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Nowadays, pain represents one of the most important societal burdens. Current treatments are, however, too often ineffective and/or accompanied by debilitating unwanted effects for patients dealing with chronic pain. Indeed, the prototypical opioid morphine, as many other strong analgesics, shows harmful unwanted effects including respiratory depression and constipation, and also produces tolerance, physical dependence, and addiction. The urgency to develop novel treatments against pain while minimizing adverse effects is therefore crucial. Over the years, the delta-opioid receptor (DOP) has emerged as a promising target for the development of new pain therapies. Indeed, targeting DOP to treat chronic pain represents a timely alternative to existing drugs, given the weak unwanted effects spectrum of DOP agonists. Here, we review the current knowledge supporting a role for DOP and its agonists for the treatment of pain. More specifically, we will focus on the cellular and subcellular localization of DOP in the nervous system. We will also discuss in further detail the molecular and cellular mechanisms involved in controlling the cellular trafficking of DOP, known to differ significantly from most G protein-coupled receptors. This review article will allow a better understanding of how DOP represents a promising target to develop new treatments for pain management as well as where we stand as of our ability to control its cellular trafficking and cell surface expression.
Learn More >Liquiritin Alleviates Pain Through Inhibiting CXCL1/CXCR2 Signaling Pathway in Bone Cancer Pain Rat.
Bone cancer pain (BCP) is an intractable clinical problem, and lacked effective drugs for treating it. Recent research showed that several chemokines in the spinal cord are involved in the pathogenesis of BCP. In this study, the antinociceptive effects of liquiritin, which is an active component extracted from Glycyrrhizae Radix, were tested and the underlying mechanisms targeting spinal dorsal horn (SDH) were investigated. The BCP group displayed a significant decrease in the mechanical withdrawal threshold on days 6, 12, and 18 when compared with sham groups. Intrathecal administration of different doses of liquiritin alleviated mechanical allodynia in BCP rats. The results of immunofluorescent staining and western blotting showed that liquiritin inhibited BCP-induced activation of astrocytes in the spinal cord. Moreover, intrathecal administration of liquiritin effectively inhibited the activation of CXCL1/CXCR2 signaling pathway and production of IL-1β and IL-17 in BCP rats. In astroglial-enriched cultures, Lipopolysaccharides (LPS) elicited the release of chemokine CXCL1, and the release was decreased in a dose-dependent manner by liquiritin. In primary neurons, liquiritin indirectly reduced the increase of CXCR2 by astroglial-enriched-conditioned medium but not directly on the CXCR2 target site. These results suggested that liquiritin effectively attenuated BCP in rats by inhibiting the activation of spinal astrocytic CXCL1 and neuronal CXCR2 pathway. These findings provided evidence regarding the the antinociceptive effect of liquiritin on BCP.
Learn More >The specific serotonin type 3 (5-HT)-receptor antagonist granisetron effectively reduces clinical as well as experimental muscle pain and hyperalgesia and with a duration that exceeds that of lidocaine. Hence, it may be an alternative to lidocaine as a local anesthetic. There are also some indications that granisetron in addition to 5-HT receptors blocks sodium channels. Thus, the local anesthetic effect by granisetron may resemble that of lidocaine, but this has not been tested. The aim of this study was therefore to compare the effect granisetron has on facial skin sensitivity to the effect of lidocaine and isotonic saline. This was a randomized, controlled, and double-blind study, in which 1 ml of either granisetron (test-substance), lidocaine (positive control), or isotonic saline (negative control) was injected into the skin over the masseter muscle at three different occasions in 18 healthy males (27.2 ± 5.8 years old). Skin detection thresholds and pain thresholds for thermal stimuli as well as mechanical detection thresholds and sensitivity to a painful mechanical (pinprick) stimulus were assessed before (baseline) and 5, 20, 40, and 60 min after injection. The quality and area of subjective sensory change over the cheek were assessed 20 min after injection. All substances increased the mechanical detection threshold (granisetron: = 0.011; lidocaine: = 0.016; saline: = 0.031). Both granisetron and lidocaine, but not isotonic saline, increased the heat detection thresholds ( < 0.001 and < 0.02, respectively), but not the cold detection thresholds. Granisetron and lidocaine also reduced pinprick pain ( = 0.001 for each comparison). There were no significant differences between granisetron and lidocaine for any of these variables. There was no effect on thermal pain thresholds for any substance. The similar analgesic patterns on mechanical sensory and pain thresholds as well as thermal sensory thresholds over the facial skin by subcutaneous injection of granisetron and lidocaine shown in this study and the absence of paresthesia, in combination with the reduced pain intensity and pressure pain sensitivity shown in previous studies, indicate that granisetron might be a novel candidate as a local anesthetic.
