Spinal Nerve Ligation in Mouse Upregulates TRPV1 Heat Function in Injured IB4-Positive Nociceptors

Department of Cell Biology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226-0509, USA.
The journal of pain: official journal of the American Pain Society (Impact Factor: 4.01). 12/2009; 11(6):588-99. DOI: 10.1016/j.jpain.2009.09.018
Source: PubMed


Peripheral nerve injury leads to neuropathic pain, but the underlying mechanisms are not clear. The TRPV1 channel expressed by nociceptors is one receptor for noxious heat and inflammatory molecules. Lumbar 4 (L4) spinal nerve ligation (SNL) in mice induced persistent heat hyperalgesia 4 to 10 days after injury. The heat hypersensitivity was completely reversed by the TRPV1 antagonist A-425619. Furthermore, DRG neurons were isolated from the injured L4 ganglia or adjacent L3 ganglia 4 to 10 days after L4 SNL. Whole-cell patch-clamp recordings were performed and heat stimuli (22 degrees C to 50 degrees C/3 s) were applied to the soma. Neurons were classified by soma size and isolectin-B4 (IB4) binding. Among directly injured L4 neurons, SNL increased the percentage of small-diameter IB4-positive neurons that were heat-sensitive from 13% (naive controls) to 56% and conversely decreased the proportion of small IB4-negative neurons that were heat-sensitive from 66% (naive controls) to 34%. There was no change in IB4 binding in neurons from the injured ganglia. Surprisingly, in neurons from the adjacent L3 ganglia, SNL had no effect on the heat responsiveness of either IB4-positive or negative small neurons. Also, SNL had no effect on heat responses in medium-large-diameter neurons from either the injured or adjacent ganglia. PERSPECTIVE: TRPV1 function is upregulated in IB4-positive sensory neurons, and TRPV1 is responsible for the behavioral heat hypersensitivity in the spinal nerve ligation model. Because IB4-positive neurons may contribute to the emotional perception of pain, TRPV1 antagonists, targeting both sensory and affective pain components, could have broad analgesic effects.

