Differential effects of neurotoxic destruction of descending noradrenergic pathways on acute and persistent nociceptive processing

Abstract

Although many pharmacological studies indicate that bulbospinal noradrenergic projections contribute to antinociception, lesions of the major brainstem noradrenergic cell groups have provided conflicting evidence. Here we used a new immunotoxin, anti-dopamine beta-hydroxylase-saporin, to re-examine the contribution of noradrenergic pathways to nociception and to morphine analgesia. We treated rats intrathecally by lumbar puncture with the immunotoxin and examined dopamine beta-hydroxylase (DbetaH) immunoreactivity seven and 14 days after treatment. There was no change in DbetaH staining at 7 days; however, 14 days after treatment we demonstrated significant destruction of noradrenergic neurons in the locus coeruleus and in the A5 and A7 cell groups. There was a concomitant loss of noradrenergic axons in the dorsal and ventral horns of the lumbosacral and cervical cord. Consistent with the lack of anatomical changes, we found no difference in nociceptive responses in the hot-plate, tail-flick or formalin tests one week post-toxin. On day 14 we examined the behavioral response to injection of formalin into the hindpaw and found that responses during the second phase of pain behavior were significantly reduced. There was no change during the first phase. Formalin-evoked fos expression in the spinal cord was also reduced. We also evaluated morphine analgesia in the formalin test and found that toxin-treated animals exhibited enhanced morphine analgesia. These results establish the utility of using this immunotoxin to selectively destroy subpopulations of noradrenergic cell groups and provide evidence that acute and persistent nociception are differentially regulated by descending noradrenergic pathways.

Temporal and Spatial Profiles of Pontine-Evoked Monoamine Release in the Rat's Spinal Cord

“…The ubiquity of this spinal innervation explains the robust locus ceruleus-evoked monoamine release found in most of the laminae presently examined. Furthermore spinal noradrenergic terminals have been reported to show greater density in lamina I, the intermediolateral column at the lateral edge of the border between laminae VI and VII, and the motor neuron pools of the ventral horn (lamina IX) (Clarke and Proudfit 1991a,b;Fuxe et al 1990;Grzanna and Fritschy 1991;Martin et al 1999;Westlund et al 1982). The laminar differences observed here in monoamine release patterns to some extent reflect these anatomical differences.…”

“…Their terminals are found throughout the spinal gray matter, although they are more concentrated in the superficial dorsal horn, the intermediolateral column, and near motor neurons (Clark and Proudfit 1991a,b;Fuxe et al 1990;Grzanna and Fritschy 1991;Martin et al 1999;Westlund et al 1982). The time course and spatial pattern of pontine-evoked changes in norepinephrine concentration in the spinal cord are not well known.…”

Role of endogenous sleep‐wake and analgesic systems in anesthesia

“…The analgesic functions of the vlPAG and the RVM are partially mediated by descending serotoninergic and noradrenergic systems (Brodie and Proudfit, 1984;Barbaro et al, 1985;Jensen and Yaksh, 1986). Three pontine noradrenergic cell groups (A5-7) that receive input from the vlPAG (Bajic et al, 2001) and project to the spinal dorsal horn (Clark and Proudfit, 1992) have been reported to modulate endogenous antinociception (Martin et al, 1999) and to mediate antinociceptive effects of morphine (Sawynok and Reid, 1987), nitrous oxide (Sawamura et al, 2000), and isoflurane (Kingery (Tomemori et al, 1981;Crisp et al, 1991), the pontine noradrenergic descending projection is also thought to mediate the antinociceptive effects of ketamine.We therefore hypothesized that a key mechanism of action for both classes of anesthetics may be to engage endogenous brain systems that control sedation and analgesia. To explore those possibilities, we examined Fos immunoreactivity throughout the brain, with particular attention to the sleep-wake regulatory system and to the descending A5-7 noradrenergic neurons following administration of anesthetics.…”

The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline

“…Although acute lesions or inhibition of noradrenergic spinal afferents produce a state of hyperalgesia and reduced antinociceptive effects of opiates (2,10,12), the increased pain behavior abates over time. In fact, long-term effects of noradrenergic denervation have been reported to result in decreased pain behavior, whereas the antinociceptive effect of morphine is either reduced, unchanged, or increased (13)(14)(15)(16)(17). These conflicting results can be caused in part by the variability in the extent of the removal of noradrenergic neurons or terminals which, when using a neurotoxin, is both incomplete and nonselective.…”