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Mutations in Nav1.9 encoded by SCN11A have been associated with episodic pain, small-fiber neuropathy and congenital insensitivity to pain. In this study, we collected and characterized one Chinese family with episodic pain. The SCN11A mutation (c.664C>A/p.Arg222Ser) was identified and cosegregated with the episodic pain phenotype. In addition, we found that alcohol intake triggered intense pain attacks and detected the ALDH2 polymorphism (c.1510G>A/p.Glu504Lys) in three patients with episodic pain. The alcohol-aggravated pain symptom and this ALDH2 polymorphism were also reconfirmed in our previously reported episodic pain patient with the Nav1.9 mutation (p.Ala808Gly, patient III-2 in HBBJ family). To assess the pathogenicity of the Nav1.9 mutation and the new trigger, we introduced a mutation (p.Ala796Gly) into the mouse (orthologous mutation in human is p.Ala808Gly). The alteration hyperpolarized channel activation, increased the residual current through non-inactivating channels, and induced hyperexcitability of dorsal root ganglion (DRG) neurons in Scn11a mice. The Scn11a mice showed increased sensitivity to mechanical, heat and cold stimuli, and hypersensitivity to acetaldehyde and formalin, which could account for the alcohol intake-induced pain phenotype in patients. Moreover, acetaldehyde increased the mutant mNav1.9 channel current and excitability of Scn11a mouse DRG neurons. Parecoxib (an anti-inflammatory medication) relieved the heat hypersensitivity in Scn11a mice not receiving inflammatory stimuli and significantly decreased the hyperexcitability of DRG neurons in Scn11a mice. These results indicated that Scn11a mice recapitulated many clinical features of patients and suggested that Nav1.9 channel contributes significantly to the inflammatory pain state.
Learn More >Low back pain (LBP) is a highly prevalent and disabling condition whose initiating factors are poorly understood. It is known that psychological and physical stress is associated with LBP but the causal relationship, mechanisms and mediators have not been elucidated, and a preclinical model enabling the investigation of causality and thereby critically contributing to clinical translation does not exist.In the present study, we first established and characterized a myofascial LBP model in mice based on NGF injection into the low back muscles. Secondly, we investigated the effect of two different stress paradigms on this mouse LBP model by applying the chronic unpredictable stress (CUS) and vertical chronic restraint stress (vCRS) paradigms, to mimic psychological and psychophysical stress, respectively. In these studies, we combined longitudinal behavioral tests with gene and protein expression analysis in the muscle, dorsal root ganglia and spinal cord. NGF-induced LBP was characterized by long-lasting local and plantar mechanical hypersensitivity, cold hyperalgesia, decreased grip strength and wheel running activity, and time-dependent changes of neuropeptide and glial markers in the spinal cord. Interestingly, the exposure to CUS slightly worsened pain behavior, whereas vCRS primed and highly aggravated pain in this LBP model, by causing per se the intramuscular upregulation of endogenous NGF and increased spinal astrocyte expression.Our mouse model, particularly the combination of NGF injection and vCRS suggest that similar mechanisms are important in non-specific LBP and might help to investigate certain aspects of stress-induced exacerbation of pain.
Learn More >The safety and efficacy of opioids are compromised as analgesic tolerance develops. Opioids are also ineffective against neuropathic pain. Recent reports have suggested that inhibitors of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK), may have analgesic effects in cancer patients suffering from neuropathic pain. It has been shown that the platelet-derived growth factor receptor-beta (PDGFR-↓), an RTK that has been shown to interact with the EGFR, mediates opioid tolerance but does not induce analgesia. Therefore, we sought to determine whether EGFR signaling was involved in opioid tolerance and if EGFR and PDGFR signaling could induce pain in rats.We found that gefitinib, an EGFR antagonist, eliminated morphine tolerance. In addition, repeated epidermal growth factor (EGF) administration rendered animals unresponsive to subsequent analgesic doses of morphine, a phenomenon we call 'pre-tolerance'. Using a nerve injury model, we found that gefitinib alone was not analgesic. Rather, it reversed insensitivity to morphine analgesia ('pre-tolerance') caused by the release of EGF by injured nerves. We also showed that repeated, but not acute EGF or platelet-derived growth factor-BB (PDGF-BB) administration induced mechanical hypersensitivity in rats. EGFR and PDGFR-↓ signaling interacted to produce this sensitization. EGFR was widely expressed in primary sensory afferent cell bodies, demonstrating a neuroanatomical substrate for our findings.Taken together, our results suggest a direct mechanistic link between opioid tolerance and mechanical sensitization. EGFR antagonism could eventually play an important clinical role in the treatment of opioid tolerance and neuropathic pain that is refractory to opioid treatment. Opioid tolerance and associated reduced effectiveness of opioids against neuropathic pain are two major clinical problems that are prime contributors to the opioid epidemic. However, the mechanisms underlying these phenomena are not clearly understood. Here we show that EGFR antagonism not only blocks morphine tolerance but also restores the effectiveness of opioids against neuropathic pain. Chronic EGF or PDGF administration induces mechanical sensitization, a prominent component of neuropathic pain, and renders animals 'pre-tolerant' to subsequent analgesic doses of morphine. Taken together, these results suggest a direct mechanistic link between opioid tolerance and neuropathic pain. EGFR antagonism could eventually play an important role in the treatment of opioid tolerance and severe neuropathic pain that requires ever increasing doses of opioids.
