Effect of lappaconitine on neuropathic pain mediated by P2X3 receptor in rat dorsal root ganglion

Ou, Shan; Zhao, Yandong; Xiao, Zhi; Han, Wen; Cui, Jian; Ruan, Han‐Li

doi:10.1016/j.neuint.2011.01.016

Cited by 49 publications

(35 citation statements)

References 74 publications

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“…In contrast, the MA+ subtype typically responded relatively weakly to menthol (Fig. 2C) (suggesting relatively low TRPM8 expression), whereas the responses to ATP (31)(32)(33) and AITC are implicated in nociception; the AITC receptor, TRPA1, is implicated in noxious cold nociception (34)(35)(36)(37)(38). These data, coupled with the relatively stable [Ca 2+ ] i at room temperature, are all consistent with the hypothesis that the MA+ subtype is a high-threshold cold thermoreceptor.…”

Section: Discussionsupporting

confidence: 76%

Functional profiling of neurons through cellular neuropharmacology

Teichert

Smith

Raghuraman

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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We describe a functional profiling strategy to identify and characterize subtypes of neurons present in a peripheral ganglion, which should be extendable to neurons in the CNS. In this study, dissociated dorsal-root ganglion neurons from mice were exposed to various pharmacological agents (challenge compounds), while at the same time the individual responses of >100 neurons were simultaneously monitored by calcium imaging. Each challenge compound elicited responses in only a subset of dorsal-root ganglion neurons. Two general types of challenge compounds were used: agonists of receptors (ionotropic and metabotropic) that alter cytoplasmic calcium concentration (receptor-agonist challenges) and compounds that affect voltage-gated ion channels (membrane-potential challenges). Notably, among the latter are K-channel antagonists, which elicited unexpectedly diverse types of calcium responses in different cells (i.e., phenotypes). We used various challenge compounds to identify several putative neuronal subtypes on the basis of their shared and/or divergent functional, phenotypic profiles. Our results indicate that multiple receptor-agonist and membrane-potential challenges may be applied to a neuronal population to identify, characterize, and discriminate among neuronal subtypes. This experimental approach can uncover constellations of plasma membrane macromolecules that are functionally coupled to confer a specific phenotypic profile on each neuronal subtype. This experimental platform has the potential to bridge a gap between systems and molecular neuroscience with a cellular-focused neuropharmacology, ultimately leading to the identification and functional characterization of all neuronal subtypes at a given locus in the nervous system. sensory neuron | neuronal subpopulation | conotoxin | conopeptide | Fura-2

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Section: Discussionsupporting

confidence: 76%

Functional profiling of neurons through cellular neuropharmacology

Teichert

Smith

Raghuraman

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The values of MWT and TWL were decreased starting 1 day after CCI surgery, and the most severe stage appeared around day 14 (MWT: 1.03 ± 0.21 g, TWL: 8.61 ± 0.44 s) and then began to recover on the following day (Figure 2). This trend was in line with our previous studies (Xiao et al, 2010; Ou et al, 2011; He et al, 2012). There was no significant difference in the thermal latency and mechanical threshold between control and sham CCI groups ( p = 0.259 of TWL, p = 0.128 of MWT).…”

Section: Resultssupporting

confidence: 93%

“…However, as systematical basic research is lacking, clinical effects are inconsistent and critical stimulus parameters are uncertain (Lee et al, 2015; Dedoncker et al, 2016). In this article, we choose a rat CCI model as the neuropathic pain model, which is the most common pain model that could finely simulate the clinical chronic neuropathic pain as reported by previous studies (Xiao et al, 2010; Ou et al, 2011; He et al, 2012). The pain threshold of MWT and TWL were evaluated at the different times after CCI.…”

Section: Discussionmentioning

confidence: 99%

Parameter Optimization Analysis of Prolonged Analgesia Effect of tDCS on Neuropathic Pain Rats

Han

Gao

Zhao

et al. 2017

Front. Behav. Neurosci.

