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Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling pain condition which occurs as a consequence of cancer chemotherapy with anti-cancer agents like paclitaxel, oxaliplatin, etc. Despite immense research in the pathological pathways involved in CIPN, treatment options still remain limited. Recently, pathological involvement of Wnt signaling has been investigated in various neuropathic pain models, however there are no reports as yet on the role of Wnt signaling in CIPN. In the present study, we have investigated the neuroprotective effects of Wnt signaling inhibitors namely LGK974 (Porcupine inhibitor), NSC668036 (Disheveled inhibitor) and PNU76454 (β-catenin inhibitor) in paclitaxel-induced neuropathic pain. Paclitaxel (2 mg/kg, i. p.) was administered to male Sprague Dawley rats on four alternate days. After 21 days, paclitaxel-treated rats showed reduced behavioral pain thresholds (cold allodynia, heat & mechanical hyperalgesia) and nerve functions (nerve conduction velocity and nerve blood flow). Moreover, Wnt signaling proteins (Wnt3a, β-catenin, c-myc and Dvl1), inflammatory marker (matrix metalloproteinase 2) and endoplasmic reticulum stress marker (GRP78) were found to be upregulated in the sciatic nerves of paclitaxel-treated rats accompanied with loss of intraepidermal nerve fiber density as compared to the control rats. Intrathecal administration of Wnt inhibitors (each at dose of 10 and 30 μM) for three consecutive days to paclitaxel-treated rats, significantly improved behavioral pain thresholds and nerve functional parameters by inhibition of Wnt signaling, inflammation, endoplasmic reticulum stress and improvement of intraepidermal nerve fiber density. All these results suggested the neuroprotective potential of Wnt signaling inhibitors in CIPN.
Learn More >Current theories associated with the cause of tension type headache are mostly focused on muscle tissues. No study has investigated the presence of role of nerve tissues in this population.
Learn More >Chronic pain is a worldwide major health problem and many pain-suffering patients are under opioid based therapy. Epidemiological data show that pain intensity correlates with the risk of misuse of prescription opioids, and other drugs of abuse including alcohol. This increased vulnerability to suffer Substance Use Disorders could be, in part, caused by functional changes that occur over the mesocorticolimbic system, a brain pathway involved in reward processing and addiction. Previous data in rats revealed that inflammatory pain desensitizes mu opioid receptors (MORs) in the ventral tegmental area (VTA). As a consequence, pain alters dopamine release in the nucleus accumbens (NAc) derived from MOR activation in the VTA and also increases intake of high doses of heroine. Given that the VTA neurons target different brain regions, in the present study we first analyzed changes induced by inflammatory pain in the MOR dependent activation pattern of the main VTA projecting areas. To do that, we administered two doses (7 or 14 ng) of DAMGO (MORs agonist) or artificial cerebrospinal fluid (aCSF) focally into the VTA of rats and measured the activation in projection areas by cFos immunohistochemistry. Our results show that focal injections of DAMGO in the VTA increases cFos expression in the majority of its projecting areas, namely NAc, basolateral amygdala (BLA), cingulate cortex (ACC) and bed nucleus of the stria terminalis (BNST), as compared to aCSF. Second, we analyzed whether inflammatory pain would affect to cFos expression using a group of rats injected with CFA in the hind paw. In this case, we found that cFos expression was not significantly different between DAMGO and aCSF administered rats in BLA, ACC and BNST. Our results confirm that inflammatory pain induces desensitization of VTA MORs in a region dependent manner which can be very relevant for addictive behaviours.
