Sensitization of cat dorsal horn neurons to innocuous mechanical stimulation after intradermal injection of capsaicin

Simone, Donald A.; Baumann, Thomas; Collins, J. G.; LaMotte, Robert H.

doi:10.1016/0006-8993(89)91293-6

Cited by 127 publications

(64 citation statements)

References 17 publications

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“…Thermal hyperalgesia appears to be caused by peripheral sensitization of nociceptors, because it is restricted to the immediate area of injection. In contrast, secondary mechanical allodynia appears to be mediated by central sensitization, because the sensitivity is observed in a much larger area surrounding the site of injection (Simone et al, 1987(Simone et al, , 1989LaMotte et al, 1991). In the present study, oral administration of both A-784168 and A-795614 reversed capsaicin-induced secondary mechanical allodynia but A-784168, with good CNS penetration, was more potent than A-795614.…”

Section: Discussioncontrasting

confidence: 59%

TRPV1 Receptors in the CNS Play a Key Role in Broad-Spectrum Analgesia of TRPV1 Antagonists

Cui

Honoré²,

Zhong³

et al. 2006

J. Neurosci.

293

198

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Vanilloid receptor type 1 (TRPV1) is a ligand-gated nonselective cation channel that is considered to be an important integrator of various pain stimuli such as endogenous lipids, capsaicin, heat, and low pH. In addition to expression in primary afferents, TRPV1 is also expressed in the CNS. To test the hypothesis that the CNS plays a differential role in the effect of TRPV1 antagonists in various types of pain, the analgesic effects of two TRPV1 antagonists with similar in vitro potency but different CNS penetration were compared in vivo. In these models, the potency of the two compounds was similar after intrathecal administration. However, when administered orally, A-784168, with good CNS penetration, was much more potent than A-795614. Together, these results demonstrate that TRPV1 receptors in the CNS play an important role in pain mediated by central sensitization. In addition, these results demonstrate that significant CNS penetration is necessary for a TRPV1 antagonist to produce broad-spectrum analgesia.

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Section: Discussioncontrasting

confidence: 59%

TRPV1 Receptors in the CNS Play a Key Role in Broad-Spectrum Analgesia of TRPV1 Antagonists

Cui

Honoré²,

Zhong³

et al. 2006

J. Neurosci.

293

198

View full text Add to dashboard Cite

show abstract

“…Because excitability increases of spinal second-order neurons have been repeatedly observed in animals following tissue injury, inflammation or chemical irritants (McMahon and Wall, 1984, Cook, et al, 1987, Woolf and King, 1990, Simone, et al, 1991, it has been proposed that prolonged or intense C-nociceptor activation leads to changes in central processing such that nociceptive dorsal horn neurons (i.e. spV in our study) show enhanced responses to Aβ low threshold mechanoreceptors (central sensitization) (Simone, et al, 1989, Woolf and King, 1990, Woolf, et al, 1994.…”

Section: Primary and Secondary Dynamic Mechanical Allodynia Versus Comentioning

confidence: 71%

Mapping the spinal and supraspinal pathways of dynamic mechanical allodynia in the human trigeminal system using cardiac-gated fMRI

et al. 2007

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Following injury and inflammation, pain to light stroking (dynamic mechanical allodynia) might develop at the damaged site (primary area) or in adjacent normal tissue (secondary area).Using fMRI we mapped changes in the spinal trigeminal nucleus (spV), and supraspinal brainstem nuclei following heat/capsaicin-induced primary and secondary dynamic mechanical allodynia in the human trigeminal system. The role of these structures in dynamic mechanical allodynia has not been clarified yet in humans. During the control session we applied the same mechanical stimuli to the same untreated trigeminal area.Primary and secondary mechanical allodynia showed equal levels of perceived pain intensity, and compared to control mechanical stimulation exhibited similar responses in the ipsilateral spV and contralateral ventrolateral periaqueductal gray (vlPAG). Activity in the spV was significantly higher during both conditions versus the control mechanical stimulation, indicating that central sensitization of second-order neurons is similar for primary and secondary mechanical allodynia. The vlPAG showed decreased activity that inversely correlated with pain ratings during primary allodynia, i.e. the more deactivated the vlPAG the higher the pain intensity (p<0.05, Pearson's correlation).Primary and secondary dynamic mechanical allodynia were also characterized by significant differences involving distinct supraspinal structures mainly involved in pain modulation and including the rostroventromedial medulla, pons reticular formation, dorsolateral PAG, all more active during primary versus secondary allodynia, and the medial reticular formation of the caudal medulla that was more active during secondary versus primary allodynia. These results indicate the pain modulatory system is involved to a different extent during primary versus secondary mechanical allodynia.

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“…This hypothesis was validated further in the capsaicin test. Intraplantar injection of capsaicin elicited primary and secondary mechanical allodynia in WT mice, but only the secondary mechanical allodynia, which is mediated by central sensitization (33,34), was attenuated in Casp6 -/-mice (Supplemental Figure 2, A and B). …”

Section: Casp6 Is Localized In Spinal Cord Central Terminals Of Primamentioning

confidence: 99%

Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion

et al. 2014

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Increasing evidence indicates that the pathogenesis of neuropathic pain is mediated through spinal cord microglia activation. The intracellular protease caspase-6 (CASP6) is known to regulate neuronal apoptosis and axonal degeneration; however, the contribution of microglia and CASP6 in modulating synaptic transmission and pain is unclear. Here, we found that CASP6 is expressed specifically in C-fiber axonal terminals in the superficial spinal cord dorsal horn. Animals exposed to intraplantar formalin or bradykinin injection exhibited CASP6 activation in the dorsal horn. Casp6-null mice had normal baseline pain, but impaired inflammatory pain responses. Furthermore, formalin-induced second-phase pain was suppressed by spinal injection of CASP6 inhibitor or CASP6-neutralizing antibody, as well as perisciatic nerve injection of CASP6 siRNA. Recombinant CASP6 (rCASP6) induced marked TNF-α release in microglial cultures, and most microglia within the spinal cord expressed Tnfa. Spinal injection of rCASP6 elicited TNF-α production and microgliadependent pain hypersensitivity. Evaluation of excitatory postsynaptic currents (EPSCs) revealed that rCASP6 rapidly increased synaptic transmission in spinal cord slices via TNF-α release. Interestingly, the microglial inhibitor minocycline suppressed rCASP6 but not TNF-α−induced synaptic potentiation. Finally, rCASP6-activated microglial culture medium increased EPSCs in spinal cord slices via TNF-α. Together, these data suggest that CASP6 released from axonal terminals regulates microglial TNF-α secretion, synaptic plasticity, and inflammatory pain.

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Sensitization of cat dorsal horn neurons to innocuous mechanical stimulation after intradermal injection of capsaicin

Cited by 127 publications

References 17 publications

TRPV1 Receptors in the CNS Play a Key Role in Broad-Spectrum Analgesia of TRPV1 Antagonists

TRPV1 Receptors in the CNS Play a Key Role in Broad-Spectrum Analgesia of TRPV1 Antagonists

Mapping the spinal and supraspinal pathways of dynamic mechanical allodynia in the human trigeminal system using cardiac-gated fMRI

Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion

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