The journal of pain : official journal of the American Pain Society
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Comparative Study
Acute pain increases phosphorylation of DCLK-long in the Edinger-Westphal nucleus but not in the hypothalamic paraventricular nucleus of the rat.
The doublecortin-like kinase (DCLK) gene is crucially involved in neuronal plasticity and microtubule-guided retrograde transport of signaling molecules. We have explored the possibility that DCLK is involved in pain-induced signaling events in adult male Wistar rats. Our results show that both DCLK-short and DCLK-long splice variants are present in the cell body and proximal dendrites of neurons in stress-related nuclei, ie, the paraventricular nucleus of the hypothalamus (PVN) and the non-preganglionic Edinger-Westphal nucleus (npEW) in the rostroventral periaqueductal grey. We found that DCLK-long but not DCLK-short is phosphorylated in its serine/proline-rich domain. Furthermore, we demonstrate that phosphorylation of DCLK-long in the npEW is increased by acute pain, whereas DCLK-long phosphorylation in the PVN remains unaffected. This is the first report revealing that DCLK isoforms in the PVN and npEW occur in the adult mammalian brain and that pain differentially affects DCLK-long-mediated neuronal plasticity in these 2 stress-sensitive brain centers. ⋯ Pain is a burden for society and the individual, and although the mechanisms underlying pain are relatively well known, its treatment remains difficult and incomplete. Pain stress can lead to diseases like chronic pain and depression. The differential DCLK-phosphorylation in stress-sensitive brain areas is a potential novel therapeutic target in pain research.
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The purpose of the study was to investigate the association between incident self-reported fibromyalgia (FM) and prior somatic diseases, lifestyle factors, and health behaviors among 3,136 women who participated in 2 cohort studies 25 to 26 years apart (the Adventist Health Study 1 and 2). The women completed a comprehensive lifestyle and medical history questionnaire at baseline in 1976. Information on new diagnosis of doctor-told FM was obtained at the second survey in 2002. A total of 136 women reported a diagnosis of FM during 25 years of follow-up, giving a period incidence of 43/1,000 or 1.72/1000 per year. In multivariable logistic regression analyses, a significant, dose-response association was found with number of allergies with OR of 1.61 (95% CI: .92-2.83) and 3.99 (95% CI: 2.31-6.88), (P[trend] < .0001), respectively, for 1 and 2 or more allergies versus none. A history of hyperemesis gravidarum was also associated with FM with OR of 1.32 (95% CI: .75-2.32) and 1.73 (95% CI: .99-3.03), (P[trend] < .05), respectively, for some or all pregnancies versus none. A positive association with smoking was also found with OR of 2.37 (95% CI: 1.33-4.23) for ever smokers versus never smokers. No significant association was found with number of surgeries, history of peptic ulcer, or taking medications to control various symptoms. ⋯ Smoking as well as prevalent allergies, and a history of hyperemesis gravidarum, seem to predict development of FM in women during 25 years of follow-up. This information may help in identifying persons at high risk of developing FM and thus initiate effective prevention strategies.
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The Critical-Care Pain Observation Tool (CPOT) is a behavioral scale recommended by experts for pain assessment in critically ill patients unable to verbally communicate. The main goal of this study was to determine the relationship between self-reports of pain intensity and the CPOT score, and establish the sensibility and the specificity of the CPOT to different levels of pain intensity in healthy subjects. A total of 18 healthy subjects participated in the study (mean age = 37.8 years). All subjects underwent a 2 minutes noxious cold pressor test (CPT) at 7°C. Verbal pain ratings were obtained with a visual analog scale (0-100) while pain behaviors were videotaped. Afterwards, 2 independent evaluators quantified pain behaviors using the CPOT. Interrater reliability was supported with an ICC of 0.963 (95%CI [0.904-0.986]). A moderate positive correlation between the CPOT scores and self-reports of pain intensity during the CPT was found (r = 0.52, p = 0.028). Such result indicates that subjects reporting high level of pain showed a higher number or more intense pain behaviors. A cut-off score >2.5/8 on the CPOT led to a sensibility of 64% and a specificity of 86%. Results from this pilot study support that an increase of CPOT score is correlated with moderate to high levels of pain intensity and further support the clinical use of the CPOT. ⋯ This article presents the psychometric properties of a behavioral pain scale called the CPOT which was developed to assess pain in critically ill adults unable to self-report. Our results in healthy subjects showed that the CPOT behavioral score is significantly correlated with the self-report of pain intensity and supports its clinical use.
