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
    • "TRPV1 is predominantly expressed in peripheral nociceptive neurons and was originally proposed to primarily mediate inflammatory heat hyperalgesia (Caterina et al., 1997, 2000). Nevertheless, in pharmacological approaches , systemically or centrally applied TRPV1 antagonists also attenuated heat sensitivity in neuropathic and postoperative pain (Pomonis et al., 2003; Vilceanu et al., 2010; Uchytilova et al., 2014). Although mechanistically less clear, there is accumulating evidence on the role of TRPV1 in mechanotransmission. "
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    ABSTRACT: Targeting peripheral neuropathic pain at its origin may prevent the development of hypersensitivity. Recently we showed this can be mediated by opioid receptors at the injured nerve trunk. Here, we searched for the most relevant peripheral site to block transient receptor potential vanilloid 1 (TRPV1), and investigated analgesic interactions between TRPV1 and opioids in neuropathy. In a chronic constriction injury (CCI) of the sciatic nerve in mice, we assessed the effects of μ-, δ- and κ-opioid receptor agonists and TRPV1 antagonist (SB366791) injected at the CCI site or into the injured nerve-innervated paw on spontaneous paw lifting, heat and mechanical sensitivity. We also examined TRPV1 expression in total membrane and plasma membrane fractions from nerves and paws. We found that opioids and SB366791 co-injected in per se nonanalgesic doses at the CCI site or into the paw diminished heat and mechanical sensitivity. SB366791 alone dose-dependently alleviated heat and mechanical sensitivity. TRPV1 blockade in the paw was more effective than at the CCI site. None of the treatments diminished spontaneous paw lifting. TRPV1 expression analysis suggests that the levels of functional TRPV1 do not critically determine the TRPV1 antagonist-mediated analgesia. Together, the identification of the primary action site in damaged nerves is crucial for effective pain control. Contrary to opioids, the TRPV1 blockade in the injured nerve peripheral terminals, rather than at the nerve trunk, appears promising against heat pain. Opioid/TRPV1 antagonist combinations at both locations partially reduced neuropathy-triggered heat and mechanical pain.
    No preview · Article · Oct 2015 · Neuropharmacology
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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.
    Full-text · Article · Dec 2013 · Current Neuropharmacology
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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.
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