Nitrous oxide exerts age-dependent antinociceptive effects in Fischer rats

Abstract Nitrous oxide (N 2 O) is an inhalational anesthetic/analgesic gas that has been used for clinical practice for more than a century. While its anesthetic mechanisms remain largely unknown, the underlying analgesic mechanisms are now being unraveled. It has been proposed that N 2 O induces opioid peptide release in the midbrain, leading to the activation of descending noradrenergic inhibitory neurons, which modulates pain processing within the spinal cord. Because descending noradrenergic inhibitory neurons are not functional at birth we posit that N 2 O only becomes an effective analgesic/antinociceptive agent in young patients when the descending noradrenergic inhibitory neurons become fully functional. In the present study, we have examined the age-dependence of N 2 O-induced antinociceptive effects on the formalin test. Fischer rats of various ages (7-, 15-, 19-, 23-, and 29-day-old, and adult) were injected 5% formalin into the hind paw during exposure to 75% N 2 O. Both their behavioral responses and changes in Fos-like immunoreactivity in the spinal cord were assessed as markers of N 2 O's antinociceptive effect. Adult-like antinociceptive responses to N 2 O, both behaviorally and immunohistochemically, were only present in rats older than 3 weeks (23- and 29-day-old). These findings support our hypothesis that N 2 O lacks antinociceptive effects in the very young animals.