Exploring Serum Biomarkers for Neuropathic Pain in Rat Models of Chemotherapy-Induced Peripheral Neuropathy: A Comparative Pilot Study with Oxaliplatin, Paclitaxel, Bortezomib, and Vincristine.

Blood biomarkers, including neurofilament light chain (NfL), have garnered attention as potential indicators for chemotherapy-induced peripheral neuropathy (CIPN), a dose-limiting adverse effect of neurotoxic anticancer drugs. However, no blood biomarker has been established for routine application or translational research. This pilot study aimed to evaluate a limited panel of blood biomarkers in rat models of CIPN and their correlations with neuropathic pain.

The Constitutive Activity of Spinal 5-HT Receptors Contributes to Diabetic Neuropathic Pain in Rats.

Diabetic neuropathy is often associated with chronic pain. Serotonin type 6 (5-HT) receptor ligands, particularly inverse agonists, have strong analgesic potential and may be new candidates for treating diabetic neuropathic pain and associated co-morbid cognitive deficits. The current study addressed the involvement of 5-HT receptor constitutive activity and mTOR signaling in an experimental model of diabetic neuropathic pain induced by streptozocin (STZ) injection in the rat.

Analgesic and preventive effects of donepezil in animal models of chemotherapy-induced peripheral neuropathy: Involvement of spinal muscarinic acetylcholine M2 receptors.

Background: Donepezil, a cholinesterase inhibitor approved in Alzheimer's disease, has demonstrated analgesic and preventive effects in animal models of oxaliplatin-induced neuropathy. To improve the clinical interest of donepezil for the management and prevention of chemotherapy-induced peripheral neuropathy (CIPN), a broader validation is required in different animal models of CIPN.

Methods: using rat models of CIPN (bortezomib, paclitaxel, and vincristine), the analgesic and preventive efficacies of donepezil were evaluated on tactile, cold and heat hypersensitivities.

TREK1 channel activation as a new analgesic strategy devoid of opioid adverse effects.

Background And Purpose: Opioids are effective painkillers. However, their risk-benefit ratio is dampened by numerous adverse effects and opioid misuse has led to a public health crisis. Safer alternatives are required, but isolating the antinociceptive effect of opioids from their adverse effects is a pharmacological challenge because activation of the μ opioid receptor triggers both the antinociceptive and adverse effects of opioids.

mTOR activation by constitutively active serotonin6 receptors as new paradigm in neuropathic pain and its treatment.

Chronic neuropathic pain is a highly disabling syndrome that is poorly controlled by currently available analgesics. Here, we show that painful symptoms and associated cognitive deficits induced by spinal nerve ligation in the rat are prevented by the administration of serotonin 5-HT receptor inverse agonists or by the mTOR inhibitor rapamycin. In contrast, they are not alleviated by the administration of 5-HT receptor neutral antagonists.

Testosterone-androgen receptor: The steroid link inhibiting TRPM8-mediated cold sensitivity.

Recent studies have revealed gender differences in cold perception, and pointed to a possible direct action of testosterone (TST) on the cold-activated TRPM8 (Transient Receptor Potential Melastatin Member 8) channel. However, the mechanisms by which TST influences TRPM8-mediated sensory functions remain elusive. Here, we show that TST inhibits TRPM8-mediated mild-cold perception through the noncanonical engagement of the Androgen Receptor (AR).

Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats.

Background: Histamine H3 receptors are mainly expressed on CNS neurons, particularly along the nociceptive pathways. The potential involvement of these receptors in pain processing has been suggested using H3 receptor inverse agonists.

Methods: The antinociceptive effect of S 38093, a novel inverse agonist of H3 receptors, has been evaluated in several neuropathic pain models in rat and compared with those of gabapentin and pregabalin.

Disruption of 5-HT-PDZ protein interaction differently affects the analgesic efficacy of SSRI, SNRI and TCA in the treatment of traumatic neuropathic pain in rats.

Antidepressants remain one of the first line treatments prescribed to neuropathic pain patients despite their limited efficacy and/or their numerous side effects. More and more, pharmacotherapy for neuropathic pain has evolved towards the use of therapeutic combinations. The goal of the present study was to assess the efficacy of the combination of antidepressants - selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors-with a peptide (TAT-2ASCV) able to disrupt the interaction between serotonin type 2A (5-HT) receptors and associated PDZ proteins.

