesize that combining MOR agonists with AT1R or AT2R antagonists might improve analgesia.

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Lucia Lisi ◽  
Paola Aceto ◽  
Pierluigi Navarra ◽  
Cinzia Dello Russo

Chronic pain represents a major public health problem worldwide. Current pharmacological treatments for chronic pain syndromes, including neuropathic pain, are only partially effective, with significant pain relief achieved in 40–60% of patients. Recent studies suggest that the mammalian target of rapamycin (mTOR) kinase and downstream effectors may be implicated in the development of chronic inflammatory, neuropathic, and cancer pain. The expression and activity of mTOR have been detected in peripheral and central regions involved in pain transmission. mTOR immunoreactivity was found in primary sensory axons, in dorsal root ganglia (DRG), and in dorsal horn neurons. This kinase is a master regulator of protein synthesis, and it is critically involved in the regulation of several neuronal functions, including the synaptic plasticity that is a major mechanism leading to the development of chronic pain. Enhanced activation of this pathway is present in different experimental models of chronic pain. Consistently, pharmacological inhibition of the kinase activity turned out to have significant antinociceptive effects in several experimental models of inflammatory and neuropathic pain. We will review the main evidence from animal and human studies supporting the hypothesis that mTOR may be a novel pharmacological target for the management of chronic pain.


2009 ◽  
Vol 15 (S3) ◽  
pp. 7-8
Author(s):  
G. Borges ◽  
E. Berrocoso ◽  
A. Ortega-Alvaro ◽  
J. A. Micó ◽  
F. L. Neto

AbstractChronic neuropathic pain is a pathology that affects thousands of people worldwide. Antidepressants have been prescribed for the treatment of this sort of pain but the mechanisms underlying their analgesic action remain unknown. Extracellular-signal regulated kinases (ERKs) are being implicated in pain transmission and modulation as well as in the pathophysiology of depression. In order to clarify some of the mechanisms which might be related to the analgesic effect of antidepressants, we started by evaluating possible changes in the pattern of activation of ERKs in rats with chronic constriction injury (CCI), an experimental model of chronic


2021 ◽  
Vol 14 (10) ◽  
pp. 1034
Author(s):  
Lamees Alhassen ◽  
Khawla Nuseir ◽  
Allyssa Ha ◽  
Warren Phan ◽  
Ilias Marmouzi ◽  
...  

The opioid epidemic was triggered by an overprescription of opioid analgesics. In the treatment of chronic pain, repeated opioid administrations are required which ultimately lead to tolerance, physical dependence, and addiction. A possible way to overcome this conundrum consists of a co-medication that maintains the analgesic benefits of opioids while preventing their adverse liabilities. YHS, the extract of the plant Corydalis yanhusuo, has been used as analgesic in traditional Chinese medicine for centuries. More recently, it has been shown to promote analgesia in animal models of acute, inflammatory, and neuropathic pain. It acts, at least in part, by inhibiting the dopamine D2 receptor, suggesting that it may be advantageous to manage addiction. We first show that, in animals, YHS can increase the efficacy of morphine antinociceptive and, as such, decrease the need of the opioid. We then show that YHS, when coadministered with morphine, inhibits morphine tolerance, dependence, and addiction. Finally, we show that, in animals treated for several days with morphine, YHS can reverse morphine dependence and addiction. Together, these data indicate that YHS may be useful as a co-medication in morphine therapies to limit adverse morphine effects. Because YHS is readily available and safe, it may have an immediate positive impact to curb the opioid epidemic.


2002 ◽  
Vol 97 (1) ◽  
pp. 102-107 ◽  
Author(s):  
Jesper Dirks ◽  
Karin L. Petersen ◽  
Michael C. Rowbotham ◽  
Jørgen B. Dahl

Background The anticonvulsant gabapentin, proven effective for neuropathic pain in two large, placebo-controlled clinical trials, is widely used for treatment of chronic pain. Preclinical studies have demonstrated analgesic and antiallodynic effects in models involving neuronal sensitization and nerve injury, without affecting acute pain transmission. The aim of the present study was to link data from animal models and clinical trials for chronic pain by investigating the effect of gabapentin on acute nociception and experimentally induced cutaneous hyperalgesia in healthy volunteers. Methods The human experimental hyperalgesia model, the heat-capsaicin sensitization model, was induced in 25 healthy male volunteers. Subjects received oral gabapentin (1,200 mg) or placebo after heat-capsaicin sensitization was established on the forearm. The primary outcome measures were the sizes of the areas of secondary hyperalgesia to von Frey hair and brush stimulation on the forearm. Secondary outcome measures were as follows: (1) size of secondary hyperalgesia area in response to brief thermal sensitization procedure on the thigh; (2) heat pain detection thresholds in normal and sensitized skin; and (3) painfulness of 1 min of 45 degrees C stimulation in normal skin. Results Oral gabapentin profoundly suppressed established cutaneous sensitization on the forearm and prevented development of cutaneous sensitization on the thigh. Thermal nociception in normal skin was unchanged. Side effects were modest. Conclusion The results link preclinical findings with results from clinical trials of neuropathic pain. The results further suggest that gabapentin may prove effective in acute pain disorders involving neuronal sensitization, such as postoperative pain and acute herpetic pain, and could prove effective in prevention of chronic pain.


