Selectively targeting pain in the trigeminal system

Kim, Hyun Yeong; Kim, Kihwan; Li, Hai Ying; Chung, Grace H.; Kim, Joong Soo; Jung, Sung Jun; Lee, Min Kyung; Ahn, Dong Kuk; Hwang, Se Jin; Kang, Youngnam; Binshtok, Alexander M.; Bean, Bruce P.; Woolf, Clifford J.; Oh, Seog Bae

doi:10.1016/j.pain.2010.02.016

Cited by 53 publications

(55 citation statements)

References 32 publications

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“…It is also apparent that at 2 weeks there were enough sensory fibers and sufficient excitability to allow for the decreased painful threshold. Thus, we conclude that the effect of QX-CAP is the result of increased TRPV1 expression in the regenerating neurons and that the effect is targeted blockade of sodium channels via TRPV1 channels as demonstrated in other pain related models [15], [16], [17], [18]. This approach can be used as an effective pain treatment taking into account the time constrains of TRPV1 expression along the timeline of regeneration after nerve injury.…”

Section: Resultsmentioning

confidence: 62%

Expression of TRPV1 Channels after Nerve Injury Provides an Essential Delivery Tool for Neuropathic Pain Attenuation

et al. 2012

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Increased expression of the transient receptor potential vanilloid 1 (TRPV1) channels, following nerve injury, may facilitate the entry of QX-314 into nociceptive neurons in order to achieve effective and selective pain relief. In this study we hypothesized that the level of QX-314/capsaicin (QX-CAP) - induced blockade of nocifensive behavior could be used as an indirect in-vivo measurement of functional expression of TRPV1 channels. We used the QX-CAP combination to monitor the functional expression of TRPV1 in regenerated neurons after inferior alveolar nerve (IAN) transection in rats. We evaluated the effect of this combination on pain threshold at different time points after IAN transection by analyzing the escape thresholds to mechanical stimulation of lateral mental skin. At 2 weeks after IAN transection, there was no QX-CAP mediated block of mechanical hyperalgesia, implying that there was no functional expression of TRPV1 channels. These results were confirmed immunohistochemically by staining of regenerated trigeminal ganglion (TG) neurons. This suggests that TRPV1 channel expression is an essential necessity for the QX-CAP mediated blockade. Furthermore, we show that 3 and 4 weeks after IAN transection, application of QX-CAP produced a gradual increase in escape threshold, which paralleled the increased levels of TRPV1 channels that were detected in regenerated TG neurons. Immunohistochemical analysis also revealed that non-myelinated neurons regenerated slowly compared to myelinated neurons following IAN transection. We also show that TRPV1 expression shifted towards myelinated neurons. Our findings suggest that nerve injury modulates the TRPV1 expression pattern in regenerated neurons and that the effectiveness of QX-CAP induced blockade depends on the availability of functional TRPV1 receptors in regenerated neurons. The results of this study also suggest that the QX-CAP based approach can be used as a new behavioral tool to detect dynamic changes in TRPV1 expression, in various pathological conditions.

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Section: Resultsmentioning

confidence: 62%

Expression of TRPV1 Channels after Nerve Injury Provides an Essential Delivery Tool for Neuropathic Pain Attenuation

et al. 2012

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“…However, it can enter neurons through Transient Receptor Potential Ankyrin 1 (TRPA1) and Transient Receptor Potential Vanilloid 1 (TRPV1) channels that are activated by capsaicin [4], protons [5], and local anesthetics [6] [7], to produce prolonged local anesthesia. Among commonly used local anesthetics, bupivacaine is the most potent one in activating TRPA1 channels.…”

Section: Introductionmentioning

confidence: 99%

The quaternary lidocaine derivative QX-314 in combination with bupivacaine for long-lasting nerve block: Efficacy, toxicity, and the optimal formulation in rats

