scholarly journals A Novel Peripheral Action of PICK1 Inhibition in Inflammatory Pain

2021 ◽  
Vol 15 ◽  
Author(s):  
Kathrine Louise Jensen ◽  
Gith Noes-Holt ◽  
Andreas Toft Sørensen ◽  
Kenneth Lindegaard Madsen
Keyword(s):  
Chronic Pain ◽  
Side Effects ◽  
Inflammatory Pain ◽  
Pain Treatment ◽  
Memory Performance ◽  
Current Treatment ◽  
Abuse Liability ◽  
Spontaneous Pain ◽  
Pain Pathways ◽  
Pain Sensitization

Chronic pain is a major healthcare problem that impacts one in five adults across the globe. Current treatment is compromised by dose-limiting side effects including drowsiness, apathy, fatigue, loss of ability to function socially and professionally as well as a high abuse liability. Most of these side effects result from broad suppression of excitatory neurotransmission. Chronic pain states are associated with specific changes in the efficacy of synaptic transmission in the pain pathways leading to amplification of non-noxious stimuli and spontaneous pain. Consequently, a reversal of these specific changes may pave the way for the development of efficacious pain treatment with fewer side effects. We have recently described a high-affinity, bivalent peptide TAT-P4-(C5)2, enabling efficient targeting of the neuronal scaffold protein, PICK1, a key protein in mediating chronic pain sensitization. In the present study, we demonstrate that in an inflammatory pain model, the peptide does not only relieve mechanical allodynia by targeting PICK1 involved in central sensitization, but also by peripheral actions in the inflamed paw. Further, we assess the effects of the peptide on novelty-induced locomotor activity, abuse liability, and memory performance without identifying significant side effects.

Nociceptors and Chronic Pain

2021 ◽  
Author(s):  
Edgar T. Walters
Keyword(s):  
Chronic Pain ◽  
Spontaneous Activity ◽  
Intracellular Signaling ◽  
Chronic Conditions ◽  
Spontaneous Pain ◽  
Pain Pathways ◽  
Low Threshold ◽  
Highly Correlated ◽  
Hyperalgesic Priming ◽  
Peripheral Activation

Chronic pain lasting months or longer is very common, poorly treated, and sometimes devastating. Nociceptors are sensory neurons that usually are silent unless activated by tissue damage or inflammation. In humans their peripheral activation evokes conscious pain, and their spontaneous activity is highly correlated with spontaneous pain. Persistently hyperactive nociceptors mediate increased responses to normally painful stimuli (hyperalgesia) in chronic conditions and promote the sensitization of central pain pathways that allows low-threshold mechanoreceptors to elicit painful responses to innocuous stimuli (allodynia). Investigations of rodent models of neuropathic pain and hyperalgesic priming have revealed many alterations in nociceptors and associated cells that are implicated in the development and maintenance of chronic pain. These include chronic nociceptor hyperexcitability and spontaneous activity, sprouting, synaptic plasticity, changes in intracellular signaling, and modified responses to opioids, along with alterations in the expression and translation of thousands of genes in nociceptors and closely linked cells.

scholarly journals Optimization of a Pyrimidinone Series for Selective Inhibition of Ca2+/Calmodulin-Stimulated Adenylyl Cyclase 1 Activity for the Treatment of Chronic Pain

2021 ◽  
Author(s):  
Jason Scott ◽  
Monica Soto-Velasquez ◽  
Michael Hayes ◽  
Justin Lavigne ◽  
Heath Miller ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Physicochemical Properties ◽  
Adenylyl Cyclase ◽  
Learning And Memory ◽  
Inflammatory Pain ◽  
Selective Inhibition ◽  
Behavioral Studies ◽  
Morphine Administration ◽  
Ic50 Values ◽  
Pain Sensitization

