D-limonene exhibits superior antihyperalgesic effects in a β-cyclodextrin-complexed form in chronic musculoskeletal pain reducing Fos protein expression on spinal cord in mice

• Published in: Neuroscience Vol. 358; pp. 158 - 169
• Main Authors: Araújo-Filho, Heitor G., Pereira, Erik W.M., Rezende, Marília M., Menezes, Paula P., Araújo, Adriano A.S., Barreto, Rosana S.S., Martins, Anita O.B.P.B., Albuquerque, Thaís R., Silva, Bruno A.F., Alcantara, Isabel S., Coutinho, Henrique D.M., Menezes, Irwin R.A., Quintans-Júnior, Lucindo J., Quintans, Jullyana S.S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.09.2017
• Subjects: Analgesics - therapeutic use; Animals; beta-Cyclodextrins - therapeutic use; C-Fos; Capsaicin - toxicity; chronic pain; cyclodextrin; Cyclohexenes - therapeutic use; D-limonene; Disease Models, Animal; Drug Combinations; Drug Interactions; fibromyalgia; GABA Agents - therapeutic use; Hyperalgesia - drug therapy; Hyperalgesia - etiology; Male; Mice; monoterpenes; Muscle Strength - drug effects; Muscle Strength - physiology; Musculoskeletal Pain - chemically induced; Musculoskeletal Pain - drug therapy; Musculoskeletal Pain - pathology; Nociception - drug effects; Pain Measurement - drug effects; Pain Measurement - methods; Pain Threshold - drug effects; Proto-Oncogene Proteins c-fos - metabolism; Spinal Cord - drug effects; Spinal Cord - metabolism; Statistics, Nonparametric; Terpenes - therapeutic use; chronic pain; FM; cyclodextrin; FLU; TRM; SC; DSC; fibromyalgia; FTIR; βCD; C-Fos; TRPV1; monoterpenes; GC-MS; D-limonene; LIM; MOR; NMR; CDs; PC; TG; DTG; GABA; NAL; LIM-βCD; PM
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2017.06.037

[Display omitted] •The pharmacological and chemical profile of Limonene (LIM) was improved by βCD.•Slurry complexation was the best method for forming the LIM- βCD complex.•The possible analgesic effect of LIM is modulated in the dorsal horn of the spinal cord. Chronic musculoskeletal pain is one of the main symptoms found in Fibromyalgia with unclear etiology and limited pharmacological treatment. The aim of this study was to complex LIM in β-cyclodextrin (LIM-βCD) and then evaluate its antihyperalgesic effect in an animal model of chronic musculoskeletal pain. Differential scanning calorimetry and scanning electron microscopy was used for the characterization of the inclusion complex. Male Swiss mice were used for experimental procedures where mechanical hyperalgesia, thermal hyperalgesia, muscular strength, Fos immunofluorescence was studied after induction of hyperalgesia. Mechanism of action was also investigated through tail flick test and capsaicin-induced nociception. Endothermic events and morphological changes showed that the slurry complex method was the best method for the complexation. After induction of hyperalgesia, the oral administration of LIM-βCD (50mg/kg) significantly increased the paw withdrawal threshold compared to uncomplexed limonene. Fos immunofluorescence showed that both compounds significantly decreased the number of Fos-positive cells in the dorsal horn. In nociceptive tests, FLU was able to reverse the antinociceptive effect of LIM-βCD. After intraplantar administration of capsaicin, LIM was able to significantly decrease time to lick. LIM-βCD has antihyperalgesic action superior to its uncomplexed form, with possible action in the dorsal horn of the spinal cord. These results suggest the possible applicability of LIM, uncomplexed or complexed with βCD, in conditions such as FM and neuropathic pain, for which there are currently only limited pharmacological options.