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The single nucleotide polymorphism 118A>G of the human μ-opioid receptor gene OPRM1, which leads to an exchange of the amino acid asparagine (N) to aspartic acid (D) at position 40 of the extracellular receptor region, alters the in vivo effects of opioids to different degrees in pain-processing brain regions. The most pronounced N40D effects were found in brain regions involved in the sensory processing of pain intensity. Using the μ-opioid receptor-specific agonist DAMGO, we analyzed the μ-opioid receptor signaling, expression, and binding affinity in human brain tissue sampled postmortem from the secondary somatosensory area (S[subII]) and from the ventral posterior part of the lateral thalamus, two regions involved in the sensory processing and transmission of nociceptive information. We show that the main effect of the N40D μ-opioid receptor variant is a reduction of the agonist-induced receptor signaling efficacy. In the S[subII] region of homoand heterozygous carriers of the variant 118G allele (n = 18), DAMGO was only 62% as efficient (p = 0.002) as in homozygous carriers of the wild-type 118A allele (n = 15). In contrast, the number of [[sup3]H]DAMGO binding sites was unaffected. Hence, the μ-opioid receptor G-protein coupling efficacy in S11 of carriers of the 118G variant was only 58% as efficient as in homozygous carriers of the 118A allele (p < 0.00 1). The thalamus was unaffected by the OPRM1 1 18A > G SNP. In conclusion, we provide a molecular basis for the reduced clinical effects of opioid analgesics in carriers of μ-opioid receptor variant N40D. [ABSTRACT FROM AUTHOR]