Learn More >About half of patients with spinal cord injury (SCI) develop debilitating central neuropathic pain (CNP), with no effective treatments. Thus, effective, safe, and novel therapies are needed urgently. Previously, docosahexaenoic acid (DHA) was reported to confer neuroprotection in preclinical SCI models. However, its therapeutic potential on SCI-CNP remains to be elucidated. Here, we demonstrated for the first time that intravenous DHA administrations with 3-day intervals (250 nmol/kg; starting 30 minutes after injury and maintained for 6 weeks) effectively prevented SCI-CNP development in a clinically relevant rat contusion model. SCI-CNP was assessed by a novel sensory profiling approach combining evoked pain measures and pain-related ethologically relevant rodent behaviours (burrowing, thigmotaxis, and place/escape avoidance) to mimic those for measuring human (sensory, affective, cognitive, and spontaneous) pain. Strikingly, already established SCI-CNP could be abolished partially by similar DHA administrations, starting from the beginning of week 4 after injury and maintained for 4 weeks. At spinal (epicenter and L5 dorsal horns) and supraspinal (anterior cingulate cortex) levels, both treatment regimens potently suppressed microglial and astrocyte activation, which underpins SCI-CNP pathogenesis. Spinal microgliosis, a known hallmark associated with neuropathic pain behaviours, was reduced by DHA treatments. Finally, we revealed novel potential roles of peroxisome proliferator-activated and retinoid X receptors and docosahexaenoyl ethanolamide (DHA's metabolite) in mediating DHA's effects on microglial activation. Our findings, coupled with the excellent long-term clinical safety of DHA even in surgical and critically ill patients, suggest that systemic DHA treatment is a translatable, effective, safe, and novel approach for preventing and managing SCI-CNP.
Learn More >Chronic pain is a heavy burden disease. Current treatments are generally weakly effective or associated with adverse effects. New therapeutic approaches are therefore needed. Recent studies have suggested T-type calcium channels as an attractive target for the treatment of chronic pain. In this perspective, it was decided to perform a preclinical evaluation of the efficacy of ethosuximide, a T-type channel blocker used clinically as an antiepileptic, as a novel pharmacological treatment for chronic pain. Assessment of the effect of ethosuximide was thus made in both nociception and pain-related comorbidities as anxiety and depression are frequently encountered in chronic pain patients. Our results show that such symptoms occurred in three animal models of chronic pain designed to reflect traumatic neuropathic, chemotherapy-induced neuropathic and inflammatory pain conditions. Administration of ethosuximide reduced both chronic pain and comorbidities with a marked intensity ranging from partial reduction to a complete suppression of symptoms. These results make ethosuximide, and more broadly the inhibition of T-type calcium channels, a new strategy for the management of uncontrolled chronic pain, likely to improve not only pain but also the accompanying anxiety and depression.
Learn More >Levcromakalim opens ATP-sensitive potassium channels (K channel) and induces head pain in healthy volunteers and migraine headache in migraine patients, but no pain in other parts of the body. K channels are expressed in C- and Aδ-fibers, and these channels might directly activate nociceptors and thereby evoke pain in humans.
Learn More >Medical treatments typically occur in the context of a social interaction between healthcare providers and patients. Although decades of research have demonstrated that patients' expectations can dramatically affect treatment outcomes, less is known about the influence of providers' expectations. Here we systematically manipulated providers' expectations in a simulated clinical interaction involving administration of thermal pain and found that patients' subjective experiences of pain were directly modulated by providers' expectations of treatment success, as reflected in the patients' subjective ratings, skin conductance responses and facial expression behaviours. The belief manipulation also affected patients' perceptions of providers' empathy during the pain procedure and manifested as subtle changes in providers' facial expression behaviours during the clinical interaction. Importantly, these findings were replicated in two more independent samples. Together, our results provide evidence of a socially transmitted placebo effect, highlighting how healthcare providers' behaviour and cognitive mindsets can affect clinical interactions.
Learn More >Migraine is associated with activation of the trigeminovascular system, release of calcitonin gene-related peptide (CGRP) and dilation of dural arteries. Novel treatments target calcitonin gene-related peptide or its receptor, which are present in all vascular beds, raising cardiovascular concerns. Erenumab is a human CGRP-receptor antibody approved for the prophylactic treatment of migraine.
Learn More >Case reports and a case series have described relief of neuropathic pain (NP) after treatment with epidermal growth factor receptor inhibitors (EGFR-Is). These observations are supported by preclinical findings. The aim of this trial was to explore a potential clinical signal supporting the therapeutic efficacy of EGFR-Is in NP.
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