Salvinorin A Reduces Mechanical Allodynia and Spinal Neuronal Hyperexcitability Induced by Peripheral Formalin Injection

Guida, Francesca; Luongo, Livio; Aviello, Gabriella; Palazzo, Enza; Chiaro, Maria De; Gatta, Luisa Benerini; Boccella, Serena; Marabese, Ida; Zjawiony, Jordan K.; Capasso, Raffaele; Izzo, Angelo A.; Novellis, Vito de; Maione, Sabatino

doi:10.1186/1744-8069-8-60

Cited by 51 publications

(51 citation statements)

References 57 publications

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“…While its hallucinogenic properties (Valdés et al, 1983) and short duration of action (Butelman et al, 2009; Prisinzano, 2005; Ranganathan et al, 2012; Teksin et al, 2009) limit its clinical usefulness, SalA has proven preclinical analgesic and anti-inflammatory properties (Aviello et al, 2011; Fichna et al, 2012; Guida et al, 2012; John et al, 2006; McCurdy et al, 2006; Rossi et al, 2016). As a KOPr agonist, SalA is structurally unique and structure–activity studies have shown that the C-2 position of SalA is important for binding to KOPr and metabolic stability (Chavkin et al, 2004; Prisinzano, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Salvinorin A (SalA) is a potent, selective KOPr agonist isolated from the plant Salvia divinorum (Chavkin et al, 2004; Roth et al, 2002). In mice, SalA has anti-nociceptive effects in the tail-withdrawal, hot-plate (McCurdy et al, 2006), abdominal constriction and formalin footpad models (Guida et al, 2012; McCurdy et al, 2006). Whilst SalA has reduced side-effects compared to traditional KOPr agonists, the short duration of action limits its usefulness (Butelman et al, 2009; Prisinzano, 2005; Ranganathan et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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The analgesic and anti‐inflammatory effects of Salvinorin A analogue β‐tetrahydropyran Salvinorin B in mice

Paton

Kumar

Crowley

et al. 2017

European Journal of Pain

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Background Drugs activating the mu opioid receptor are routinely used to treat severe acute and chronic pain. Unfortunately, side effects including nausea, constipation, respiratory depression, addiction and tolerance can limit clinical utility. In contrast, kappa opioid receptor (KOPr) agonists, such as Salvinorin A (SalA), have analgesic properties with little potential for abuse. Methods We evaluated SalA and the novel analogue β-tetrahydropyran Salvinorin B (β-THP SalB) for the ability to modulate pain and inflammation in vivo. The hot water tail-withdrawal assay, intradermal formalin-induced inflammatory pain and paclitaxel-induced neuropathic pain models were used to evaluate analgesic properties in mice. Tissue infiltration of inflammatory cells was measured by histology and flow cytometry. Results β-THP SalB produced a longer duration of action in the tail-withdrawal assay compared to the parent compound SalA, and, like SalA and U50,488, β-THP SalB is a full agonist at the KOPr. In the formalin-induced inflammatory pain model, β-THP SalB and SalA significantly reduced pain score, paw oedema and limited the infiltration of neutrophils into the inflamed tissue. β-THP SalB and SalA supressed both mechanical and cold allodynia in the paclitaxel-induced neuropathic pain model, in a dose-dependent manner. Conclusions Structural modification of SalA at the C-2 position alters its analgesic potency and efficacy in vivo. Substitution with a tetrahydropyran group at C-2 produced potent analgesic and anti-inflammatory effects, including a reduction in paclitaxel-induced neuropathic pain. This study highlights the potential for KOPr agonists as analgesics with anti-inflammatory action and little risk of abuse.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The analgesic and anti‐inflammatory effects of Salvinorin A analogue β‐tetrahydropyran Salvinorin B in mice

Paton

Kumar

Crowley

et al. 2017

European Journal of Pain

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“…In vivo electrophysiology was performed as previously reported (Gatta et al, ; Guida et al, ). On the day of the electrophysiological recording experiments, mice were initially anesthetized with sodium pentobarbital (50 mg/kg, intraperitoneally).…”

