ABSTRACT
Title
Salvinorin A reduce formalin-induced allodynia through spinal glial/microglial phenotypical changes in mice.
Authors
F. Guida1, M. De Chiaro1, G. Aviello2, L. Luongo1, A. Izzo2, M.A. Scafuro1, V de Novellis1, R. Capasso2, S. Maione1.
1 Department of Experimental Medicine, Pharmacology Division, The Second University of Naples
2 Departement of Experimental Pharmacology, University of Naples Federico II
1 Department of Experimental Medicine, Pharmacology Division, The Second University of Naples
2 Departement of Experimental Pharmacology, University of Naples Federico II
Abstract
Chronic untreatable pain is a common disease which often become unbearable and limits the patient's life.
The hallucinogenic compound from Salvia divinorum, salvinorin A is a potent k-opioid receptor (KOR) selective agonist. However, other targets such as the cannabinoid CB1 receptor, have been proposed to explain its pleiotropic pharmacological effects. In the present study we have investigated the anti-allodynic and anti-hyperalgesic properties of salvinorin A on formalin-induced pain behaviours. Moreover, we have investigated the effect of salvinorin A on the glial/microglial-mediated spinal wind-up responsible of the establishment of allodynia. In particular, we have analyzed the microglial and astrocytic phenotypical changes in the dorsal horn of spinal cord at 3, 7 and 14 days after a single intraplantar formalin injection with or without salvinorin A chronic treatment. We have observed that intraplantar injection of formalin (1,25% 100 μl), induced mechanical allodynia and thermal hyperalgesia, peaking at the day 7 after formalin injection. Chronic systemic administration of salvinorin A (2 mg/Kg i.p., once per day) significantly enhanced mechanical and thermal thresholds 3, 7 and 14 days after formalin injection in a way prevented by the nor-binaltorphimine, a selective KOR antagonist, and by the rimonabant, a well established CB1 antagonist pre-treatment. Spinal cord immunohistochemistry revealed that formalin leads to increased number of astrocytes and microglia in the spinal dorsal horn ipsilateral to the paw injection. Both astrocytes and microglial cells appeared activated, hypertrophic cells. Salvinorin A chronic treatment significantly reduced the number of hypertrophic cells in the dorsal horn as compared to the vehicle-treated mice. Reactive gliosis reduction was also associated to the decreased expression of pro-inflammatory markers (inos, IL-1β).
In conclusion our data confirm the ultrapotent anti-inflammatory effect of salvinorin A and evidenced a possible targeted glial/microglial effects of this drug in the spinal cord of chronic pain-affected subjects.
The hallucinogenic compound from Salvia divinorum, salvinorin A is a potent k-opioid receptor (KOR) selective agonist. However, other targets such as the cannabinoid CB1 receptor, have been proposed to explain its pleiotropic pharmacological effects. In the present study we have investigated the anti-allodynic and anti-hyperalgesic properties of salvinorin A on formalin-induced pain behaviours. Moreover, we have investigated the effect of salvinorin A on the glial/microglial-mediated spinal wind-up responsible of the establishment of allodynia. In particular, we have analyzed the microglial and astrocytic phenotypical changes in the dorsal horn of spinal cord at 3, 7 and 14 days after a single intraplantar formalin injection with or without salvinorin A chronic treatment. We have observed that intraplantar injection of formalin (1,25% 100 μl), induced mechanical allodynia and thermal hyperalgesia, peaking at the day 7 after formalin injection. Chronic systemic administration of salvinorin A (2 mg/Kg i.p., once per day) significantly enhanced mechanical and thermal thresholds 3, 7 and 14 days after formalin injection in a way prevented by the nor-binaltorphimine, a selective KOR antagonist, and by the rimonabant, a well established CB1 antagonist pre-treatment. Spinal cord immunohistochemistry revealed that formalin leads to increased number of astrocytes and microglia in the spinal dorsal horn ipsilateral to the paw injection. Both astrocytes and microglial cells appeared activated, hypertrophic cells. Salvinorin A chronic treatment significantly reduced the number of hypertrophic cells in the dorsal horn as compared to the vehicle-treated mice. Reactive gliosis reduction was also associated to the decreased expression of pro-inflammatory markers (inos, IL-1β).
In conclusion our data confirm the ultrapotent anti-inflammatory effect of salvinorin A and evidenced a possible targeted glial/microglial effects of this drug in the spinal cord of chronic pain-affected subjects.