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Background: Transcranial direct current stimulation (tDCS) is widely used to treat human nerve disorders and neuropathic pain by modulating the excitability of cortex. The effectiveness of tDCS is influenced by its stimulation parameters, but there have been no systematic studies to help guide the selection of different parameters.Objective: This study aims to assess the effects of tDCS of primary motor cortex (M1) on chronic neuropathic pain in rats and to test for the optimal parameter combinations for analgesia.Methods: Using the chronic neuropathic pain models of chronic constriction injury (CCI), we measured pain thresholds before and after anodal-tDCS (A-tDCS) using different parameter conditions, including stimulation intensity, stimulation time, intervention time and electrode located (ipsilateral or contralateral M1 of the ligated paw on male/female CCI models).Results: Following the application of A-tDCS over M1, we observed that the antinociceptive effects were depended on different parameters. First, we found that repetitive A-tDCS had a longer analgesic effect than single stimulus, and both ipsilateral-tDCS (ip-tDCS) and contralateral-tDCS (con-tDCS) produce a long-lasting analgesic effect on neuropathic pain. Second, the antinociceptive effects were intensity-dependent and time-dependent, high intensities worked better than low intensities and long stimulus durations worked better than short stimulus durations. Third, timing of the intervention after injury affected the stimulation outcome, early use of tDCS was an effective method to prevent the development of pain, and more frequent intervention induced more analgesia in CCI rats, finally, similar antinociceptive effects of con- and ip-tDCS were observed in both sexes of CCI rats.Conclusion: Optimized protocols of tDCS for treating antinociceptive effects were developed. These findings should be taken into consideration when using tDCS to produce analgesic effects in clinical applications.

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“…Two to four weeks following unilateral CCI, the number of P2X3 positive small and medium diameter neurons increased in DRG, and expression levels were higher in spinal cord on the side ipsilateral to the ligated nerve, consistent with up-regulation of receptors in presynaptic terminals of the primary sensory neurons. Since then, several reports have surfaced that essentially corroborate the findings of Novakovic et al [95] in CCI and ganglion compression models of sciatic and trigeminal nerves [52, 96–100], and a single report has examined a clinical neuropathic pain condition [101] and shown upregulation of P2X3 neuronal expression.…”

Section: Introductionmentioning

confidence: 62%

In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization

Ford¹

2011

Purinergic Signalling

145

124

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Treating pain by inhibiting ATP activation of P2X3-containing receptors heralds an exciting new approach to pain management, and Afferent's program marks the vanguard in a new class of drugs poised to explore this approach to meet the significant unmet needs in pain management. P2X3 receptor subunits are expressed predominately and selectively in so-called C- and Aδ-fiber primary afferent neurons in most tissues and organ systems, including skin, joints, and hollow organs, suggesting a high degree of specificity to the pain sensing system in the human body. P2X3 antagonists block the activation of these fibers by ATP and stand to offer an alternative approach to the management of pain and discomfort. In addition, P2X3 is expressed pre-synaptically at central terminals of C-fiber afferent neurons, where ATP further sensitizes transmission of painful signals. As a result of the selectivity of the expression of P2X3, there is a lower likelihood of adverse effects in the brain, gastrointestinal, or cardiovascular tissues, effects which remain limiting factors for many existing pain therapeutics. In the periphery, ATP (the factor that triggers P2X3 receptor activation) can be released from various cells as a result of tissue inflammation, injury or stress, as well as visceral organ distension, and stimulate these local nociceptors. The P2X3 receptor rationale has aroused a formidable level of investigation producing many reports that clarify the potential role of ATP as a pain mediator, in chronic sensitized states in particular, and has piqued the interest of pharmaceutical companies. P2X receptor-mediated afferent activation has been implicated in inflammatory, visceral, and neuropathic pain states, as well as in airways hyperreactivity, migraine, itch, and cancer pain. It is well appreciated that oftentimes new mechanisms translate poorly from models into clinical efficacy and effectiveness; however, the breadth of activity seen from P2X3 inhibition in models offers a realistic chance that this novel mechanism to inhibit afferent nerve sensitization may find its place in the sun and bring some merciful relief to the torment of persistent discomfort and pain. The development philosophy at Afferent is to conduct proof of concept patient studies and best identify target patient groups that may benefit from this new intervention.

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Effect of lappaconitine on neuropathic pain mediated by P2X3 receptor in rat dorsal root ganglion

Cited by 49 publications

References 74 publications

Functional profiling of neurons through cellular neuropharmacology

Functional profiling of neurons through cellular neuropharmacology

Parameter Optimization Analysis of Prolonged Analgesia Effect of tDCS on Neuropathic Pain Rats

In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization

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