Our meta-analyses found GWS association with CNIH3 SNPs conferring robust protective effects against ODE, findings that map onto reports of AMPA glutamatergic involvement in opioid dependence.25–29 The finding of significantly greater habituation in the right amygdala rs10799590 A allele carriers supports this SNP’s in vivo functional effects in humans (complementing evidence of epigenetic functionality). The genetic analyses of mouse strain data support the involvement of CNIH3, but not the more highly expressed CNIH2, in murine opioid physical dependence. The significant correlations observed for genes encoding AMPAR subunits and related proteins provide additional evidence for genetic risk mediated via this pathway. These convergent findings implicate CNIH3’s involvement in opioid dependence and could provide a route to target glutamatergic processes for translational research focusing on improving opioid dependence treatments and developing opioid analgesics with lower dependence risk.
