title: Coexpression of alpha 2A-adrenergic and delta-opioid receptors in substance P-containing terminals in rat dorsal horn.
abstract: Agonists acting at alpha(2)-adrenergic and opioid receptors (alpha(2)ARs and ORs, respectively) inhibit pain transmission in the spinal cord. When coadministered, agonists activating these receptors interact in a synergistic manner. Although the existence of alpha(2)AR/OR synergy has been well characterized, its mechanism remains poorly understood. The formation of heterooligomers has been proposed as a molecular basis for interactions between neuronal G-protein-coupled receptors. The relevance of heterooligomer formation to spinal analgesic synergy requires demonstration of the expression of both receptors within the same neuron as well as the localization of both receptors in the same neuronal compartment. We used immunohistochemistry to investigate the spatial relationship between alpha(2)ARs and ORs in the rat spinal cord to determine whether coexpression could be demonstrated between these receptors. We observed extensive colocalization between alpha(2A)-adrenergic and delta-opioid receptors (DOP) on substance P (SP)-immunoreactive (-ir) varicosities in the superficial dorsal horn of the spinal cord and in peripheral nerve terminals in the skin. alpha(2A)AR- and DOP-ir elements were colocalized in subcellular structures of 0.5 mum or less in diameter in isolated nerve terminals. Furthermore, coincubation of isolated synaptosomes with alpha(2)AR and DOP agonists resulted in a greater-than-additive increase in the inhibition of K(+)-stimulated neuropeptide release. These findings suggest that coexpression of the synergistic receptor pair alpha(2A)AR-DOP on primary afferent nociceptive fibers may represent an anatomical substrate for analgesic synergy, perhaps as a result of protein-protein interactions such as heterooligomerization.
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Maureen S
authors.initials: MS
authors.lastname: Riedl
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Schnell
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Overland
authors.forename: Anne-Julie
authors.initials: AJ
authors.lastname: Chabot-Doré
authors.forename: Anna M
authors.initials: AM
authors.lastname: Taylor
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ribeiro-da-Silva
authors.forename: Robert P
authors.initials: RP
authors.lastname: Elde
authors.forename: George L
authors.initials: GL
authors.lastname: Wilcox
authors.forename: Laura S
authors.initials: LS
authors.lastname: Stone
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D000818:Animals; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D009479:Neuropeptides / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism / Q000648:ultrastructure; D020671:Posterior Horn Cells / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism*; D012867:Skin / Q000294:innervation; D013373:Substance P / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D009479:Neuropeptides; D018341:Receptors, Adrenergic, alpha-2; D017465:Receptors, Opioid, delta; D013373:Substance P; D011188:Potassium