QX-314 Induces Analgesia to Nociceptive Thermal Stimulus by Co-Application with Capsiate or Anandamide

Research Article

Austin Biomark Diagn. 2014;1(1): 4.

QX-314 Induces Analgesia to Nociceptive Thermal Stimulus by Co-Application with Capsiate or Anandamide

Nakagawa H1* and Hiura A2

1Pediatric Dentistry, Tokushima University Hospital, Japan

2Department of Oral Histology, University of Tokushima, Japan

*Corresponding author: Nakagawa H, Pediatric Dentistry, Tokushima University Hospital, Tokushima, 3-18-15 Kuramoto cho, Tokushima 770-8054, Japan.

Received: Sep 12, 2014; Accepted: Oct 13, 2014; Published: Oct 14, 2014


Recently, N-ethyl-lidocaine (QX-314) was demonstrated to pass through a nociceptor membrane when the drug was co-applied with capsaicin, thereby leading to analgesia due to selective blockade of a sodium channel associated with the excitability in nociceptors. However, capsaicin induces a pain in the case of injection with QX-314. Therefore this good idea is unfavorable for a clinical therapy. Then, we exam–ined whether non pungent Capsiate (CST) and arachidonylethanolamide (anandamide: AEA) can deliver QX-314 into nociceptive neurons through the pores of Transient Receptor Protein Vanilloid 1 (TRPV1) and contribute to the antinociceptive effect. Dimethyl sulfoxide (DMSO), CST, QX-314, a mixture (combination) of CST and QX-314 (CST/ QX-314), and a combination of AEA and QX-314 (AEA/QX-314) were injected into the hind paws of rats to evaluate anti-noxious heat effect. A long-lasting sensory nerve block (analgesia) was induced by CST/QX-314 or AEA/QX-314. Especially, the CST/QX-314 caused more effective than our previous studies with the combination of capsaicin and QX-314 (CAP/QX-314). The present results also indicate that CST can induce analgesia by itself. The study aimed at developing a new method with substances distinct from capsai–cin to eliminate the action-potential firing in nociceptors (but effective only for pain sensation). As a result, CST is likely to be a potent candidate for pain relief.

Keywords: Anesthetics; Capsiate; Anandamide; QX-314; Noxious heat tests


Local anesthetic can produce reversible suppression of the nerve conduction when applied to the peripheral nociceptors. The drugs block the voltage-gated sodium channel, leading to loss of pain or hypoalgesia in the applied area [1]. An anesthetic lidocaine, well used clinically, is a tertiary amine that possesses a mixed state of prorogated and uncharged base forms under physiological conditions [2]. Because the uncharged hydrophobic form of lidocaine can penetrate all neuronal membranes, it affects on multiple functions other than anesthesia; in addition to numbness by blockade of the low threshold sensory nerve, dyskinesia and insufficient physical conditions occur due to the blockades of motor nerve and the autonomic nerve, respectively.

Binshtok et al [3] devised a new method for pain relief using permanently charged sodium channel blockers such as N-ethyllidocaine (QX-314), a lipophobic lidocaine derivative. QX-314 can block sodium channel when injected directly into the cytoplasm of the cell. On the contrary, when QX-314 was applied extra cellular in a standard local anesthetic, it cannot cut off a sodium channel because of failure to penetrate the membrane by its lipophobic nature [4,5]. However, QX-314is able to selectively enter into nociceptors if coapplied with capsaicin and lead to a preferential blockade of sodium channel responsible for the excitability on nociceptors [3,6]. The pore size of the Transient Receptor Protein Vanilloid 1 (TRPV1) channels, which are opened by capsaicin, is enough to deliver QX-314 into nociceptive sensory neurons [3,6]. Quite recently, the passage of QX- 314 through TRPV1 channel was visually confirmed by use of [5,6] – Carboxyl fluoresce in-conjugated QX-314 [7]. Therefore, the new method without numbness and motor paralysis was expected for a selective blockade of nociception. Since capsaicin produces a pain when it is co-applied with QX-314, this improvable method cannot be recommended for a clinical use. As lidocaine can activate TRPV1 channel, QX-314 was assumed to enter into a nociceptor through TRPV1 channel by co-application with lidocaine [8,9].

Unexpectedly co-application of QX-314 and lidocainecuts off the excitability of various types of neurons other than nociceptors [8,9]. The purpose of this study is to find the material in place of capsaicin to develop a new method in the clinical setting. In the previous studies, we examined the ability of allylisothiocyanate (AITC) and menthol for delivery of QX-314 into nociceptive neurons through the pores of both Transient Receptor Potential Ankyrin 1 (TRPA1) and transient receptor potential melastatin-8 (TRPM8), respectively, and whether they can produce antinociceptive effects or not [7]. The results indicated that AITC (via TRPA1 channel) and melastatin-8 (via TRPM8 channel) are ineffective in the transport of QX-314 compared with capsaicin (via TRPV1 channel) [7]. Therefore, it is meaningful to search a new TRPV1 agonist with no irritation like capsaicin.

For the first time, capsiate (CST) and arachidonylethanolamide (AEA: an andamide) were chosen as candidates. CST is extracted from the fruit of non-pungent cultivar of the pepper (CH-19 Sweet species), and its chemical structure is very similar to capsaicin except the ester bond in substitution for an amide bond between vanillyl structure and fatty acid chains (Figure 1) [10,11]. Therefore, it is called capsinoid different from capsaicinoid as an analog of capsaicin. Iida et al. reported that CST with high lipophilicity is an agonist of TRPV1, exciting peripheral nociceptors when subcutaneously injected into hind paws but not skin of mice [12]. About 20 years ago, AEA was found as a component binding to the cannabinoid receptor in the brain (Figure1)? Continuously, multiple new receptors for AEA were identified such as TRPV1, and demonstrated that AEA has an ability to activate TRPV1 [13]. At present, the AEA is often introduced as “endovanilloid” [13]. The ability of CST and AEA to deliver QX-314 into nociceptive neurons via theTRPV1channel and whether they can produce an antinociceptive effect were investigated in this study.