Spinal Noradrenergic Terminal System Mediates Antinociception

Intrathecal administration of norepinephrine (NE) into the lumbar subarachnoid space of rats and cats implanted with chronic spinal catheters produced a strong, dose-dependent, behaviorally defined analgesia. The effect appeared mediated by an alpha-receptor inasmuch as phenylephrine, but not isoproterenol produced the intrathecal effect. Moreover, the antinociceptive effect of NE was antagonized by the prior systemic or intrathecal administration of phentolamine (an alpha-blocker), but was unaffected by pretreatment with propranolol (a beta-blocker). The effect of intrathecal NE was significantly potentiated by prior administration of Lilly 51641 (a monoamine oxidase inhibitor) and protriptyline (a re-uptake inhibitor), and was not antagonized by the intrathecal administration of a non-specific vasodilator, papaverine. The antinociceptive effect of intrathecal NE showed tachyphylaxis following repeated injections. No cross-tolerance between intrathecal NE and morphine was observed, suggesting that the spinal action of morphine is not mediated by spinal noradrenergic terminals. Importantly, naloxone had no effect on the intrathecal NE effect. The present data provide further evidence for the modulatory role of a spinal noradrenergic system on the spinal processing of nociceptive transmission.