Genotype-dependence of gabapentin and pregabalin sensitivity: the pharmacogenetic mediation of analgesia is specific to the type of pain being inhibited.
The antiepileptic drug, gabapentin, and another structurally related compound, pregabalin, are increasingly employed in the pharmacotherapy of chronic pain states, although their primary mechanism of action remains a topic of active study. A genomic approach to the study of these drugs may elucidate their potentially novel mechanisms. We examined the heritability of sensitivity to analgesia from gabapentin and pregabalin as a precursor to linkage mapping efforts. Accordingly, 11 inbred mouse strains were tested for inhibition of nociception by gabapentin or pregabalin (50-300 mg/kg, i.p.) in two different preclinical assays of inflammatory pain, the formalin test (5% formalin; 20 microl) and zymosan thermal hyperalgesia on the paw-withdrawal test (3 mg/ml zymosan; 20 microl). Significant strain-dependence of drug action was noted in each case, indicating that sensitivity to these analgesics is heritable. Furthermore, the pattern of strain sensitivities to gabapentin and pregabalin were mostly similar, supporting the notion that they act via similar genetic and physiological mechanisms. However, there was virtually no correlation between strain sensitivities to pregabalin inhibition of formalin nociception and zymosan thermal hyperalgesia. In light of previous data from our laboratory and others regarding morphine analgesia, we now establish and empirically demonstrate the general principle that pharmacogenetic mechanisms underlying analgesic sensitivity are specific to the type of pain being inhibited. This has considerable implications for ongoing pharmacogenetic investigations and, more generally, for the choices of preclinical models of pain used in drug development.
Chesler
Elissa J
EJ
Department of Psychology and Neuroscience Program, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA Department of Psychology and Centre for Research on Pain, McGill University, 1205 Dr Penfield Avenue, Montreal, Que., Canada H3A 1B1.
Ritchie
Jennifer
J
Kokayeff
Anna
A
Lariviere
William R
WR
Wilson
Sonya G
SG
Mogil
Jeffrey S
JS
D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use*; D000588:Amines; D000698:Analgesia / Q000379:methods; D000818:Animals; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D005260:Female; D000077206:Gabapentin; D005838:Genotype; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D010146:Pain / Q000188:drug therapy* / Q000235:genetics*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010597:Pharmacogenetics / Q000379:methods*; D000069583:Pregabalin; D013045:Species Specificity; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*
D000085:Acetates; D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin