Lack of efficacy of a partial adenosine A1 receptor agonist in neuropathic pain models in mice

AbstractPrevious studies suggest that adenosine A1 receptors (A1R) modulate the processing of pain. The aim of this study was to characterize the distribution of A1R in nociceptive tissues and to evaluate whether targeting A1R with the partial agonist capadenoson may reduce neuropathic pain in mice. The cellular distribution of A1R in dorsal root ganglia (DRG) and the spinal cord was analyzed using fluorescent in situ hybridization. In behavioral experiments, neuropathic pain was induced by spared nerve injury or intraperitoneal injection of paclitaxel, and tactile hypersensitivities were determined using a dynamic plantar aesthesiometer. Whole-cell patch-clamp recordings were performed to assess electrophysiological properties of dissociated DRG neurons. We found A1R to be expressed in populations of DRG neurons and dorsal horn neurons involved in the processing of pain. However, administration of capadenoson at established in vivo doses (0.03–1.0 mg/kg) did not alter mechanical hypersensitivity in the spared nerve injury and paclitaxel models of neuropathic pain, whereas the standard analgesic pregabalin significantly inhibited the pain behavior. Moreover, capadenoson failed to affect potassium currents in DRG neurons, in contrast to a full A1R agonist. Despite expression of A1R in nociceptive neurons, our data do not support the hypothesis that pharmacological intervention with partial A1R agonists might be a valuable approach for the treatment of neuropathic pain.

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Abnormal Reinnervation of Denervated Areas Following Nerve Injury Facilitates Neuropathic Pain

Cells ◽

10.3390/cells9041007 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1007 ◽

Cited By ~ 2

Author(s):

Hodaya Leibovich ◽

Nahum Buzaglo ◽

Shlomo Tsuriel ◽

Liat Peretz ◽

Yaki Caspi ◽

...

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Peripheral Nerves ◽

Dorsal Root ◽

Pain Sensitivity ◽

Spared Nerve Injury ◽

Drg Neurons ◽

Nociceptive Neurons ◽

Peripheral Innervation ◽

Innervation Patterns

An injury to peripheral nerves leads to skin denervation, which often is followed by increased pain sensitivity of the denervated areas and the development of neuropathic pain. Changes in innervation patterns during the reinnervation process of the denervated skin could contribute to the development of neuropathic pain. Here, we examined the changes in the innervation pattern during reinnervation and correlated them with the symptoms of neuropathic pain. Using a multispectral labeling technique—PainBow, which we developed, we characterized dorsal root ganglion (DRG) neurons innervating distinct areas of the rats’ paw. We then used spared nerve injury, causing partial denervation of the paw, and examined the changes in innervation patterns of the denervated areas during the development of allodynia and hyperalgesia. We found that, differently from normal conditions, during the development of neuropathic pain, these areas were mainly innervated by large, non-nociceptive neurons. Moreover, we found that the development of neuropathic pain is correlated with an overall decrease in the number of DRG neurons innervating these areas. Importantly, treatment with ouabain facilitated reinnervation and alleviated neuropathic pain. Our results suggest that local changes in peripheral innervation following denervation contribute to neuropathic pain development. The reversal of these changes decreases neuropathic pain.

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The Role of TMEM16A/ERK/NK-1 Signaling in Dorsal Root Ganglia Neurons in the Development of Neuropathic Pain Induced by Spared Nerve Injury (SNI)

Molecular Neurobiology ◽

10.1007/s12035-021-02520-9 ◽

2021 ◽

Author(s):

Qinyi Chen ◽

Liangjingyuan Kong ◽

Zhenzhen Xu ◽

Nan Cao ◽

Xuechun Tang ◽

...

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Dorsal Root ◽

Electrophysiological Recording ◽

Erk Pathway ◽

Spared Nerve Injury ◽

Positive Interaction ◽

Nociceptive Neurons ◽

Nociceptive Responses

AbstractIncreasing evidence suggests that transmembrane protein 16A (TMEM16A) in nociceptive neurons is an important molecular component contributing to peripheral pain transduction. The present study aimed to evaluate the role and mechanism of TMEM16A in chronic nociceptive responses elicited by spared nerve injury (SNI). In this study, SNI was used to induce neuropathic pain. Drugs were administered intrathecally. The expression and cellular localization of TMEM16A, the ERK pathway, and NK-1 in the dorsal root ganglion (DRG) were detected by western blot and immunofluorescence. Behavioral tests were used to evaluate the role of TMEM16A and p-ERK in SNI-induced persistent pain and hypersensitivity. The role of TMEM16A in the hyperexcitability of primary nociceptor neurons was assessed by electrophysiological recording. The results show that TMEM16A, p-ERK, and NK-1 are predominantly expressed in small neurons associated with nociceptive sensation. TMEM16A is colocalized with p-ERK/NK-1 in DRG. TMEM16A, the MEK/ERK pathway, and NK-1 are activated in DRG after SNI. ERK inhibitor or TMEM16A antagonist prevents SNI-induced allodynia. ERK and NK-1 are downstream of TMEM16A activation. Electrophysiological recording showed that CaCC current increases and intrathecal application of T16Ainh-A01, a selective TMEM16A inhibitor, reverses the hyperexcitability of DRG neurons harvested from rats after SNI. We conclude that TMEM16A activation in DRG leads to a positive interaction of the ERK pathway with activation of NK-1 production and is involved in the development of neuropathic pain after SNI. Also, the blockade of TMEM16A or inhibition of the downstream ERK pathway or NK-1 upregulation may prevent the development of neuropathic pain.

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Increased expression of CaV3.2 T-type calcium channels in damaged DRG neurons contributes to neuropathic pain in rats with spared nerve injury

Molecular Pain ◽

10.1177/1744806918765808 ◽

2018 ◽

Vol 14 ◽

pp. 174480691876580 ◽

Cited By ~ 14

Author(s):

Xue-Jing Kang ◽

Ye-Nan Chi ◽

Wen Chen ◽

Feng-Yu Liu ◽

Shuang Cui ◽

...

Keyword(s):

Neuropathic Pain ◽

Calcium Channels ◽

Nerve Injury ◽

Spared Nerve Injury ◽

Drg Neurons

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The Antiallodynic Action of Pregabalin May Depend on the Suppression of Spinal Neuronal Hyperexcitability in Rats with Spared Nerve Injury

Pain Research and Management ◽

10.1155/2014/623830 ◽

2014 ◽

Vol 19 (4) ◽

pp. 205-211 ◽

Cited By ~ 6

Author(s):

Lei Ding ◽

Jie Cai ◽

Xiang-Yang Guo ◽

Xiu-Li Meng ◽

Guo-Gang Xing

Keyword(s):

Neuropathic Pain ◽

Dorsal Horn ◽

Nerve Injury ◽

Dynamic Range ◽

Inhibitory Effect ◽

Electrophysiological Recording ◽

Spared Nerve Injury ◽

Withdrawal Threshold ◽

Wdr Neurons

BACKGROUND: Pregabalin (PGB) is a novel antiepileptic drug and is also used as a first-line medication for the treatment of neuropathic pain. However, the mechanisms of its analgesic effects remain largely unknown.OBJECTIVES: To elucidate the mechanisms underlying the antiallodynic action of PGB in rats with neuropathic pain.METHODS: In a rat model of neuropathic pain induced by spared nerve injury, mechanical allodynia, as a behavioural sign of neuropathic pain, was assessed by measuring 50% paw withdrawal threshold with von Frey filaments. Activities of dorsal horn wide dynamic range (WDR) neurons were examined by extracellular electrophysiological recording in vivo.RESULTS: Spinal administration of PGB exerted a significant antiallodynic effect and a prominent inhibitory effect on the hypersensitivity of dorsal horn WDR neurons in rats with spared nerve injury.CONCLUSION: The antiallodynic action of PGB is likely dependent on the suppression of WDR neuron hyperexcitability in rats with neuropathic pain.

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Nuclear Factor κB-COX2 Pathway Activation in Non-myelinating Schwann Cells Is Necessary for the Maintenance of Neuropathic Pain in vivo

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.782275 ◽

2022 ◽

Vol 15 ◽

Author(s):

Alison Xiaoqiao Xie ◽

Sarah Taves ◽

Ken McCarthy

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Schwann Cells ◽

Nerve Injury ◽

Glial Cells ◽

Nuclear Factor Κb ◽

Pain Behavior ◽

Nuclear Factor ◽

Nociceptive Neurons

Chronic neuropathic pain leads to long-term changes in the sensitivity of both peripheral and central nociceptive neurons. Glial fibrillary acidic protein (GFAP)-positive glial cells are closely associated with the nociceptive neurons including astrocytes in the central nervous system (CNS), satellite glial cells (SGCs) in the sensory ganglia, and non-myelinating Schwann cells (NMSCs) in the peripheral nerves. Central and peripheral GFAP-positive cells are involved in the maintenance of chronic pain through a host of inflammatory cytokines, many of which are under control of the transcription factor nuclear factor κB (NFκB) and the enzyme cyclooxygenase 2 (COX2). To test the hypothesis that inhibiting GFAP-positive glial signaling alleviates chronic pain, we used (1) a conditional knockout (cKO) mouse expressing Cre recombinase under the hGFAP promoter and a floxed COX2 gene to inactivate the COX2 gene specifically in GFAP-positive cells; and (2) a tet-Off tetracycline transactivator system to suppress NFκB activation in GFAP-positive cells. We found that neuropathic pain behavior following spared nerve injury (SNI) significantly decreased in COX2 cKO mice as well as in mice with decreased glial NFκB signaling. Additionally, experiments were performed to determine whether central or peripheral glial NFκB signaling contributes to the maintenance of chronic pain behavior following nerve injury. Oxytetracycline (Oxy), a blood-brain barrier impermeable analog of doxycycline was employed to restrict transgene expression to CNS glia only, leaving peripheral glial signaling intact. Signaling inactivation in central GFAP-positive glia alone failed to exhibit the same analgesic effects as previously observed in animals with both central and peripheral glial signaling inhibition. These data suggest that the NFκB-COX2 signaling pathway in NMSCs is necessary for the maintenance of neuropathic pain in vivo.

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Thiamine Suppresses Thermal Hyperalgesia, Inhibits Hyperexcitability, and Lessens Alterations of Sodium Currents in Injured, Dorsal Root Ganglion Neurons in Rats

Anesthesiology ◽

10.1097/aln.0b013e3181942f1e ◽

2009 ◽

Vol 110 (2) ◽

pp. 387-400 ◽

Cited By ~ 11

Author(s):

Xue-Song Song ◽

Zhi-Jiang Huang ◽

Xue-Jun Song

Keyword(s):

Neuropathic Pain ◽

Dorsal Root Ganglion ◽

Nerve Injury ◽

Dorsal Root ◽

Thermal Hyperalgesia ◽

B Vitamins ◽

Drg Neurons ◽

Na Currents

Background B vitamins can effectively attenuate inflammatory and neuropathic pain in experimental animals, while their efficacy in treating clinical pain syndromes remains unclear. To understand possible mechanisms underlying B vitamin-induced analgesia and provide further evidence that may support the clinical utility of B vitamins in chronic pain treatment, this study investigated effects of thiamine (B1) on the excitability and Na currents of dorsal root ganglion (DRG) neurons that have been altered by nerve injury. Methods Nerve injury was mimicked by chronic compression of DRG in rats. Neuropathic pain was evidenced by the presence of thermal hyperalgesia. Intracellular and patch-clamp recordings were made in vitro from intact and dissociated DRG neurons, respectively. Results (1) In vivo intraperitoneal administration of B1 (66 mg/kg/day, 10-14 doses) significantly inhibited DRG compression-induced neural hyperexcitability, in addition to suppressing thermal hyperalgesia. (2) In vitro perfusion of B1 (0.1, 1 and 10 mM) resulted in a dose-dependent inhibition of DRG neuron hyperexcitability. In addition, the DRG neurons exhibited size-dependent sensitivity to B1 treatment, i.e., the small and the medium-sized neurons, compared to the large neurons, were significantly more sensitive. (3) Both in vitro (1 mM) and in vivo application of B1 significantly reversed DRG compression-induced down-regulation of tetrodotoxin-resistant but not tetrodotoxin-sensitive Na current density in the small neurons. B1 at 1 mM also reversed the compression-induced hyperpolarizing shift of the inactivation curve of the tetrodotoxin-resistant currents and the upregulated ramp currents in small DRG neurons. Conclusion Thiamine can reduce hyperexcitability and lessen alterations of Na currents in injured DRG neurons, in addition to suppressing thermal hyperalgesia.

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