Learn More >Migraine is a common and disabling brain disorder with a broad and heterogeneous phenotype, involving both pain and painless symptoms. Over recent years, more clinical and research attention has been focused toward the premonitory phase of the migraine attack, which can start up to days before the onset of head pain. This early phase can involve symptomatology, such as cognitive and mood change, yawning, thirst and urinary frequency and sensory sensitivities, such as photophobia and phonophobia. In some patients, these symptoms can warn of an impending headache and therefore offer novel neurobiological insights and therapeutic potential. As well as characterization of the phenotype of this phase, recent studies have attempted to image this early phase using functional neuroimaging and tried to understand how the symptoms are mediated, how a migraine attack may be initiated, and how nociception may follow thereafter. This review will summarize the recent and evolving findings in this field and hypothesize a mechanism of subcortical and diencephalic brain activation during the start of the attack, including that of basal ganglia, hypothalamus, and thalamus prior to headache, which causes a top-down effect on brainstem structures involved in trigeminovascular nociception, leading ultimately to headache.
Learn More >Kappa opioid receptor (KOPr) agonists represent alternative analgesics for their low abuse potential, although relevant adverse effects have limited their clinical use. Functionally selective KOPr agonists may activate, in a pathway-specific manner, G protein-mediated signaling, that produces antinociception, over β-arrestin 2-dependent induction of p38MAPK, which preferentially contributes to adverse effects. Thus, functionally selective KOPr agonists biased toward G protein-coupled intracellular signaling over β-arrestin-2-mediated pathways may be considered candidate therapeutics possibly devoid of many of the typical adverse effects elicited by classic KOPr agonists. Nonetheless, the potential utility of functionally selective agonists at opioid receptors is still highly debated; therefore, further studies are necessary to fully understand whether it will be possible to develop more effective and safer analgesics by exploiting functional selectivity at KOPr. In the present study we investigated functional selectivity and antinociceptive effects of LOR17, a novel KOPr selective peptidic agonist that we synthesized. LOR17-mediated effects on adenylyl cyclase inhibition, ERK1/2, p38MAPK phosphorylation, and astrocyte cell proliferation were studied in HEK-293 cells expressing hKOPr, U87-MG glioblastoma cells, and primary human astrocytes; biased agonism was investigated cAMP ELISA and β-arrestin 2 recruitment assays. Antinociception and antihypersensitivity were assessed in mice warm-water tail-withdrawal test, intraperitoneal acid-induced writhing, and a model of oxaliplatin-induced neuropathic cold hypersensitivity. Effects of LOR17 on locomotor activity, exploratory activity, and forced-swim behavior were also assayed. We found that LOR17 is a selective, G protein biased KOPr agonist that inhibits adenylyl cyclase and activates early-phase ERK1/2 phosphorylation. Conversely to classic KOPr agonists as U50,488, LOR17 neither induces p38MAPK phosphorylation nor increases KOPr-dependent, p38MAPK-mediated cell proliferation in astrocytes. Moreover, LOR17 counteracts, in a concentration-dependent manner, U50,488-induced p38MAPK phosphorylation and astrocyte cell proliferation. Both U50,488 and LOR17 display potent antinociception in models of acute nociception, whereas LOR17 counteracts oxaliplatin-induced thermal hypersensitivity better than U50,488, and it is effective after single or repeated s.c. administration. LOR17 administered at a dose that fully alleviated oxaliplatin-induced thermal hypersensitivity did not alter motor coordination, locomotor and exploratory activities nor induced pro-depressant-like behavior. LOR17, therefore, may emerge as a novel KOPr agonist displaying functional selectivity toward G protein signaling and eliciting antinociceptive/antihypersensitivity effects in different animal models, including oxaliplatin-induced neuropathy.
