Antihyperalgesic activity of a novel synthesized analogue of lidocaine in diabetic rats Liliana García-Hernández a , Gabriel Navarrete-Vázquez b , María Eva González-Trujano c , Francisco Javier López-Muñoz a and Myrna Déciga-Campos d a Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados Sede Sur, b Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, México, c Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría ‘Ramón de la Fuente Muñiz’, and d Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional Keywords analogue of lidocaine; diabetic painful neuropathy; hyperalgesia; nociception Correspondence Myrna Déciga-Campos, Sección de Estudios de Posgrado e Investigación, Instituto Politécnico Nacional. Plan de San Luis y Díaz Mirón s/n Col. Santo Tomas, Delegación Miguel Hidalgo, México, D.F. 11340, México. E-mail: myrnadeciga@hotmail.com; mdeciga@ipn.com.mx Received June 27, 2012 Accepted December 19, 2012 doi: 10.1111/jphp.12025 Abstract Objectives The purpose of this study was to assess the antinociceptive and anti- hyperalgesic effects of a lidocaine analogue N-(2,6-dichlorophenyl)-2-(4-methyl- 1-piperidinyl)acetamide (LIA). Methods The structure of LIA was established by elemental analysis and compat- ible IR, 1 H NMR, 13 C NMR, and spectral data. Nociceptive and hyperalgesic activ- ity were evaluated in normoglycaemic and streptozocin-induced diabetic rats using the formalin test. Formalin-evoked flinching, an indication of nociception and hyperalgesia, was increased in diabetic rats (using 0.5% formalin) compared with nondiabetic rats (using 1% formalin). Key findings Local administration of LIA into the dorsal surface of the right hind paw (0.18–5.6 mg per paw) significantly reduced the formalin-induced nocicep- tive and hyperalgesic behaviour of nondiabetic and diabetic rat. The antinocicep- tive effect of LIA was higher than that of lidocaine injection, furthermore this effect was higher than that of gabapentin. Conclusions LIA may have potential as a treatment for diabetic hyperalgesia. Further investigations of the antinociceptive mechanisms and the safety of this new compound are necessary. Introduction Neuropathic pain has become a global public health issue, and the most common precipitating cause is diabetes, particularly in patients with poorly controlled blood glucose. [1–3] Several mechanisms have been proposed for the development of diabetic neuropathic pain, including intrac- ellular sorbitol accumulation, production of advanced gly- cosylation end products (AGEs), free radical-mediated oxidative stress, altered essential fatty acid metabolism, and reduction in the level of growth factors. [1] Moreover, nor- malized blood glucose concentration reverses neuropathic pain in some patients. [4] Pharmacological therapies for dia- betic neuropathy, such as antidepressants, anticonvulsants, opioids, antioxidant drugs, and vitamins, fail to relieve the pain adequately, and several of these therapies are able to produce side effects. [3,5,6] Thus, there is a clear medical need for improved treatments. Voltage-gated sodium channels (VGSCs) in sensory neurons play crucial roles in several chronic painful neu- ropathies that arise from peripheral nerve injury. It has been suggested that specific isoforms of VGSCs contribute to painful diabetic neuropathy. [7,8] Local anaesthetics and some other agents that cause a use-dependent blockade of these channels have been effective in the treatment of neuro- pathic pain and diabetic neuropathy. [5,9] Lidocaine is a local anaesthetic and anti-arrhythmic agent that decreases nocic- eption by blocking VGSCs at the peripheral and central levels, including the spinal cord. [10] Lidocaine has been widely used for treatment of several painful clinical condi- tions, and has been frequently prescribed in a patch formu- lation. [11,12] Application of local anaesthetics may lead to nerve damage. Increasing evidence suggests that the risk of neurotoxicity is higher in patients with diabetic peripheral neuropathy. In addition, block duration may be prolonged in neuropathy. There are still concerns about the safety of different local anaesthetics in diabetics undergoing neuro- axial anaesthesia. And Pharmacology Journal of Pharmacy Research Paper © 2013 The Authors. JPP © 2013 Royal Pharmaceutical Society 2013 Journal of Pharmacy and Pharmacology, 65, pp. 689–696 689