2018 ◽  
Vol 25 (32) ◽  
pp. 3895-3916 ◽  
Author(s):  
Andrea Bedini ◽  
Santi Spampinato

Background: Chronic pain states are clinically relevant and yet unsolved conditions impacting on quality of life and representing an important social and economic burden; these diseases are poorly treated with the currently available drugs, being urgent the need of innovative analgesics. In this frame, novel analogues of endomorphin-1 and dermorphin emerge as promising starting points to develop innovative, more effective analgesics to treat neuropathic pain. Methods: An extensive and structured search of bibliographic databases for peer-reviewed research literature was undertaken using focused review questions; all the retrieved papers were published on prestigious international journals by the experts of the field and were carefully analyzed to collect all the information and data necessary to the conceptual framework of this review. Results: One hundred papers were included in this review; forty-one defined the up-to-date findings on neuropathic pain etiopathogenesis and its currently available treatment options. Thirty-five papers described all the advantages and drawbacks of using endomorphin-1 (23) or dermorphin (12) in the frame of neuropathic pain and outlined the most relevant advances in developing endomorphin-1 and dermorphin analogs useful as potential, innovative analgesics. Twenty-four papers provided the latest insights into exploiting biased agonism at opioid receptor as an innovative strategy to develop more effective and safer analgesics. Conclusion: This review reports that innovative opioid peptides will be of great help in better understanding the multifaceted scenario of neuropathic pain treatment, providing very interesting opportunities for the identification of novel and more effective opioid analgesics to be employed as medications.


2020 ◽  
Vol 48 (5) ◽  
pp. 030006052090365
Author(s):  
Razia Abdool Gafaar Khammissa ◽  
Raoul Ballyram ◽  
Jeanine Fourie ◽  
Michael Bouckaert ◽  
Johan Lemmer ◽  
...  

Pain induced by inflammation and nerve injury arises from abnormal neural activity of primary afferent nociceptors in response to tissue damage, which causes long-term elevation of the sensitivity and responsiveness of spinal cord neurons. Inflammatory pain typically resolves following resolution of inflammation; however, nerve injury—either peripheral or central—may cause persistent neuropathic pain, which frequently manifests as hyperalgesia or allodynia. Neuralgias, malignant metastatic bone disease, and diabetic neuropathy are some of the conditions associated with severe, often unremitting chronic pain that is both physically and psychologically debilitating or disabling. Therefore, optimal pain management for patients with chronic neuropathic pain requires a multimodal approach that comprises pharmacological and psychological interventions. Non-opioid analgesics (e.g., paracetamol, aspirin, or other non-steroidal anti-inflammatory drugs) are first-line agents used in the treatment of mild-to-moderate acute pain, while opioids of increasing potency are indicated for the treatment of persistent, moderate-to-severe inflammatory pain. N-methyl D-aspartate receptor antagonists, antidepressants, anticonvulsants, or a combination of these should be considered for the treatment of chronic neuropathic pain. This review discusses the various neural signals that mediate acute and chronic pain, as well as the general principles of pain management.


2021 ◽  
Vol 11 (8) ◽  
pp. 758
Author(s):  
Songjin Ri ◽  
Anatol Kivi ◽  
Jörg Wissel

There are few reports on the safety and effectiveness of long-term botulinumtoxin A (BoNT A) therapy in severe chronic pain of post-herpetic neuralgia (PHN). The literature was searched with the term “neuropathic pain” and “botulinum” on PubMed (up to 29 February 2020). Pain was assessed with the Visual Analogue Scale (VAS) before and after BoNT A therapy. A total of 10 clinical trials and six case reports including 251 patients with PHN were presented. They showed that BoNT A therapy had significant pain reduction (up to 30–50%) and improvement in quality of life. The effect duration seems to be correlated with BoNT A doses injected per injection site. Intervals between BoNT A injections were 10–14 weeks. No adverse events were reported in cases and clinical studies, even in the two pregnant women, whose babies were healthy. The repeated (≥6 times) intra/subcutaneous injections of incobotulinumtoxin A (Xeomin®, Merz Pharmaceuticals, Germany) over the two years of our three cases showed marked pain reduction and no adverse events. Adjunctive local BoNT A injection is a promising option for severe PHN, as a safe and effective therapy in long-term management for chronic neuropathic pain. Its effect size and -duration seem to be depended on the dose of BoNT A injected per each point.


Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 816
Author(s):  
Rosmara Infantino ◽  
Consalvo Mattia ◽  
Pamela Locarini ◽  
Antonio Luigi Pastore ◽  
Sabatino Maione ◽  
...  

Chronic pain, including neuropathic pain, represents an untreated disease with important repercussions on the quality of life and huge costs on the national health system. It is well known that opioids are the most powerful analgesic drugs, but they represent the second or third line in neuropathic pain, that remain difficult to manage. Moreover, these drugs show several side effects that limit their use. In addition, opioids possess addictive properties that are associated with misuse and drug abuse. Among available opioids compounds, buprenorphine has been suggested advantageous for a series of clinical reasons, including the effectiveness in neuropathic pain. Some properties are partly explained by its unique pharmacological characteristics. However, questions on the dynamic profile remain to be answered. Pharmacokinetics optimization strategies, and additional potentialities, are still to be explored. In this paper, we attempt to conceptualize the potential undiscovered dynamic profile of buprenorphine.


2019 ◽  
Vol 20 (1) ◽  
pp. 33-37 ◽  
Author(s):  
Marzia Malcangio

AbstractBackgroundAcute pain is a warning mechanism that exists to prevent tissue damage, however pain can outlast its protective purpose and persist beyond injury, becoming chronic. Chronic Pain is maladaptive and needs addressing as available medicines are only partially effective and cause severe side effects. There are profound differences between acute and chronic pain. Dramatic changes occur in both peripheral and central pathways resulting in the pain system being sensitised, thereby leading to exaggerated responses to noxious stimuli (hyperalgesia) and responses to non-noxious stimuli (allodynia).Critical role for immune system cells in chronic painPreclinical models of neuropathic pain provide evidence for a critical mechanistic role for immune cells in the chronicity of pain. Importantly, human imaging studies are consistent with preclinical findings, with glial activation evident in the brain of patients experiencing chronic pain. Indeed, immune cells are no longer considered to be passive bystanders in the nervous system; a consensus is emerging that, through their communication with neurons, they can both propagate and maintain disease states, including neuropathic pain. The focus of this review is on the plastic changes that occur under neuropathic pain conditions at the site of nerve injury, the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. At these sites both endothelial damage and increased neuronal activity result in recruitment of monocytes/macrophages (peripherally) and activation of microglia (centrally), which release mediators that lead to sensitisation of neurons thereby enabling positive feedback that sustains chronic pain.Immune system reactions to peripheral nerve injuriesAt the site of peripheral nerve injury following chemotherapy treatment for cancer for example, the occurrence of endothelial activation results in recruitment of CX3C chemokine receptor 1 (CX3CR1)-expressing monocytes/macrophages, which sensitise nociceptive neurons through the release of reactive oxygen species (ROS) that activate transient receptor potential ankyrin 1 (TRPA1) channels to evoke a pain response. In the DRG, neuro-immune cross talk following peripheral nerve injury is accomplished through the release of extracellular vesicles by neurons, which are engulfed by nearby macrophages. These vesicles deliver several determinants including microRNAs (miRs), with the potential to afford long-term alterations in macrophages that impact pain mechanisms. On one hand the delivery of neuron-derived miR-21 to macrophages for example, polarises these cells towards a pro-inflammatory/pro-nociceptive phenotype; on the other hand, silencing miR-21 expression in sensory neurons prevents both development of neuropathic allodynia and recruitment of macrophages in the DRG.Immune system mechanisms in the central nervous systemIn the dorsal horn of the spinal cord, growing evidence over the last two decades has delineated signalling pathways that mediate neuron-microglia communication such as P2X4/BDNF/GABAA, P2X7/Cathepsin S/Fractalkine/CX3CR1, and CSF-1/CSF-1R/DAP12 pathway-dependent mechanisms.Conclusions and implicationsDefinition of the modalities by which neuron and immune cells communicate at different locations of the pain pathway under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction and provides opportunities for novel approaches for the treatment of chronic pain.


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