Knockout of spinophilin, an endogenous antagonist of arrestin-dependent α2-adrenoceptor functions, enhances receptor-mediated antinociception yet does not eliminate sex-related differences

Academic Article

Abstract

  • We have previously shown gonadal steroid-dependent, gender specific modulation of nociception by α -adrenoceptors. Agonist activation of the receptor enhances its association with spinophilin that antagonizes arrestin functions both by diminishing receptor phosphorylation by G-protein-coupled receptor kinase 2 (GRK2) and by competing for receptor interactions with arrestin. Since spinophilin is highly enriched in dendritic spines, we investigated whether α -adrenoceptor-induced antinociception as well as sex-related differences are modified in spinophilin knockout mice. We evaluated α -adrenoceptor antinociception in a heat-evoked tail flick test in spinophilin wild type (Sp ) and knockout (Sp ) mice. Baseline tail flick latencies (TFLs) did not change between any groups. Interestingly, the α -adrenoceptor agonist, clonidine, increased TFL in male and diestrous (low estrogen) Sp as well as Sp mice; in fact, this increase in TFL was significantly higher in Sp male and diestrous groups than in their Sp counterparts. This unexpected finding is consistent with enhanced α -adrenoceptor-mediated sedation observed previously in Sp mice, presumably due to accelerated endocytosis of desensitized receptors and recycling of refreshed receptors when arrestin is not competed for by spinophilin in Sp mice. Despite modulation of α -adrenoceptor effects in Sp mice, sex-related differences were retained; thus, clonidine was ineffective in proestrous females (highest estrogen levels), in both Sp and Sp mice, reaffirming that estrogen suppresses α -adrenoceptor-evoked antinociception. These findings show that elimination of spinophilin enhances α -adrenoceptor-evoked antinociception in estrogen-deprived physiological settings, suggesting a role for spinophilin to suppress these effects, and yet this enhanced response cannot overcome the absence of antinociception with elevated estrogen levels. © 2008 Elsevier B.V. All rights reserved. 2 2 2 2 2 2 2 2 +/+ -/- -/- +/+ -/- +/+ -/- -/- -/- -/- +/+
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    Digital Object Identifier (doi)

    Author List

  • Nag S; Wang Q; Limbird LE; Mokha SS
  • Start Page

  • 457
  • End Page

  • 461
  • Volume

  • 197
  • Issue

  • 2