Development of the First Two-Pore Domain Potassium Channel TWIK-Related K Channel 1-Selective Agonist Possessing in Vivo Antinociceptive Activity.

The TWIK-related K channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs, suggesting that activation of TREK-1 could result in pain inhibition. Here, we report the synthesis of a series of substituted acrylic acids (1-54) based on our previous work with caffeate esters. The analogues were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid-induced writhing and hot plate assays), leading to the identification of a series of novel molecules able to activate TREK-1 and displaying potent antinociceptive activity in vivo.

Agomelatine: a new opportunity to reduce neuropathic pain-preclinical evidence.

Antidepressants are first-line treatments of neuropathic pain but not all these drugs are really effective. Agomelatine is an antidepressant with a novel mode of action, acting as an MT1/MT2 melatonergic receptor agonist and a 5-HT2C receptor antagonist that involves indirect norepinephrine release. Melatonin, serotonin, and norepinephrine have been involved in the pathophysiology of neuropathic pain.

The Nav1.9 channel is a key determinant of cold pain sensation and cold allodynia.

Cold-triggered pain is essential to avoid prolonged exposure to harmfully low temperatures. However, the molecular basis of noxious cold sensing in mammals is still not completely understood. Here, we show that the voltage-gated Nav1.

Synthesis and structure-activity relationship study of substituted caffeate esters as antinociceptive agents modulating the TREK-1 channel.

The TWIK-related K(+) channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs. It has been reported that TREK-1 -/- mice were more sensitive than wild-type mice to painful stimuli, suggesting that activation of TREK-1 could result in pain inhibition. Here we report the synthesis of a series of substituted caffeate esters (12a-u) based on the hit compound CDC 2 (cinnamyl 3,4-dihydroxyl-α-cyanocinnamate).

Alleviating pain hypersensitivity through activation of type 4 metabotropic glutamate receptor.

Hyperactivity of the glutamatergic system is involved in the development of central sensitization in the pain neuraxis, associated with allodynia and hyperalgesia observed in patients with chronic pain. Herein we study the ability of type 4 metabotropic glutamate receptors (mGlu4) to regulate spinal glutamate signaling and alleviate chronic pain. We show that mGlu4 are located both on unmyelinated C-fibers and spinal neurons terminals in the inner lamina II of the spinal cord where they inhibit glutamatergic transmission through coupling to Cav2.

Fatty acid amide hydrolase-dependent generation of antinociceptive drug metabolites acting on TRPV1 in the brain.

The discovery that paracetamol is metabolized to the potent TRPV1 activator N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404) and that this metabolite contributes to paracetamol's antinociceptive effect in rodents via activation of TRPV1 in the central nervous system (CNS) has provided a potential strategy for developing novel analgesics. Here we validated this strategy by examining the metabolism and antinociceptive activity of the de-acetylated paracetamol metabolite 4-aminophenol and 4-hydroxy-3-methoxybenzylamine (HMBA), both of which may undergo a fatty acid amide hydrolase (FAAH)-dependent biotransformation to potent TRPV1 activators in the brain. Systemic administration of 4-aminophenol and HMBA led to a dose-dependent formation of AM404 plus N-(4-hydroxyphenyl)-9Z-octadecenamide (HPODA) and arvanil plus olvanil in the mouse brain, respectively.

Study of emotional and cognitive impairments in mononeuropathic rats: effect of duloxetine and gabapentin.

Chronic pain is a multidimensional experience that not only includes changes in nociception, but also impairments in emotion and cognitive functions. These last 2 components are not often taken into account in preclinical research. We investigated emotional and cognitive impairments in a model of neuropathic pain in rats induced by chronic constriction injury (CCI) of the sciatic nerve.

Nav1.9 channel contributes to mechanical and heat pain hypersensitivity induced by subacute and chronic inflammation.

Inflammation is known to be responsible for the sensitization of peripheral sensory neurons, leading to spontaneous pain and invalidating pain hypersensitivity. Given its role in regulating neuronal excitability, the voltage-gated Nav1.9 channel is a potential target for the treatment of pathological pain, but its implication in inflammatory pain is yet not fully described.

Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia.

Acetaminophen is the most used analgesic/antipyretic drug. Its unclear mechanism of action could rely on cyclooxygenase inhibition, NO synthesis blockade or reinforcement of the serotonergic system. Here we show that in thermal, mechanical and chemical pain tests, AM-251, a specific CB(1) receptor antagonist, abolished the analgesic action of acetaminophen, which was also lost in CB(1) receptor knockout mice.