Yin

Zheng

et al. 2017

PLoS ONE

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ObjectiveThe quaternary lidocaine derivative (QX-314) in combination with bupivacaine can produce long-lasting nerve blocks in vivo, indicating potential clinical application. The aim of the study was to investigate the efficacy, safety, and the optimal formulation of this combination.MethodsQX-314 and bupivacaine at different concentration ratios were injected in the vicinity of the sciatic nerve in rats; bupivacaine and saline served as controls (n = 6~10). Rats were inspected for durations of effective sensory and motor nerve blocks, systemic adverse effects, and histological changes of local tissues. Mathematical models were established to reveal drug-interaction, concentration-effect relationships, and the optimal ratio of QX-314 to bupivacaine.Results0.2~1.5% QX-314 with 0.03~0.5% bupivacaine produced 5.8~23.8 h of effective nerve block; while 0.5% bupivacaine alone was effective for 4 h. No systemic side effects were observed; local tissue reactions were similar to those caused by 0.5% bupivacaine if QX-314 were used < 1.2%. The weighted modification model was successfully established, which revealed that QX-314 was the main active ingredient while bupivacaine was the synergist. The formulation, 0.9% QX-314 plus 0.5% bupivacaine, resulted in 10.1 ± 0.8 h of effective sensory and motor nerve blocks.ConclusionThe combination of QX-314 and bupivacaine facilitated prolonged sciatic nerve block in rats with a satisfactory safety profile, maximizing the duration of nerve block without clinically important systemic and local tissue toxicity. It may emerge as an alternative approach to post-operative pain treatment.

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“…Electrical stimulation of pulpal afferents and recording of the jaw-opening reflex in the form of digastric muscle electromyogram (dEMG) were performed in adult SD rats (300-400 g) as previously described (Kim et al, 2010). Briefly, under urethane anesthesia, a cavity was drilled in the first right mandibular molar.…”

Section: Tooth Pulp Stimulation and Demg Recordingmentioning

confidence: 99%

“…A new approach to local anesthetic has utilized a cocktail containing the charged lidocaine derivative, QX-314, in combination with the TRPV1 receptor agonist capsaicin to block transmission in pain fibers (Binshtok et al, 2007). We have recently used this approach to anesthetize nociceptive neurons selectively while sparing non-nociceptive sensory and motor neurons in the trigeminal system (Kim et al, 2010).…”

mentioning

confidence: 99%

Pain Fiber Anesthetic Reduces Brainstem Fos after Tooth Extraction

Badral¹,

Davies²,

Kim³

et al. 2013

J Dent Res

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We recently demonstrated that pain-sensing neurons in the trigeminal system can be selectively anesthetized by co-application of QX-314 with the TRPV1 receptor agonist, capsaicin (QX cocktail). Here we examined whether this new anesthetic strategy can block the neuronal changes in the brainstem following molar tooth extraction in the rat. Adult male Sprague-Dawley rats received infiltration injection of anesthetic 10 min prior to lower molar tooth extraction. Neuronal activation was determined by immunohistochemistry for the proto-oncogene protein c-Fos in transverse sections of the trigeminal subnucleus caudalis (Sp5C). After tooth extraction, c-Fos-like immunoreactivity (Fos-LI) detected in the dorsomedial region of bilateral Sp5C was highest at 2 hrs (p < .01 vs. naïve ipsilateral) and declined to pre-injury levels by 8 hrs. Pre-administration of the QX cocktail significantly reduced to sham levels Fos-LI examined 2 hrs after tooth extraction; reduced Fos-LI was also observed with the conventional local anesthetic lidocaine. Pulpal anesthesia by infiltration injection was confirmed by inhibition of the jaw-opening reflex in response to electrical tooth pulp stimulation. Our results suggest that the QX cocktail anesthetic is effective in reducing neuronal activation following tooth extraction. Thus, a selective pain fiber 'nociceptive anesthetic' strategy may provide an effective local anesthetic option for dental patients in the clinic.

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Selectively targeting pain in the trigeminal system

Cited by 53 publications

References 32 publications

Expression of TRPV1 Channels after Nerve Injury Provides an Essential Delivery Tool for Neuropathic Pain Attenuation

Expression of TRPV1 Channels after Nerve Injury Provides an Essential Delivery Tool for Neuropathic Pain Attenuation

The quaternary lidocaine derivative QX-314 in combination with bupivacaine for long-lasting nerve block: Efficacy, toxicity, and the optimal formulation in rats

Pain Fiber Anesthetic Reduces Brainstem Fos after Tooth Extraction

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