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Analgesic effect

The analgesic effects of N O are linked to the interaction between the endogenous opioid system and the descending noradrenergic system. When animals are given morphine chronically, they develop tolerance to its pain-killing effects, and this also renders the animals tolerant to the analgesic effects of N O. Administration of antibodies that bind and block the activity of some endogenous opioids (not β-endorphin) also block the antinociceptive effects of N O. Drugs that inhibit the breakdown of endogenous opioids also potentiate the antinociceptive effects of N O. Several experiments have shown that opioid receptor antagonists applied directly to the brain block the antinociceptive effects of N O, but these drugs have no effect when injected into the spinal cord.

Apart from an indirect action, nitrous oxide, like morphine also interacts directly with the endogenous opioid system by binding at opioid receptor binding sites.

Conversely, α -adrenoceptor antagonists block the pain-reducing effects of N O when given directly to the spinal cord, but not when applied directly to the brain. Indeed, α -adrenoceptor knockout mice or animals depleted in norepinephrine are nearly completely resistant to the antinociceptive effects of N O. Apparently N O -induced release of endogenous opioids causes disinhibition of brainstem noradrenergic neurons, which release norepinephrine into the spinal cord and inhibit pain signalling. Exactly how N O causes the release of endogenous opioid peptides remains uncertain.