Effects of systemic administration of lidocaine and QX-314 on hyperexcitability of spinal dorsal horn neurons after incision in the rat

Abstract

Although systemic lidocaine has been shown to suppress postoperative pain in a clinical setting, the mechanisms of action of lidocaine have not been elucidated. The present study was therefore designed to determine the relative contribution of central and peripheral sites to the action of lidocaine on incision-induced hyperexcitation of spinal dorsal horn (SDH) neurons in the rat. Receptive field (RF) areas, spontaneous activities, and responses of single wide-dynamic-range (WDR) neurons of the SDH to nonnoxious and noxious stimuli were recorded before and after longitudinal incisions of 1cm through the skin, fascia, and muscle had been made in the center of their RFs of the hindquarters. Significant increases in spontaneous activities, RF sizes, and responses of WDR neurons to both nonnoxious and noxious stimuli were observed at 30 min after the incision (P<0.001). Systemic administration of lidocaine (1 mg/kg bolus plus 0.5 mg/kg/h and 2 mg/kg bolus plus 1 mg/kg/h) and QX-314 (1mg/kg bolus plus 0.5 mg/kg/h and 2 mg/kg bolus plus 1 mg/kg/h) significantly but temporarily suppressed and reversed the increases in spontaneous activity, responses to nonnoxious, and noxious stimuli and RF sizes (P<0.01). Systemic administration of the same doses of lidocaine and QX-314 did not affect responses of WDR neurons to nonnoxious or noxious stimuli or their RF sizes in sham-operated animals in which an incision had not been made. The results suggest that systemic administration of lidocaine has suppressive effects on postoperative pain mainly through peripheral sites of action.

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

“…This result is consistent with the observations that QX-314 alone produced long lasting local anesthesia at similar concentrations to lidocaine, 16,49,69–71 and reduced the hyperexcitability of dorsal root ganglion neurons in two different pain models. 72,73 Therefore, QX-314 is either capable of acting at extracellular sites or entering cells by mechanisms that are independent of TRPV1 channel activation.…”

A comparison of the systemic toxicity of lidocaine versus its quaternary derivative QX-314 in mice

“…Several authors have suggested that QX-314 does not cross the blood-brain barrier, or if it does, it does so extremely slowly. 24,25 Since the CNS effects in response to QX-314 still occurred relatively quickly after injection, it is theoretically possible that observed convulsions may have been due in part to QX-314 having caused cerebral hypoxia secondary to cardiac toxicity rather than due to direct action of QX-314 in the brain. Supportive of this possibility would be our findings that the majority of animals with evidence of CNS toxicity following QX-314 injection died within three minutes, whereas all animals injected with lidocaine recovered fully.…”

Mecanismos envolvidos na analgesia da lidocaína por via venosa

“…Data in the literature indicate that central sensitization, resulting from tissue damage, would be minimized by intravenous lidocaine in different levels of the nervous system (peripheral and central), depending on the tissue damaged. For example, incision of rat skin (skin is an example of somatic tissue) resulted in a decrease of the receptive field of peripheral nociceptive stimuli and did not reduce the response of spinal wide-dynamic-range neurons to this stimulus 14 , suggesting a peripheral anti-hyperalgic action of lidocaine in this model of pain 14 . As for acute neuropathic pain secondary to spinal cord trauma, it was blocked by the intravenous administration of lidocaine, through the action of this drug on Na + channels and blockade of the central hyperexcitability 15 .…”

“…Dados da literatura levam a crer que a sensibilização central resultante de lesão do tecido seria minimizada pela lidocaína por via venosa em diferentes níveis do sistema nervoso (periférico ou central), dependendo do tecido lesado. Por exemplo, a incisão da pele em ratos (pele é exemplo de tecido somático) resultou em diminuição do campo de recepção de estímulos perifé-ricos nociceptivos e não diminuiu a resposta dos neurônios espinais wide-dynamic-range em resposta a esse estímu-lo 14 , sugerindo uma ação anti-hiperalgésica periférica da lidocaína nesse modelo de dor 14 . Já, a dor neuropática aguda secundária ao trauma da medula espinal foi bloqueada pela administração de lidocaína por via venosa pela ação em canais de Na + e bloqueio da hiperexcitabilidade central 15 .…”