Differential Effects of Peripheral versus  Central Coadministration of QX-314 and Capsaicin on Neuropathic Pain in Rats

Abstract

Background Neuropathic pain is common and difficult to treat. Recently a technique was developed to selectively inhibit nociceptive inputs by simultaneously applying two drugs: capsaicin, a transient receptor potential vanilloid receptor 1 channel activator and QX-314, a lidocaine derivative that intracellularly blocks sodium channels. We used this technique to investigate whether transient receptor potential vanilloid receptor 1-expressing nociceptors contribute to neuropathic pain. Methods The rat chronic constriction injury model was used to induce neuropathic pain in order to test the analgesic effects of both peripheral (perisciatic) and central (intrathecal) administration of the QX-314/capsaicin combination. The Hargreaves and von Frey tests were used to monitor evoked pain-like behaviors and visual observations were used to rank spontaneous pain-like behaviors. Results Perisciatic injections of the QX-314/capsaicin combination transiently increased the withdrawal thresholds by ~3 fold for mechanical and thermal stimuli in rats (n = 6/group) with nerve injuries suggesting that peripheral transient receptor potential vanilloid receptor 1-expressing nociceptors contribute to neuropathic pain. In contrast, intrathecal administration of the QX-314/capsaicin combination did not alleviate pain-like behaviors (n = 5/group). Surprisingly, intrathecal QX-314 alone (n = 9) or in combination with capsaicin (n = 8) evoked spontaneous pain-like behaviors. Conclusions Data from the perisciatic injections suggested that a component of neuropathic pain was mediated by peripheral nociceptive inputs. The role of central nociceptive terminals could not be determined because of the severe side effects of the intrathecal drug combination. We concluded that only peripheral blockade of transient receptor potential vanilloid receptor 1-expressing nociceptive afferents by the QX-314/capsaicin combination was effective at reducing neuropathic allodynia and hyperalgesia.

Interaction of Local Anesthetics with Biomembranes Consisting of Phospholipids and Cholesterol: Mechanistic and Clinical Implications for Anesthetic and Cardiotoxic Effects

“…Once inside, QX-314 is able to bind to the acting site on sodium channels. Shen et al [118] reported that the peripheral block of nociceptive afferents by QX-314 combined with capsaicin was effective in reducing neuropathic pain. It was also suggested that capsaicin could be applied in combination with bupivacaine and lidocaine instead of QX-314 [119].…”

A novel animal model for testing the in vivo potency of putative local anesthetic compounds

“…Furthermore, it was revealed that QX-314 did not produce any effects on motor fiber function by itself, but it slightly prolonged the effect of lidocaine in agreement with the earlier behavioral studies, which described a potentiated motor paralysis after perisciatic co-administrations of QX-314 with bupivacaine or lidocaine (Binshtok et al, 2009;Brenneis et al, 2014;Roberson et al, 2011). As it was mentioned in the Introduction, QX-314 can produce selective inactivation of VGSCs in sensory neurons by entering the cells through TRPV channels (expressed only in the sensory fibers), therefore, its topical administration alone does not influence the motor functions (Binshtok et al, 2007;Binshtok et al, 2009;Kim et al, 2010;Shen et al, 2012). Until now only one study has recorded the EMG activity from the digastric muscle to painful stimuli of the dental cavity after QX-314 (and/or capsaicin) administration (Kim et al, 2010).…”

Mesenchymal Stem Cells Reversed Morphine Tolerance and Opioid-induced Hyperalgesia

“…Each rat was placed in a box (22 × 12 × 12 cm) containing a smooth glass floor ( Stoelting, Wood Dale, IL, USA )6266. The temperature of the glass was measured and maintained at 27 °C ± 0.5 °C.…”