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Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain.

ABSTRACT: The peripheral terminals of primary nociceptive neurons play an essential role in pain detection mediated by membrane receptors like TRPV1, a molecular sensor of heat and capsaicin. However, the contribution of central terminal TRPV1 in the dorsal horn to chronic pain has not been investigated directly. Combining primary sensory neuron-specific GCaMP3 imaging with a trigeminal neuropathic pain model, we detected robust neuronal hyperactivity in injured and uninjured nerves in the skin, soma in trigeminal ganglion, and central terminals in the spinal trigeminal nucleus. Extensive TRPV1 hyperactivity was observed in central terminals innervating all dorsal horn laminae. The central terminal TRPV1 sensitization was maintained by descending serotonergic (5-HT) input from the brainstem. Central blockade of TRPV1 or 5-HT/5-HT3A receptors attenuated central terminal sensitization, excitatory primary afferent inputs, and mechanical hyperalgesia in the territories of injured and uninjured nerves. Our results reveal central mechanisms facilitating central terminal sensitization underlying chronic pain.

SUBMITTER: Kim YS

PROVIDER: S-EPMC3943838 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain.

Kim Yu Shin YS Chu Yuxia Y Han Liang L Li Man M Li Zhe Z LaVinka Pamela Colleen PC Sun Shuohao S Tang Zongxiang Z Park Kyoungsook K Caterina Michael J MJ Ren Ke K Dubner Ronald R Wei Feng F Dong Xinzhong X

Neuron 20140123 4

The peripheral terminals of primary nociceptive neurons play an essential role in pain detection mediated by membrane receptors like TRPV1, a molecular sensor of heat and capsaicin. However, the contribution of central terminal TRPV1 in the dorsal horn to chronic pain has not been investigated directly. Combining primary sensory neuron-specific GCaMP3 imaging with a trigeminal neuropathic pain model, we detected robust neuronal hyperactivity in injured and uninjured nerves in the skin, soma in t ...[more]

PMID: 24462040

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Project description:BackgroundCentral sensitization is considered a key mechanism underlying neuropathic pain (NP) after spinal cord injury (SCI).MethodsTwo novel proxies for central sensitization were investigated in thoracic SCI subjects with (SCI-NP) and without NP (SCI-nonNP) compared to healthy controls (HC). Specifically, temporal summation of pain (TSP) was investigated by examining pain ratings during a 2-min tonic heat application to the volar forearm. Additionally, palmar heat-induced sympathetic skin responses (SSR) were recorded in order to reveal changes in pain-autonomic interaction above the lesion level. Pain extent was assessed as the percentage of the body area and the number of body regions being affected by NP.ResultsEnhanced TSP was observed in SCI-NP (+66%) compared to SCI-nonNP (-75%, p = 0.009) and HC (-59%, p = 0.021). In contrast, no group differences were found (p = 0.685) for SSR habituation. However, pain extent in SCI-NP was positively correlated with deficient SSR habituation (body area: r = 0.561, p = 0.024; body regions: r = 0.564, p = 0.023).ConclusionsThese results support the value of TSP and heat-induced SSRs as proxies for central sensitization in widespread neuropathic pain syndromes after SCI. Measures of pain-autonomic interaction emerged as a promising tool for the objective investigation of sensitized neuronal states in chronic pain conditions.SignificanceWe present two surrogate readouts for central sensitization in neuropathic pain following SCI. On the one hand, temporal summation of tonic heat pain is enhanced in subjects with neuropathic pain. On the other hand, pain-autonomic interaction reveals potential advanced measures in chronic pain, as subjects with a high extent of neuropathic pain showed diminished habituation of pain-induced sympathetic measures. A possible implication for clinical practice is constituted by an improved assessment of neuronal hyperexcitability potentially enabling mechanism-based treatment.

Project description:Despite accumulating evidence on a role of immune cells and their associated chemicals in mechanisms of pain, few studies have addressed the potential role of chemokines in the descending facilitation of persistent pain. The present study was undertaken to test the hypothesis that the chemokine (C-C motif) ligand 2 (CCL2) (commonly known as monocyte chemoattractant protein-1) signaling in the rostral ventromedial medulla (RVM), a pivotal structure in brainstem pain modulatory circuitry, is involved in descending pain facilitation in rats.An L5 spinal nerve ligation (SNL) was produced in rats under pentobarbital anesthesia. Western blot and immunohistochemistry were used to detect the expression levels of CCL2 and CCL2 receptor (CCR2), and examine their distributions compared with the neuronal marker NeuN as well as glial markers glial fibrillary acidic protein (GFAP, astroglial) and CD11b (microglial), respectively.SNL induced an increase in CCL2 expression in the RVM, and this returned to the control level at 4 weeks after injury. The induced CCL2 colocalized with NeuN, but not with GFAP and CD11b. CCR2 was also upregulated by SNL in the RVM, and this increase lasted for at least 4 weeks. CCR2 was colocalized with CD11b but not GFAP. Few RVM neurons also exhibited CCR2 staining. Neutralizing CCL2 with an anti-CCL2 antibody (0.2-20 ng) or injecting RS-102895 (0.1-10 pmol), a CCR2b chemokine receptor antagonist, into the RVM on day 1 after SNL, significantly attenuated the established thermal and mechanical hypersensitivity. In addition, injection of recombinant rat CCL2 (0.03-3 pmol) into the RVM induced dose-dependent hyperalgesia, which was prevented by pretreatment with RS-102895 (10 pmol). Interleukin-1β (IL-1β), a potent inducer of neuronal CCL2, was also selectively upregulated in RVM reactive astrocytes. Injection of IL-1β (120 fmol) into the RVM induced behavioral hyperalgesia, which was blocked by RS-102895 (10 pmol). However, an IL-1 receptor antagonist (3 pmol) did not prevent CCL2 (3 pmol)-induced hyperalgesia. These results suggest that the effect of CCL2 is downstream to IL-1β signaling.The IL-1β and CCL2-CCR2 signaling cascades play a role in neuron-glia-cytokine interactions and the descending facilitation of neuropathic pain.

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Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain.

Publications

Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain.

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