Section: Methodsmentioning

confidence: 99%

The A1 adenosine receptor as a new player in microglia physiology

Luongo

Guida

Imperatore

et al. 2013

Glia

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The purinergic system is highly involved in the regulation of microglial physiological processes. In addition to the accepted roles for the P2 X4,7 and P2 Y12 receptors activated by adenosine triphosphate (ATP) and adenosine diphosphate, respectively, recent evidence suggests a role for the adenosine A2A receptor in microglial cytoskeletal rearrangements. However, the expression and function of adenosine A1 receptor (A1AR) in microglia is still unclear. Several reports have demonstrated possible expression of A1AR in microglia, but a new study has refuted such evidence. In this study, we investigated the presence and function of A1AR in microglia using biomolecular techniques, live microscopy, live calcium imaging, and in vivo electrophysiological approaches. The aim of this study was to clarify the expression of A1AR in microglia and to highlight its possible roles. We found that microglia express A1AR and that it is highly upregulated upon ATP treatment. Moreover, we observed that selective stimulation of A1AR inhibits the morphological activation of microglia, possibly by suppressing the Ca(2+) influx induced by ATP treatment. Finally, we recorded the spontaneous and evoked activity of spinal nociceptive-specific neuron before and after application of resting or ATP-treated microglia, with or without preincubation with a selective A1AR agonist. We found that the microglial cells, pretreated with the A1AR agonist, exhibit lower capability to facilitate the nociceptive neurons, as compared with the cells treated with ATP alone.

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“…S. divinorum is actually primarily used by adolescent and young adults for its hallucinogenic properties with a prevalence of use ranging, for example, from 1.3% among adults in the USA to 11% of attendees to rave musical events in Italy (Mahendran et al, 2016). The main active ingredient of the plant is the neoclerodane diterpenoid Salvinorin A. Pharmacodynamic studies have shown that Salvinorin A is a potent and selective kappa opioid receptor agonist (Roth et al, 2002; Chavkin et al, 2004), may exert CB1-like effects, without being able to activate such receptors (Braida et al, 2007; Capasso et al, 2008; Fichna et al, 2012; Guida et al, 2012). In addition Salvinorin A has demonstrated to exert anti-inflammatory actions (Aviello et al, 2011; Rossi et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

et al. 2017

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Salvinorin A, a neoclerodane diterpene isolated from Salvia divinorum, exerts a number of pharmacological actions which are not solely limited to the central nervous system. Recently it has been demonstrated that Salvinorin A inhibits acute inflammatory response affecting leukotriene (LT) production. Since LTs are potent lipid mediators implicated in allergic diseases, we evaluated the effect of Salvinorin A on allergic inflammation and on airways following sensitization in the mouse. Mice were sensitized with s.c. injection of ovalbumin (OVA) on days 1 and 8. Sensitized mice received on days 9 and 12 on the shaved dorsal surface air administration to induce the development of the air-pouches. On day 15 animals were challenged by injection of OVA into the air-pouch. Salvinorin A, administered (10 mg/kg) before each allergen exposure, significantly reduced OVA-induced LT increase in the air pouch. This effect was coupled to a reduction in cell recruitment and Th2 cytokine production. In another set of experiments, mice were sensitized with OVA and both bronchial reactivity and pulmonary inflammation were assessed. Salvinorin A abrogated bronchial hyperreactivity and interleukin (IL)-13 production, without effect on pulmonary inflammation. Indeed cell infiltration and peribronchial edema were still present following diterpenoid treatment. Similarly, pulmonary IL-4 and plasmatic IgE levels were not modulated. Conversely, Salvinorin A significantly reduced LTC4 production in the lung of sensitized mice. Finally mast cell activity was evaluated by means of toluidine blue staining. Data obtained evidenced that Salvinorin A significantly inhibited mast cell degranulation in the lung. Our study demonstrates that Salvinorin A inhibits airway hyperreactivity induced by sensitization by inhibition of LT production and mast cell degranulation. In conclusion Salvinorin A could represent a promising candidate for drug development in allergic diseases such as asthma.

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Salvinorin A Reduces Mechanical Allodynia and Spinal Neuronal Hyperexcitability Induced by Peripheral Formalin Injection

Cited by 51 publications

References 57 publications

The analgesic and anti‐inflammatory effects of Salvinorin A analogue β‐tetrahydropyran Salvinorin B in mice

The analgesic and anti‐inflammatory effects of Salvinorin A analogue β‐tetrahydropyran Salvinorin B in mice

The A1 adenosine receptor as a new player in microglia physiology

Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

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