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Activation of Rho kinase (ROCK) has been shown to play a role in neuronal regeneration and development of posttraumatic neuropathic pain. The ROCK inhibitor Fasudil, used clinically for the treatment of vasospasm, was used to investigate the analgesic profile of a ROCK inhibitor. Fasudil was evaluated in different preclinical models of neuropathic, osteoarthritic (OA), and inflammatory pain as well as capsaicin-induced acute pain and secondary mechanical hypersensitivity. In addition, Fasudil was tested in in vivo electrophysiology to determine the mechanism by which Fasudil produces analgesia. Fasudil at the highest dose tested (30 mg/kg) significantly attenuated mechanical allodynia in spinal-nerve ligation (SNL; 77%), chronic constriction injury (CCI; 53%), capsaicin-induced secondary mechanical hypersensitivity (63%), sodium iodoacetate-induced OA pain (88%), and capsaicin-induced acute flinching behaviors (56%). However, Fasudil (at 30 mg/kg) failed to attenuate or had only modest effects on inflammatory thermal hyperalgesia following carrageenan injection and mechanical allodynia following Complete Freund's Adjuvant (CFA) injection. Fasudil produced ED(50) of 10.8 mg/kg in the SNL, and 5.7 mg/kg in the OA pain models. The ED(50) and 95% CI could not be obtained in the other models. Furthermore, administration of Fasudil (10 mg/kg, iv) significantly reduced both spontaneous and evoked firing of wide dynamic range (WDR) neurons in SNL, but not sham rats. Finally, Fasudil significantly decreased exploratory behaviors at 30 mg/kg. These results suggest that the acute administration of a ROCK inhibitor produces efficacy in both neuropathic and nociceptive pain states at doses devoid of locomotor side effects, with specific effects on WDR neurons. ⋯ In this article, the potential analgesic effects of Fasudil in a range of preclinical pain models were assessed. Fasudil was shown to have efficacy in neuropathic and nociceptive pain models. These findings may help identify new therapeutic treatments for pain in the clinic.
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The present study evaluated the antinociceptive effect of (1→3),(1→6)-linked β-glucan (GL) isolated from Pleurotus pulmonarius (Fr.) Quel. in mice and its possible mechanism of action. Intraperitoneal administration of GL inhibited glutamate-induced licking with an ID(50) of 0.34 mg/kg and inhibition of 96% ± 3%. The treatment of animals with GL (1 mg/kg i.p.) inhibited nociception induced by intrathecal injection of N-methyl-D-aspartic acid, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate and interleukin -1β in 67% ± 13%, 89% ± 11%, 74% ± 9%, and 75% ± 7%, respectively, but not the nociceptive response induced by (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid, substance P, and tumor necrosis factor-α. Moreover, GL (30 mg/kg i.p.) also reduced mechanical allodynia caused by partial sciatic nerve ligation for 2 hours, with inhibition of 47% ± 10% observed 0.5 hours after treatment. When given chronically (twice a day) over 7 days, GL reversed the mechanical allodynia caused by partial sciatic nerve ligation (inhibition of 45% ± 13% to 60% ± 8%). Interestingly, GL did not affect the locomotor activity of mice in an open field test with doses that produce antinociceptive effects. Our findings show that GL inhibits acute and neuropathic pain in mice through mechanisms that involve the inhibition of ionotropic glutamate receptors and the interleukin -1β pathway. ⋯ This article presents the antinociceptive activity of GL in acute and neuropathic pain with participation of ionotropic glutamate receptors and pro-inflammatory cytokines (interleukin-1β). After further experiments, this compound may represent a new pharmacological agent for the treatment of clinical pain.