Group III metabotropic glutamate receptors inhibit hyperalgesia in animal models of inflammation and neuropathic pain.

Glutamate plays a key role in modulation of nociceptive processing. This excitatory amino acid exerts its action through two distinct types of receptors, ionotropic and metabotropic glutamate receptors (mGluRs). Eight mGluRs have been identified and divided in three groups based on their sequence similarity, pharmacology and G-protein coupling.

Acetaminophen recruits spinal p42/p44 MAPKs and GH/IGF-1 receptors to produce analgesia via the serotonergic system.

The mechanism of action of acetaminophen is currently widely discussed. Direct inhibition of cyclooxygenase isoforms remains the commonly advanced hypothesis. We combined behavioral studies with molecular techniques to investigate the mechanism of action of acetaminophen in a model of tonic pain in rats.

Age-related impact of neuropathic pain on animal behaviour.

The number of old and very old persons is increasing and there is evidence that aging coincides with chronic painful conditions. Pain induces behavioural disorders that have been so far poorly identified in old and even less in very old animals. The aim of this study was to: (1) compare the evolution of pain in senescent animals (37-39 months) to old (20-22 months) and young (4-6 months) Lou/cjall rats after a chronic constriction of the sciatic nerve; (2) evaluate pain during four weeks after surgery with an experimental and an observational approach to determine how the response to noxious stimuli correlates with recorded spontaneous behaviour.

Rectal instillation of butyrate provides a novel clinically relevant model of noninflammatory colonic hypersensitivity in rats.

Background & Aims: The treatment of irritable bowel syndrome (IBS), characterized by abdominal pain and bloating, is empirical and often poorly efficient. Research lacks suitable models for studying the pathophysiologic mechanisms of the colonic hypersensitivity and new pharmacologic targets. The present study aimed to develop a novel model of colonic hypersensitivity possessing several of the characteristics encountered in patients with IBS.

Spinal 5-HT1A receptors differentially influence nociceptive processing according to the nature of the noxious stimulus in rats: effect of WAY-100635 on the antinociceptive activities of paracetamol, venlafaxine and 5-HT.

The regulation of nociceptive processing by 5-HT at the spinal level is intricate since the neurotransmitter has been implicated in both pro and antinociception. The aim of our study was to investigate, according to the nature of the noxious stimulus, how the blockade of spinal 5-HT(1A) receptors could influence the antinociceptive actions of exogenous 5-HT as well as two analgesics involving endogenous 5-HT, paracetamol and venlafaxine. Rats were submitted either to the formalin test (tonic pain) or the paw pressure test (acute pain).

Memory impairment means less pain for mice.

Background: Clinical observations have reported that individuals with memory deterioration, like in Alzheimer's disease, display a lesser pain sensibility than patients with no cognitive impairment.

Objective: To clarify the link between pain and loss of memory, we studied how memory-impaired mice behave when submitted to hotplate nociceptive tests.

Methods: For 5 days (D1-D5), male CD1 mice were injected daily intraperitonealy with saline or scopolamine (s, an anticholinergic drug, 0.

Orally administered paracetamol does not act locally in the rat formalin test: evidence for a supraspinal, serotonin-dependent antinociceptive mechanism.

Background: The mechanism of action of paracetamol (acetaminophen) remains elusive because it is still under discussion as to whether it acts locally and/or centrally. The primary aim of this study was to clarify its site(s) of action (central and/or local) using the rat formalin test.

Methods: Spontaneous biting and licking of the injected paw following intraplantar injection of formalin 2.

Evidence for an involvement of supraspinal delta- and spinal mu-opioid receptors in the antihyperalgesic effect of chronically administered clomipramine in mononeuropathic rats.

The mechanisms of involvement of the opioidergic system in the antinociceptive effect of antidepressants remain to be elucidated. The present study was designed to determine what type of opioid receptors may be involved at the spinal and supraspinal levels in the antihyperalgesic effect of clomipramine, a tricyclic antidepressant commonly prescribed in the treatment of neuropathic pain. Its antihyperalgesic effect on mechanical hyperalgesia (paw pressure test) in rats induced by chronic constriction injury of the sciatic nerve was assessed after repeated administrations (five injections every half-life, a regimen close to clinical use).