Learn More >To ensure reproducibility in research quantifying episodic migraine attacks, and identifying attack onset, a sound theoretical model of a migraine attack, paired with a uniform standard for counting them, is necessary. Many studies report on migraine frequencies-e.g. the fraction of migraine-days of the observed days-without paying attention to the number of discrete attacks. Furthermore, patients' diaries frequently contain single, migraine-free days between migraine-days, and we argue here that such 'migraine-locked days' should routinely be interpreted as part of a single attack. We tested a simple Markov model of migraine attacks on headache diary data and estimated transition probabilities by mapping each day of each diary to a unique Markov state. We explored the validity of imputing migraine days on migraine-locked entries, and estimated the effect of imputation on observed migraine frequencies. Diaries from our patients demonstrated significant clustering of migraine days. The proposed Markov chain model was shown to approximate the progression of observed migraine attacks satisfactorily, and imputing on migraine-locked days was consistent with the conceptual model for the progression of migraine attacks. Hence, we provide an easy method for quantifying the number and duration of migraine attacks, enabling researchers to procure data of high inter-study validity.
Learn More >Chronic pain is a frequent and disabling condition that is significantly maintained by central sensitization, which results in pathological amplification of responses to noxious and innocuous stimuli. As such, mechanical allodynia, or pain in response to a tactile stimulus that does not normally provoke pain, is a cardinal feature of chronic pain. Recent evidence suggests that the dorsal horn excitatory interneurons that express the γ isoform of protein kinase C (PKCγ) play a critical role in the mechanism of mechanical allodynia during chronic pain. Here, we review this evidence as well as the main aspects of the development, anatomy, electrophysiology, inputs, outputs, and pathophysiology of dorsal horn PKCγ neurons. Primary afferent high-threshold neurons transmit the nociceptive message to the dorsal horn of the spinal cord and trigeminal system where it activates second-order nociceptive neurons relaying the information to the brain. In physiological conditions, low-threshold mechanoreceptor inputs activate inhibitory interneurons in the dorsal horn, which may control activation of second-order nociceptive neurons. During chronic pain, low-threshold mechanoreceptor inputs now activate PKCγ neurons that forward the message to second-order nociceptive neurons, turning thus tactile inputs into pain. Several mechanisms may contribute to opening this gate, including disinhibition, activation of local astrocytes, release of diffusible factors such as reactive oxygen species, and alteration of the descending serotoninergic control on PKCγ neurons through 5-HT serotonin receptors. Dorsal horn PKCγ neurons, therefore, appear as a relevant therapeutic target to alleviate mechanical allodynia during chronic pain.
Learn More >Little is known about the validity of numeric and verbal rating scales (NRS and VRS) for itch and itch frequency for assessing itch severity in AD. We evaluated the Patient-Reported Outcomes Information System (PROMIS ) Itch Questionnaire (PIQ) – itch severity assessment, including multiple NRS, VRS and frequency of itch assessments, in adults with AD and compared their performance.
Learn More >Pharmacological evaluation of the mu-opioid receptor (MOR) agonist properties of NKTR-181 in rodent models.
