Neurokinin-1 Projection Cells in the Rat Dorsal Horn Receive Synaptic Contacts from Axons That Possess α_2C-Adrenergic Receptors

Abstract

Thealpha2C subclass of adrenergic receptor (alpha2C-AR) mediates some of the antinociceptive actions of norepinephrine in the spinal cord. Axon terminals, which possess this receptor, are concentrated in the superficial dorsal horn and originate from spinal interneurons. We performed a series of combined tract-tracing and immunocytochemical studies to determine whether alpha2C-AR-immunoreactive axons target projection neurons that possess the neurokinin-1 (NK-1) receptor because such cells are likely to transmit nociceptive information to the brain. Spinomedullary neurons were labeled by stereotaxic injection of the B-subunit of cholera toxin (CTb) into the caudal ventrolateral medulla of three anesthetized adult rats. After 3 d, the animals were anesthetized again and fixed by perfusion. Sections were cut from midlumbar segments and reacted with antibodies to reveal alpha2C-ARs, CTb, and NK-1 receptors. Retrogradely labeled neurons possessing the NK-1 receptor (n = 45) were examined with confocal microscopy to investigate their relationship with alpha2C-AR-immunoreactive axons. Numerous alpha2C-AR axons were apposed to cell bodies and proximal dendrites of cells in lamina I and also to distal dendrites that originate from labeled cell bodies in lamina III/IV. A combined confocal and electron microscopic method confirmed that these appositions were synaptic. Additional experiments showed that virtually all alpha2C-AR terminals in contact with labeled cells are also immunoreactive for the vesicular glutamate transporter 2 and therefore are glutamatergic. These data suggest that norepinephrine can modulate excitatory synaptic transmission from spinal interneurons to projection cells by acting at alpha2C-ARs. This could be one of the mechanisms that underlie the antinociceptive actions of norepinephrine.

Differential contribution of opioid and noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain

“…The a2A-adrenoceptor subtype is located presynaptically on the central terminals of primary afferent C-fibers (Stone et al, 1998) and on Ad fibers where they inhibit glutamatergic nociceptive transmission (Kawasaki et al, 2003). The a2C subtype is expressed on axon terminals of excitatory interneurons that innervate nociceptive projection neurons in the dorsal spinal cord (Olave and Maxwell, 2003). Both a2Aand a2C-adrenoceptors have been shown to mediate spinal adrenergic-opioid synergy in the substance P assay of acute nociceptive pain (Stone et al, 1997;Fairbanks et al, 2002).…”

Antinociceptive Properties of Fadolmidine (MPV‐2426), a Novel α2‐Adrenoceptor Agonist

“…This concept is supported by neurochemical (14) and electrophysiological evidence (8,20). Subtype á 2C of the á 2 -AR is found on axonal endings of excitatory spinal dorsal horn interneurons (17). The spinal interneurons with axon terminals containing the á 2C -AR innervate nociceptive spinal dorsal horn neurons with verified ascending projections to the medulla (17).…”

Pharmacological profiles of alpha 2 adrenergic receptor agonists identified using genetically altered mice and isobolographic analysis

“…Whereas strong mRNA labeling for α 2C AR is detected in large cells in the ventral horn, only very weak, diffuse signal was observed in the dorsal horn (Nicholas et al, 1993) (Shi et al, 1999). In contrast, numerous IHC studies have reported α 2C AR-ir in spinal cord neurons (Olave & Maxwell, 2002; Olave & Maxwell, 2003a,b; Stone et al, 1998). The attenuation of spinal α 2C AR-ir following treatment with antisense oligonucleotides targeting the α 2C AR gene supports the specificity of the antisera used in the aforementioned studies (Fairbanks et al, 2002).…”