Antihyperalgesic activity of a mexicanolide isolated from Swietenia humilis extract in nicotinamide-streptozotocin hyperglycemic mice Berenice Ovalle-Magallanes a , Myrna Déciga-Campos b, *, Rachel Mata a, ** a Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, 04510, Mexico b Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, 11340, Mexico A R T I C L E I N F O Article history: Received 15 March 2017 Received in revised form 2 May 2017 Accepted 15 May 2017 Keywords: Swietenia humilis 2-Hydroxy-destigloyl-6-deoxyswietenine acetate Antihyperalgesia Hyperalgesia Diabetes Formalin A B S T R A C T Swietenia humilis Zucc. (Meliaceae) seeds are used in Mexico for the treatment of type 2 diabetes mellitus. Mexicanolides are the main hypoglycemic and antihyperglycemic compounds of the species. This study was conducted to investigate the antihyperalgesic effect of an aqueous extract of the seeds of Swietenia humilis (SHAE) and of mexicanolide 2-hydroxy-destigloyl-6-deoxyswietenine acetate (1), using the formalin test in mice. The antihyperalgesic actions of SHAE and mexicanolide 1, as well as its possible transductional activity, were assessed in nicotinamide-streptozotocin (NA-STZ) hyperglycemic mice. Local injection of SHAE (10–177 mg) and mexicanolide 1 (0.5–3.5 mg) exhibited concentration-dependent antihyperalgesic action in NA-STZ hyperglycemic mice. Ketanserin (6 mg), a 5-HT 2A/C receptor antagonist, and flumazenil (6 mg), a GABA A receptor antagonist, abolished the antihyperalgesic effect of mexicanolide 1 (3 mg). On the other hand, naloxone (3 mg), L-arginine (50 mg), and Nv-Nitro-L-arginine methyl ester hydrochloride (150 mg) diminished the antihyperalgesic effect of mexicanolide 1. The aqueous extract of the seeds possesses significant antihyperalgesic action. Compound 1 produces antihyperalgesia through GABA A , 5-HT 2A/C and opioid receptors. Also, the nitrergic system is involve in the antihyperalgesic effect of 1. Data obtained with Swietenia humilis Zucc. seeds give evidence of its potential for pain associated with diabetes treatment. © 2017 Published by Elsevier Masson SAS. 1. Introduction Peripheral neuropathies are complex and heterogeneous complications that affect half of diabetic patients, who experience sensorial changes in feet and hands such as numbness or tickling. In addition, some of them suffer a non-localized type of pain, particularly during night. Peripheral neuropathies are conse- quence of chronic hyperglycemia, which triggers the production of advanced glycation end products (AGEs), and prostaglandins; in consequence damage of peripheral and central neurons occurs [1– 3]. Pharmacological treatment of diabetic peripheral neuropathies is symptomatic, and includes antidepressant drugs, anticonvul- sants, and opiates [4]. Alternative remedies comprise acupuncture and medicinal plants derivatives, which have a long history of use to treat painful disorders. Medicinal plants preparations, complex in nature, can exert their action interacting with multiple targets (polyvalence), therefore they are a good alternative to develop integral therapies that could reduce diabetic neuropathies and ameliorate hyperglycemia [5]. In this context, we have previously demonstrated that an aqueous extract of the seeds of Swietenia humilis Zucc. (Meliaceae), a medicinal species used in Mexico to treat diabetes, and several mexicanolides isolated from the plant, possessed antidiabetic properties [6]. Herein, we present the results of a study undertaken to assess the antihyperalgesic activities of this extract, and the potential antihyperalgesic effect and mode of action of mexicanolides by testing 2-hydroxy- destigloyl-6-deoxyswietenine acetate (1) using the formalin test in nicotinamide-streptozotocin hyperglycemic mice. 2. Materials and methods 2.1. Chemicals 1-H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, 3-morpholino- sydnonimine hydrochloride, dimethyl sulfoxide, flumazenil, * Corresponding author at: Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n Col. Santo Tomas, Delegación Miguel Hidalgo, México D.F. 11340, Mexico. ** Corresponding author at: Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Delegación Coyoacán, México D.F. 04510, Mexico. E-mail addresses: myrnadeciga@hotmail.com, mdeciga@ipn.com.mx (M. Déciga-Campos), rachel@unam.mx (R. Mata). http://dx.doi.org/10.1016/j.biopha.2017.05.073 0753-3322/© 2017 Published by Elsevier Masson SAS. Biomedicine & Pharmacotherapy 92 (2017) 324–330 Available online at ScienceDirect www.sciencedirect.com