Learn More >Endothelin-1 (ET-1), an endogenous vasoactive peptide, has been found to play an important role in peripheral pain signaling. Acid-sensing ion channels (ASICs) are key sensors for extracellular protons and contribute to pain caused by tissue acidosis. It remains unclear whether an interaction exists between ET-1 and ASICs in primary sensory neurons. In this study, we reported that ET-1 enhanced the activity of ASICs in rat dorsal root ganglia (DRG) neurons. In whole-cell voltage-clamp recording, ASIC currents were evoked by brief local application of pH 6.0 external solution in the presence of TRPV1 channel blocker AMG9810. Pre-application with ET-1 (1-100 nM) dose-dependently increased the proton-evoked ASIC currents with an EC value of 7.42 ± 0.21 nM. Pre-application with ET-1 (30 nM) shifted the concentration-response curve of proton upwards with a maximal current response increase of 61.11% ± 4.33%. We showed that ET-1 enhanced ASIC currents through endothelin-A receptor (ETR), but not endothelin-B receptor (ETR) in both DRG neurons and CHO cells co-expressing ASIC3 and ETR. ET-1 enhancement was inhibited by blockade of G-protein or protein kinase C signaling. In current-clamp recording, pre-application with ET-1 (30 nM) significantly increased acid-evoked firing in rat DRG neurons. Finally, we showed that pharmacological blockade of ASICs by amiloride or APETx2 significantly alleviated ET-1-induced flinching and mechanical hyperalgesia in rats. These results suggest that ET-1 sensitizes ASICs in primary sensory neurons via ETR and PKC signaling pathway, which may contribute to peripheral ET-1-induced nociceptive behavior in rats.
Learn More >Background and aims The placebo response has been identified as one factor responsible for the lack of therapeutic trials with positive outcomes in neuropathic pain. Reviews have suggested that certain neuropathic pain conditions, including HIV-associated sensory neuropathy (HIV-SN), exhibit a greater placebo response than other neuropathic aetiologies. If true, such a finding could substantially affect clinical trial design and therapeutic developments for these conditions. This study aimed to identify any difference in placebo response between trials of systemic pharmacological intervention in HIV-SN and a comparable neuropathic condition, diabetic polyneuropathy (DPN) and to identify factors influencing the placebo response. Methods A systematic review search to identify randomised, double-blind studies of systemic pharmacological interventions for painful HIV-SN and DPN published between January 1966 and June 2019 was performed. A meta-analysis of the magnitude of placebo response and the proportion of placebo responders was conducted and compared between the two disease conditions. A meta-regression was used to assess for any study and participant characteristics that were associated with the placebo response. Only studies meeting a methodological quality threshold were included. Results Seventy-five trials were identified. There was no statistically significant difference in the proportion of placebo responders (HIV-SN = 0.35; versus DPN = 0.27, p = 0.129). The difference observed in the magnitude of the placebo response [pain reduction of 1.68 (1.47-1.88) DPN; 2.38 (1.87-2.98) in HIV-SN] was based on only 2 trials of HIV-SN and 35 of DPN. Potential factors influencing the placebo response such as psychological measures, were reported inconsistently. Conclusions We found no statistically significant difference in the placebo response rate between painful HIV-SN and DPN. Too few studies were available that reported the necessary information to clarify potential differences in the magnitude of placebo response or to elucidate parameters that could be contributing such differences. Implications The placebo response is one factor that may contribute to a lack of positive trials in neuropathic pain; some etiologies may display larger responses than others. This meta-analysis found no significant difference in placebo response between trials of HIV-associated sensory neuropathy and painful diabetic polyneuropathy, although limited data were available.
Learn More >IL-4 is a pleiotropic antiinflammatory cytokine, which can be neuroprotective after nervous system injury. The beneficial actions of IL-4 are thought to result from the blunting of action of inflammatory mediators, such as proinflammatory cytokines. Here, we demonstrate that IL-4 induces M2 macrophages to continuously produce opioid peptides and ameliorate pain. IL-4 application at injured nerves in mice shifted F4/80+ macrophages from the proinflammatory M1 to the antiinflammatory M2 phenotype, which synthesized opioid peptides (Met-enkephalin, β-endorphin, and dynorphin A 1-17). These effects were accompanied by a long-lasting attenuation of neuropathy-induced mechanical hypersensitivity, beyond the IL-4 treatment. This IL-4-induced analgesia was decreased by opioid peptide antibodies and opioid receptor (δ, μ, κ) antagonists applied at injured nerves, which confirms the involvement of the local opioid system. The participation of M2 macrophages was supported by analgesia in recipient mice injected at injured nerves with F4/80+ macrophages from IL-4-treated donors. Together, IL-4-induced M2 macrophages at injured nerves produced opioid peptides, which activated peripheral opioid receptors to diminish pain. Fostering the opioid-mediated actions of intrinsic M2 macrophages may be a strategy to tackle pathological pain.
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