Analgesic effects mediated by neuronal nicotinic acetylcholine receptor agonists: correlation with desensitization of α4β2* receptors

Eur J Pharm Sci. 2012 Dec 18;47(5):813-23. doi: 10.1016/j.ejps.2012.09.014. Epub 2012 Oct 2.

Abstract

Nicotinic α4β2* agonists are known to be effective in a variety of preclinical pain models, but the underlying mechanisms of analgesic action are not well-understood. In the present study, we characterized activation and desensitization properties for a set of seventeen novel α4β2*-selective agonists that display druggable physical and pharmacokinetic attributes, and correlated the in vitro pharmacology results to efficacies observed in a mouse formalin model of analgesia. ABT-894 and Sazetidine-A, two compounds known to be effective in the formalin assay, were included for comparison. The set of compounds displayed a range of activities at human (α4β2)(2)β2 (HS-α4β2), (α4β2)(2)α5 (α4β2α5) and (α4β2)(2)α4 (LS-α4β2) receptors. We report the novel finding that desensitization of α4β2* receptors may drive part of the antinociceptive outcome. Our molecular modeling approaches revealed that when receptor desensitization rather than activation activitiesat α4β2* receptors are considered, there is a better correlation between analgesia scores and combined in vitro properties. Our results suggest that although all three α4β2 subtypes assessed are involved, it is desensitization of α4β2α5 receptors that plays a more prominent role in the antinociceptive action of nicotinic compounds. For modulation of Phase I responses, correlations are significantly improved from an r(2) value of 0.53 to 0.67 and 0.66 when HS- and LS-α4β2 DC(50) values are considered, respectively. More profoundly, considering the DC(50) at α4β2α5 takes the r(2) from 0.53 to 0.70. For Phase II analgesia scores, adding HS- or LS-α4β2 desensitization potencies did not improve the correlations significantly. Considering the α4β2α5 DC(50) value significantly increased the r(2) from 0.70 to 0.79 for Phase II, and strongly suggested a more prominent role for α4β2α5 nAChRs in the modulation of pain in the formalin assay. The present studies demonstrate that compounds which are more potent at desensitization of α4β2* receptors display better analgesia scores in the formalin test. Consideration of desensitization propertiesat α4β2* receptors, especially at α4β2α5, in multiple linear regression analyses significantly improves correlations with efficacies of analgesia. Thus, α4β2* nicotinic acetylcholine receptor desensitization may contribute to efficacy in the mediation of pain, and represent a mechanism for analgesic effects mediated by nicotinic agonists.

MeSH terms

  • Analgesics / pharmacology
  • Analgesics / therapeutic use*
  • Animals
  • Binding, Competitive
  • Cell Line
  • Cell Line, Tumor
  • Formaldehyde
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Motor Activity / drug effects
  • Nicotinic Agonists / pharmacology
  • Nicotinic Agonists / therapeutic use*
  • PC12 Cells
  • Pain / chemically induced
  • Pain / drug therapy*
  • Pain / physiopathology
  • Rats
  • Receptors, Nicotinic / physiology*

Substances

  • Analgesics
  • Nicotinic Agonists
  • Receptors, Nicotinic
  • nicotinic receptor alpha4beta2
  • Formaldehyde