Knockout of spinophilin, an endogenous antagonist of arrestin-dependent alpha2-adrenoceptor functions, enhances receptor-mediated antinociception yet does not eliminate sex-related differences

Behav Brain Res. 2009 Feb 11;197(2):457-61. doi: 10.1016/j.bbr.2008.09.036. Epub 2008 Oct 8.


We have previously shown gonadal steroid-dependent, gender specific modulation of nociception by alpha(2)-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 alpha(2)-adrenoceptor-induced antinociception as well as sex-related differences are modified in spinophilin knockout mice. We evaluated alpha(2)-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 alpha(2)-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 alpha(2)-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 alpha(2)-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 alpha(2)-adrenoceptor-evoked antinociception. These findings show that elimination of spinophilin enhances alpha(2)-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-2 Receptor Agonists
  • Adrenergic alpha-Agonists / pharmacology
  • Adrenergic alpha-Antagonists / pharmacology
  • Animals
  • Arrestin / antagonists & inhibitors
  • Arrestin / metabolism
  • Clonidine / administration & dosage
  • Clonidine / pharmacology*
  • Estrogens / metabolism
  • Estrogens / physiology
  • Female
  • Hot Temperature / adverse effects
  • Male
  • Mice
  • Mice, Knockout
  • Microfilament Proteins / deficiency*
  • Microfilament Proteins / genetics
  • Nerve Tissue Proteins / deficiency*
  • Nerve Tissue Proteins / genetics
  • Pain / drug therapy
  • Pain / metabolism*
  • Pain / physiopathology
  • Pain Measurement / drug effects
  • Pain Threshold / drug effects
  • Reaction Time / drug effects
  • Reaction Time / physiology
  • Receptors, Adrenergic, alpha-2 / metabolism*
  • Receptors, Adrenergic, alpha-2 / physiology
  • Sex Factors


  • Adrenergic alpha-2 Receptor Agonists
  • Adrenergic alpha-Agonists
  • Adrenergic alpha-Antagonists
  • Arrestin
  • Estrogens
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Receptors, Adrenergic, alpha-2
  • neurabin
  • Clonidine