It is likely that the α2c subclass of adrenergic receptor (α2c-AR) mediates some of the antinociceptive actions of noradrenaline in the spinal cord (Fairbanks et al. 2002). Axon terminals, which possess this receptor, are concentrated in the superficial dorsal horn and originate from spinal interneurons (Stone et al. 1998). We performed a series of combined tract-tracing and immunocytochemical studies to determine if α2c-AR-immunoreactive axons target projection neurons that possess the neurokinin-1 (NK-1) receptor as such neurons are likely to transmit nociceptive information to the brain (Naim et al. 1997).

Spinomedullary neurons were labelled by stereotaxic injection of the B subunit of cholera toxin (CTb) in the caudal ventrolateral medulla of three anaesthetized adult rats (ketamine-xylazine mixture, 7.33 and 0.73 mg per 100 g I.P.). After 3 days, the animals were anaesthetized again with sodium pentobarbitone (1 ml I.P.), killed humanely and fixed by perfusion. Sections were cut from midlumbar segments and reacted with antibodies to reveal α2c-ARs, CTb and NK-1 receptors. Retrogradely labelled neurons possessing the NK-1 receptor (n = 45) were examined with confocal microscopy to investigate their relationship with α2c-AR-immunoreactive axons. Numerous α2c-AR axons were apposed to cell bodies and proximal dendrites of cells in lamina I and also with distal dendrites that originate from labelled cell bodies in lamina III. A combined confocal and electron microscopic method revealed that appositions were synaptic. Further experiments showed that most α2c-AR terminals in contact with labelled cells are immunoreactive for the vesicular glutamate transporter 2 and therefore are glutamatergic.

These data suggest that noradrenaline can modulate excitatory synaptic transmission from spinal interneurons to projection cells by acting at α2c-ARs. This could be one of the mechanisms that underlie the antinociceptive actions of noradrenaline.

M.J.O. is supported by a University of Glasgow Postgraduate Studentship.