Adenylyl cyclase type 1 is an emerging target for the treatment of chronic pain that is downstream on the analgesic pathway from the traditional µ-opioid receptor. AC1 is expressed in the central nervous system and critical for signaling in pain sensitization. Behavioral studies have revealed AC1 knockout mice exhibit reduced behavioral pain sensitization responses similar to morphine administration. AC1, and a closely related isoform AC8, are also implicated to have a role in learning and memory signaling processes. However, reports suggest selectively targeting AC1 over AC8 may be a viable strategy to eliminate potential deleterious effects on learning and memory. Our team has carried out cellular screening for inhibitors of AC1 that yielded a pyrazolyl-pyrimidinone scaffold with potency comparable to previously published AC1 inhibitors, selectivity versus AC8, and improved drug-like physicochemical properties. Structure-activity relationship (SAR) studies produced 36 analogs that balanced improvements in potency with cellular IC50 values as low as 0.25 µM and selectivity versus AC8. Prioritized analogs were selective for AC1 compared to other AC isoforms and other common neurological targets. A representative analog was assessed for efficacy in a mouse model of inflammatory pain and displayed modest anti-allodynic effects. This series of compounds represents the most potent and selective inhibitors of Ca2+/Calmodulin-stimulated AC1 activity to date with reduced off-target liabilities and improved drug-like physicochemical properties making them promising lead compounds for the treatment of inflammatory pain.

Pharmacology of pain management in general practice

2016 ◽  
Vol 9 (12) ◽  
pp. 742-752
Author(s):  
Christopher Evans ◽  
Alison Hoggarth ◽  
Colm Lanigan
Keyword(s):  
Chronic Pain ◽  
Pain Management ◽  
Side Effects ◽  
Wide Spectrum ◽  
Pharmacological Action ◽  
The Novel ◽  
Drug Dosing ◽  
Pain Pathways ◽  
Analgesic Agents ◽  
First Time

Pain is described as the fifth vital sign, yet its importance is frequently not fully recognised, despite 68 000 000 analgesic prescriptions being dispensed annually. GPs treat pain in the context of a wide spectrum of patient conditions and co-morbidities, recognising potential drug interactions and side-effects. They also factor in the patient’s anxieties, coping strategies, cultural background and previous experiences of pain. It is no wonder that we frequently do not get it right first time. This article discusses the pharmacological action of the major groups of analgesic drugs, considers common pitfalls, and suggests appropriate drug dosing. A titrated multi-modal approach is recommended to target nociceptor pain pathways, and to reduce the side-effects caused by large doses of monotherapy. It discusses the novel use of analgesic agents previously only used for chronic pain. It does not, however, discuss acute-on-chronic pain, drug tolerance, drug addiction or complex pain management.

scholarly journals Itaconate as a Promising Therapy for Neuropathic Pain and Inflammatory Pain

2021 ◽  
Author(s):  
Jinxuan Ren ◽  
Lina Yu ◽  
Jiaqi Lin ◽  
Longfei Ma ◽  
Dave Schwinn Gao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Chronic Pain ◽  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Glial Cells ◽  
Inflammatory Pain ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Pain Treatment ◽  
Cell Functions

Abstract Background: Chronic pain is a complex experience that often leads to multiple complications. Neuroinflammation in the immune system as well as in the peripheral and central nervous system contributes to the development and persistence of chronic pain. The metabolite itaconate, recently emerged as a regulator of immune cell functions, has features of anti-inflammation and immunomodulation via the activation of Nrf2. However, its effect on chronic pain is unclear. Methods: Chronic C57BL/6 neuropathic pain and inflammatory pain were induced followed by dimethyl itaconate (DI) treatment, an itaconate derivative. We evaluated the effect of DI on the changes of pain behaviors induced by chronic pain model. The effect of DI on inflammatory cytokine release, glial cells activation, ERK1/2 phosphorylation, inflammatory cell infiltration and Nrf2 expression in the DRGs, spinal cord and hind paw tissues was determined using the histochemistry, RT-PCR and western blot. Microglia was cultured to study the effect of DI on microglial inflammatory response and Nrf2 level.Results: DI reduced the secretion of inflammatory cytokines in DRGs, spinal cord and hind paw tissues, suppressed the activation of glial cells (like microglia and astrocytes) in spina dorsal horn and infiltration of inflammatory cells in the hind paw tissues, and decreased the phosphorylation of ERK1/2, but boosted Nrf2 levels in the DRGs and spinal dorsal horn. Similarly, administration of DI potently reversed the LPS-induced inflammatory effect in the microglia. Reduction of endogenous itaconate pretreated with irg1 siRNA prevented the expression of Nrf2, which did not exert the analgesic and anti-inflammatory effects in vitro experiment. Conclusions: Our findings verify for the first time that DI alleviates painful behaviors and suppresses neuroinflammation in neuropathic pain and inflammatory pain models through molecular mechanisms, suggesting that DI elicits sustained chronic pain relief, which will be regarded as a novel therapeutic agent for chronic pain treatment.

