Journal of molecular medicine : official organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
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The hallucinogenic compound, salvinorin A, is a potent κ-opioid receptor (KOR) agonist. However, other target(s) than the KOR, such as the cannabinoid CB1 receptor, have been proposed to explain its multiple pharmacological actions. Here, we have evaluated the effect of salvinorin A in lipopolysaccharide (LPS)-stimulated macrophages as well as in models of inflammation in vivo. ⋯ The effect of salvinorin A on nitrite levels was reverted by the opioid antagonist naloxone, the KOR antagonist nor-binaltorphimine and by the CB1 antagonist rimonabant Salvinorin A also prevented KOR and CB1 hyperexpression induced by LPS. In vivo, salvinorin A reduced the LPS- and the carrageenan-induced paw oedema and formalin-induced inflammatory pain, in a nor-binaltorphimine and rimonabant-sensitive manner. It is concluded that salvinorin A-via KORs and CB1 receptors-exerts ultrapotent actions on macrophages and also shows moderate antinflammatory effects in vivo.
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Synaptic plasticity in the spinal cord and the cortex is believed to be important for the amplification of painful information in chronic pain conditions. The investigation of molecular mechanism responsible for maintaining injury-related plastic changes, such as through the study of long-term potentiation in these structures, provides potential novel targets for designing new medicine for chronic pain. Recent studies using integrative neurobiological approaches demonstrate that protein kinase M zeta (PKMζ) maintains pain-induced persistent changes in the anterior cingulate cortex (ACC), and inhibiting PKMζ by ζ-pseudosubstrate inhibitory peptide produces analgesic effects in animal models of chronic pain. We propose that targeting PKMζ, or its up- or downstream signaling proteins, in the ACC may provide novel clinical treatment for chronic pain.