Learn More >To explore the efficacy of cathodal tDCS applied ipsilateral to the cold patch, as determined by thermographic evaluation, in the treatment of chronic migraine. Transcranial direct current stimulation (tDCS) is a non-invasive and safe technique that modulates the activity of the underlying cerebral cortex. tDCS has been extensively tested as a possible treatment for chronic pain and migraine with controversial results mainly due to the different setting procedure and location of electrodes. Since the presence of a hypothermic patch region detected through thermography has been suggested as a possible support for headache diagnosis, this "cold patch" could considered as possible effective location for tDCS application. Forty-five patients with chronic migraine were randomized to receive either cathodal (25 patients) or sham tDCS, for 5 consecutive daily sessions plus a recall session after 1 month. Cathodal tDCS was delivered at 1.5 mA for 15 min in each session. Subjects were evaluated before treatment (baseline, T0), and after 10 (T10), 60 (T60), and 120 (T120) days after treatment. The number of attacks, duration of attacks, pain intensity, number of days with headache, and number of analgesics were collected at each time evaluation. Patients in the tDCS group showed a significant improvement compared to the sham group, during the whole study period in the frequency of migraine attacks (tDCS vs. sham: -47.8 ± 50.1% vs. -14.2 ± 16.5%, = 0.004), number of days with headache (tDCS vs. sham: -42.7 ± 65.4% vs. -11.3 ± 18.0%, = 0.015), duration of attacks (tDCS vs. sham: -29.1 ± 43.4% vs. -7.5 ± 17.6%, = 0.016), intensity of the pain during an attack (tDCS vs. sham -31.1 ± 36.9% vs. 8.3 ± 13.5%, = 0.004), and number of analgesics (tDCS vs. sham -54.3 ± 37.4% vs. -16.0 ± 19.6%, < 0.0001). Our results suggest that cathodal tDCS is an effective adjuvant technique in migraine provided that an individual correct montage of the electrodes is applied, according to thermographic investigation.
Learn More >Chemotherapy-induced neuropathic pain is a disabling condition following cancer treatment. Vincristine has more neurotoxicity than other vinca alkaloid agents. This study evaluated the correlation of different doses of nefopam with antiallodynic effects in a mouse vincristine neuropathy model.
Learn More >Osteoarthritis is the most prominent form of arthritis, affecting approximately 15% of the population in the United States. Knee osteoarthritis (KOA) has become one of the leading causes of disability in older adults. Besides knee replacement, there are no curative treatments for KOA, so persistent pain is commonly treated with opioids, acetaminophen, and nonsteroidal anti-inflammatory drugs. However, these drugs have many unpleasant side effects, so there is a need for alternative forms of pain management. We sought to test the efficacy of a dietary intervention to reduce KOA.
Learn More >Tumor-related cancer pain often comprises mixed pain with both nociceptive and neuropathic components. Whether tumor-related cancer pain includes a neuropathic component impacts the therapeutic strategy. The aim of this cross-sectional study was to investigate the usefulness of two screening tools for neuropathic pain, painDETECT and Self-Report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS), in identifying the neuropathic component of mixed pain among patients with tumor-related cancer pain.
Learn More >Migraine is a neurovascular disease with recurrent headache attacks. A polymorphism (rs2651899) of the PRDM16 gene, which is associated with migraine, was identified in recent genome-wide association studies. The potential role of the PRDM16 rs2651899 polymorphism in migraine is still unknown. Therefore, we conducted this systematic review and meta-analysis to examine this issue.
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