Post-surgical analgesia and acute pain management

2017 ◽  
Author(s):  
Francis Bonnet ◽  
Marc E. Gentili ◽  
Christophe Aveline
Keyword(s):  
Chronic Pain ◽  
Pain Intensity ◽  
Acute Pain ◽  
Surgical Procedure ◽  
Pain Treatment ◽  
Pain Syndrome ◽  
Multimodal Analgesia ◽  
Opioid Administration ◽  
Pain Sensitization ◽  
Sparing Effect

Postoperative and acute pain remains uncontrolled in many instances, leading to the risk of development of chronic pain syndromes. After tissue damage, activation of postsynaptic NMDA receptors, also induced by opioid administration, plays a key role in postoperative pain sensitization, allodynia, and hyperalgesia. Pain intensity may depend on sex, age, anxiety, and genetic factors but in clinical practice, surgical procedure is the main determinant of pain, although pain may vary from one patient to one another. Serial pain measurements are mandatory to assess pain intensity and to guide pain treatment. They are based on unidimensional simple pain scales. Multimodal analgesia combining opioid and non-opioid agent and regional block or infiltration is the rule postoperatively, although evidence is sometimes lacking to support all the combinations commonly used. Opioids should be used on demand while other agents are administered systematically. Non-steroidal anti-inflammatory drugs decrease opioid demand as well as paracetamol although to a less extend. Antihyperalgesic agents including NMDA blockers (ketamine) and α‎2-δ‎ ligands (gabapentin, pregabalin) have an opioid-sparing effect and may prevent the occurrence of chronic pain syndrome after surgery. Regional blocks and infiltration provide good quality analgesia but the balance between advantages and drawbacks of central block need to be evaluated carefully for each surgical procedure.

scholarly journals TRP Channel Cooperation for Nociception: Therapeutic Opportunities

2021 ◽  
Vol 61 (1) ◽  
pp. 655-677
Author(s):  
Dorien Bamps ◽  
Joris Vriens ◽  
Jan de Hoon ◽  
Thomas Voets
Keyword(s):  
Chronic Pain ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Pain Treatment ◽  
Treatment Options ◽  
Receptor Potential ◽  
Current Treatment ◽  
Trp Channel ◽  
Current Status ◽  
Number Of Patients

Chronic pain treatment remains a sore challenge, and in our aging society, the number of patients reporting inadequate pain relief continues to grow. Current treatment options all have their drawbacks, including limited efficacy and the propensity of abuse and addiction; the latter is exemplified by the ongoing opioid crisis. Extensive research in the last few decades has focused on mechanisms underlying chronic pain states, thereby producing attractive opportunities for novel, effective and safe pharmaceutical interventions. Members of the transient receptor potential (TRP) ion channel family represent innovative targets to tackle pain sensation at the root. Three TRP channels, TRPV1, TRPM3, and TRPA1, are of particular interest, as they were identified as sensors of chemical- and heat-induced pain in nociceptor neurons. This review summarizes the knowledge regarding TRP channel–based pain therapies, including the bumpy road of the clinical development of TRPV1 antagonists, the current status of TRPA1 antagonists, and the future potential of targeting TRPM3.

scholarly journals Pharmacological Management of Chronic Pain: How to Deal with the Catch-22 Situation