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Available from: Cheryl Stucky, Mar 11, 2014
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    • "In a partial infraorbital nerve ligation-induced trigeminal neuropathic pain model, the number of TRPV1-positive trigeminal neurons is also markedly increased [58]. Consistent with enhanced activity of TRPV1 in neuropathic pain, administration of selective TRPV1 inhibitors alleviates SNL-induced heat hyperalgesia and mechanical allodynia [57-60]. Furthermore, the function of TRPV1 at the central terminals of primary afferent neurons in the spinal cord is also up-regulated after sciatic nerve transection in rats [61]. "
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    ABSTRACT: Chronic pain affects billions of lives globally and is a major public health problem in the United States. However, pain management is still a challenging task due to a lack of understanding of the fundamental mechanisms of pain. In the past decades transient receptor potential (TRP) channels have been identified as molecular sensors of tissue damage and inflammation. Activation/sensitization of TRP channels in peripheral nociceptors produces neurogenic inflammation and contributes to both somatic and visceral pain. Pharmacological and genetic studies have affirmed the role of TRP channels in multiple forms of inflammatory and neuropathic pain. Thus pain-evoking TRP channels emerge as promising therapeutic targets for a wide variety of pain and inflammatory conditions.
    Current Neuropharmacology 12/2013; 11(6):652-63. DOI:10.2174/1570159X113119990040 · 3.05 Impact Factor
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    • "Transient receptor potential vanilloid type 1 (TRPV1), an important signal integrator in sensory nociceptors, plays a key role in neuropathic pain [4]. TRPV1 up-regulation contributes to mechanical allodynia and thermal hyperalgisea caused by various nerve injuries, while its antagonists can reverse the allodynia and hyperalgisea [5–7]. Furthermore, TRPV1 is coexpressed with various neuropeptides including calcitonin gene-related peptide (CGRP) in sensory ganglia and small sensory C and Aδ fibers [8, 9]. "
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    ABSTRACT: Neuropathic pain is an intractable problem in clinical practice. Accumulating evidence shows that electroacupuncture (EA) with low frequency can effectively relieve neuropathic pain. Transient receptor potential vanilloid type 1 (TRPV1) plays a key role in neuropathic pain. The study aimed to investigate whether neuropathic pain relieved by EA administration correlates with TRPV1 inhibition. Neuropathic pain was induced by right L5 spinal nerve ligation (SNL) in rats. 2 Hz EA stimulation was administered. SNL induced mechanical allodynia in ipsilateral hind paw. SNL caused a significant reduction of TRPV1 expression in ipsilateral L5 dorsal root ganglia (DRG), but a significant up-regulation in ipsilateral L4 and L6 DRGs. Calcitonin gene-related peptide (CGRP) change was consistent with that of TRPV1. EA alleviated mechanical allodynia, and inhibited TRPV1 and CGRP overexpressions in ipsilateral L4 and L6 DRGs. SNL did not decrease pain threshold of contralateral hind paw, and TRPV1 expression was not changed in contralateral L5 DRG. 0.001, 0.01 mg/kg TRPV1 agonist 6'-IRTX fully blocked EA analgesia in ipsilateral hind paw. 0.01 mg/kg 6'-IRTX also significantly decreased pain threshold of contralateral paw. These results indicated that inhibition of TRPV1 up-regulation in ipsilateral adjacent undamaged DRGs contributed to low frequency EA analgesia for mechanical allodynia induced by spinal nerve ligation.
    Evidence-based Complementary and Alternative Medicine 07/2013; 2013(8):170910. DOI:10.1155/2013/170910 · 1.88 Impact Factor
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    • "We found that WT mice exhibited marked heat hypersensitivity following skin-only incision on POD1 and that the heat sensitivity returned to levels similar to baseline by POD3 (Figure 5a). In order to determine whether TRPV1 mediates the heat hypersensitivity, we conducted the heat behavior assay on WT and TRPV1-deficient (TRPV1 KO) [38] mice with skin-only incisions (Figure 5b). We found that both WT and TRPV1 KO mice become significantly more sensitive to heat compared to their baseline values. "
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    ABSTRACT: Background Mechanisms underlying postoperative pain remain poorly understood. In rodents, skin-only incisions induce mechanical and heat hypersensitivity similar to levels observed with skin plus deep incisions. Therefore, cutaneous injury might drive the majority of postoperative pain. TRPA1 and TRPV1 channels are known to mediate inflammatory and nerve injury pain, making them key targets for pain therapeutics. These channels are also expressed extensively in cutaneous nerve fibers. Therefore, we investigated whether TRPA1 and TRPV1 contribute to mechanical and heat hypersensitivity following skin-only surgical incision. Results Behavioral responses to mechanical and heat stimulation were compared between skin-incised and uninjured, sham control groups. Elevated mechanical responsiveness occurred 1 day post skin-incision regardless of genetic ablation or pharmacological inhibition of TRPA1. To determine whether functional changes in TRPA1 occur at the level of sensory neuron somata, we evaluated cytoplasmic calcium changes in sensory neurons isolated from ipsilateral lumbar 3–5 DRGs of skin-only incised and sham wild type (WT) mice during stimulation with the TRPA1 agonist cinnamaldehyde. There were no changes in the percentage of neurons responding to cinnamaldehyde or in their response amplitudes. Likewise, the subpopulation of DRG somata retrogradely labeled specifically from the incised region of the plantar hind paw showed no functional up-regulation of TRPA1 after skin-only incision. Next, we conducted behavior tests for heat sensitivity and found that heat hypersensitivity peaked at day 1 post skin-only incision. Skin incision-induced heat hypersensitivity was significantly decreased in TRPV1-deficient mice. In addition, we conducted calcium imaging with the TRPV1 agonist capsaicin. DRG neurons from WT mice exhibited sensitization to TRPV1 activation, as more neurons (66%) from skin-incised mice responded to capsaicin compared to controls (46%), and the sensitization occurred specifically in isolectin B4 (IB4)-positive neurons where 80% of incised neurons responded to capsaicin compared to just 44% of controls. Conclusions Our data suggest that enhanced TRPA1 function does not mediate the mechanical hypersensitivity that follows skin-only surgical incision. However, the heat hypersensitivity is dependent on TRPV1, and functional up-regulation of TRPV1 in IB4-binding DRG neurons may mediate the heat hypersensitivity after skin incision injury.
    Molecular Pain 03/2013; 9(1):9. DOI:10.1186/1744-8069-9-9 · 3.65 Impact Factor
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