Sympathetic activation triggers endogenous opioid release and analgesia within peripheral inflamed tissue

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Abstract
Stress induces analgesia by mechanisms within and outside the brain. Here we show that the sympathetic nervous system is an essential trigger of intrinsic opioid analgesia within peripheral injured tissue. Noradrenaline, injected directly into inflamed hind paws of male Wistar rats, produced dose‐dependent antinociception, reversible by α1‐, α2‐ and β2‐antagonists. α1‐, α2‐ and β2‐adrenergic receptors were demonstrated on β‐endorphin‐containing immune cells and noradrenaline induced adrenergic receptor‐specific release of β‐endorphin from immune cell suspensions. This antinociceptive effect of noradrenaline was reversed by µ‐ and δ‐opioid antagonists as well as by anti‐β‐endorphin. Stress‐induced peripheral analgesia was abolished by chemical sympathectomy and by adrenergic antagonists. These findings indicate that sympathetic neuron‐derived noradrenaline stimulates adrenergic receptors on inflammatory cells to release β‐endorphin, which induces analgesia via activation of peripheral opioid receptors.