2021 ◽  
Vol 4 (02) ◽  
Author(s):  
Trine Andresen ◽  
Marieke Niesters ◽  
Albert Dahan ◽  
Bart Morlion ◽  
Tony O´Brien ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Side Effects ◽  
Pain Treatment ◽  
Pharmacological Management ◽  
Chronic Pain Patients ◽  
Education And Awareness ◽  
Integral Element ◽  
Catch 22 ◽  
The Individual ◽  
Pain Patients

Management of chronic pain is multidisciplinary, but pharmacotherapy is one of the mainstays of pain management. As applies in all medical therapies, clinicians must strive to achieve the best possible outcome for patients in terms of maximising benefit and minimizing risks, and ensure that this is conducted for each treatment and as an integral element in selecting appropriate therapies. If the balance between risk and benefits is not achieved and understood by the patient. Chronic pain patients may already experience a degree of stigmatisation, which can be further exacerbated by evolving socio-political pressures in respect of analgesic availability and accessibility.  Hence, we have a Catch-22 situation in which patients become ensnared; they may need supervised access to legitimate analgesic medication(s) but these are not easily accessible because of concerns of the analgesic side-effects and abuse/misuse potential influencing both the individual and wider society.   In this paper, we review the evidence in respect of analgesic use in chronic pain. We highlight the importance of: 1) better education and awareness of the problem, 2) evaluate the balance between effect and side effects rather than focusing on pain intensity alone, and include such composite measures in clinical trials, 3) identification of responders to treatment and systematic monitoring for misuse and 4) the use of big data to guide politicians away from inappropriate regulatory restrictions. Such a strategy will improve pain treatment and due to the major costs associated with chronic pain it will also be of benefit for society.

Side-effects of opioids in chronic pain treatment

1998 ◽  
Vol 11 (5) ◽  
pp. 539-545 ◽  
Author(s):  
Peter G. Lawlor ◽  
Eduardo Bruera
Keyword(s):  
Chronic Pain ◽  
Side Effects ◽  
Pain Treatment ◽  
Chronic Pain Treatment

scholarly journals Activation of peripheral neuronal FLT3 promotes exaggerated sensorial and emotional pain-related behaviors facilitating the transition from acute to chronic pain

2021 ◽  
Author(s):  
Adrien Tassou ◽  
Maxime Thouaye ◽  
Damien Gilarbert ◽  
Antoine Jouvenel ◽  
Jean-Philippe Leyris ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Microglial Activation ◽  
Persistent Pain ◽  
Spontaneous Pain ◽  
Emotional Pain ◽  
Knock Out ◽  
Induced Mood ◽  
Pain Chronification ◽  
Pain Sensitization ◽  
Incisional Pain

Background. Acute pain events have been associated with persistent pain sensitization of nociceptive pathways increasing the risk of transition from acute to chronic pain. However, it is unclear whether injury-induced persistent pain sensitization can promote long-term mood disorders. The receptor tyrosine kinase FLT3 is causally required for peripheral nerve injury-induced pain chronification, questioning its role in the development of pain-induced mood alterations. Methods. In a model of paw incisional pain, mice underwent single (SI) or double incision (DI) and went through behavioral and molecular phenotyping with the evaluation of both sensorial and emotional pain components. The role of FLT3 was then investigated either by inhibition using transgenic knock-out mice and functional antibodies or by activation with FLT3 ligand (FL) administrations. Results. DI mice showed significant anxiodepressive-like and spontaneous pain behaviors while SI mice did not. DI also promoted and extended mechanical pain hypersensitivity compared to SI. This emotional and sensorial pain exaggeration correlated with a potentiation of spinal microglial activation after DI versus SI. Intrathecal minocycline, a microglial inhibitor, specifically reversed DI induced-mechanical hypersensitivity. Finally, FL injections in naive animals provoked mechanical allodynia and anxiodepressive-like disorders concomitant with a significant microglial activation while FLT3 inhibition blunted the development of persistent pain and depression after DI. Conclusions. Our results show for the first time that the repetition of a peripheral lesion facilitates not only exaggerated nociceptive behaviors but also anxiodepressive disorders. The inhibition of FLT3 could become a promising therapy in the management of pain sensitization and related mood alterations.

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