Asymmetry of the endogenous opioid system in the human anterior cingulate: a putative molecular basis for lateralization of emotions and pain

Abstract

Lateralization of the processing of positive and negative emotions and pain suggests an asymmetric distribution of the neurotransmitter systems regulating these functions between the left and right brain hemispheres. By virtue of their ability to selectively mediate euphoria, dysphoria, and pain, the μ-, δ-, and κ-opioid receptors and their endogenous ligands may subserve these lateralized functions. We addressed this hypothesis by comparing the levels of the opioid receptors and peptides in the left and right anterior cingulate cortex (ACC), a key area for emotion and pain processing. Opioid mRNAs and peptides and 5 "classical" neurotransmitters were analyzed in postmortem tissues from 20 human subjects. Leu-enkephalin-Arg (LER) and Met-enkephalin-Arg-Phe, preferential δ-/μ- and κ-/μ-opioid agonists, demonstrated marked lateralization to the left and right ACC, respectively. Dynorphin B (Dyn B) strongly correlated with LER in the left, but not in the right ACC suggesting different mechanisms of the conversion of this κ-opioid agonist to δ-/μ-opioid ligand in the 2 hemispheres; in the right ACC, Dyn B may be cleaved by PACE4, a proprotein convertase regulating left-right asymmetry formation. These findings suggest that region-specific lateralization of neuronal networks expressing opioid peptides underlies in part lateralization of higher functions, including positive and negative emotions and pain in the human brain.

Keywords: anterior cingulate cortex; emotions; endogenous opioid system; lateralization; pain.

Figure 1.

Comparison of the opioid mRNA, opioid peptide, and neurotransmitter levels between the left and the right pgACC. Data are shown as mean ± SD of the normalized levels in the LH [L/(L + R)] and RH [R/(L + R)], where L and R are levels in the LH and RH, respectively. Dashed lines at a 0.66 value mark 2-fold differences between the hemispheres. Significance levels in ANOVAs followed by ANCOVAs when appropriate: Lateralization effects, *P < 0.05, **P < 0.01; sex effects, ##P < 0.01; lateralization × sex interactions, §P < 0.05.

Figure 2.

The AI of the opioid mRNAs, opioid peptides, and neurotransmitters in the pgACC. The AI [(R − L)/(R + L)] is a measure of hemispheric differences, which the −1.0 and +1.0 values indicate a complete left or right lateralization, respectively, and the 0.0 value symmetric distribution. Data bars represent the means ± SD. Dashed lines at the −0.33 and +0.33 AI values mark 2-fold differences between hemispheres. Significance in the MANOVA followed by ANCOVAs when appropriate: Lateralization effect, *P < 0.05, **P < 0.01, ***P < 0.001; sex effects, #P < 0.05.

Figure 3.

Comparison of the opioid peptide levels between the left and the right hemispheres of the dl-PFC, caudate, and putamen. Data are shown as means ± SD of the normalized levels in the LH [L/(L + R)] and RH [R/(L + R)]. Dashed lines at a 0.66 value mark 2-fold differences between hemispheres. Significance levels in ANOVAs followed by ANCOVAs when appropriate: Lateralization effects, *P < 0.05; lateralization × sex interactions, §§p < 0.01.

Figure 4.

The AI of the opioid peptides in the dl-PFC, caudate, and putamen. The −1.0 and +1.0 values of the AI [(R − L)/(R + L)] indicate a complete left or right lateralization, respectively, and the 0.0 value symmetric distribution. Data bars represent the means ± SD. Dashed lines at the −0.33 and +0.33 AI values mark 2-fold differences between hemispheres. Significance in MANOVAs followed by ANCOVAs when appropriate: Lateralization effects, *P < 0.05, **P < 0.01, ***P < 0.001.