Asymmetry of the Endogenous Opioid System in the Human Anterior Cingulate: a Putative Molecular Basis for Lateralization of Emotions and Pain

Cerebral Cortex, Dec 2014

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.

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Asymmetry of the Endogenous Opioid System in the Human Anterior Cingulate: a Putative Molecular Basis for Lateralization of Emotions and Pain

Advance Access publication August Asymmetry of the Endogenous Opioid System in the Human Anterior Cingulate: a Putative Molecular Basis for Lateralization of Emotions and Pain Hiroyuki Watanabe 3 Sylvia Fitting 0 Muhammad Z. Hussain 3 Olga Kononenko 3 6 Anna Iatsyshyna 3 5 Takashi Yoshitake 4 Jan Kehr 4 Kanar Alkass 9 Henrik Druid 9 Henrik Wadensten 1 Per E. Andren 1 Ingrid Nylander 3 Douglas H. Wedell 8 Oleg Krishtal 6 Kurt F. Hauser 0 7 Fred Nyberg 3 Victor M. Karpyak 2 Tatjana Yakovleva 3 Georgy Bakalkin 3 0 Department of Pharmacology and Toxicology 1 Medical Mass Spectrometry, Department of Pharmaceutical Biosciences, Uppsala University , Uppsala , Sweden 2 Department of Psychiatry and Psychology, Mayo Clinic , Rochester, MN , USA 3 Division of Biological Research on Drug Dependence, Department of Pharmaceutical Biosciences 4 Pharmacological Neurochemistry, Department of Physiology and Pharmacology 5 Department of Human Genetics, Institute of Molecular Biology and Genetics , Kyiv , Ukraine 6 Key State Laboratory, Bogomoletz Institute of Physiology , Kyiv , Ukraine 7 Institute for Drug and Alcohol Studies, Virginia Commonwealth University , Richmond, VA , USA 8 Department of Psychology, University of South Carolina , Columbia , USA 9 Forensic Medicine, Department of Oncology and Pathology, Karolinska Institutet , Stockholm , Sweden anterior cingulate cortex; emotions; endogenous opioid system; lateralization; pain - 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. Introduction A fundamental property of the human brain is lateralization of higher functions. The left hemisphere (LH) is dominant for language, mathematical, and logical reasoning; while the right hemisphere (RH) is specialized in shape recognition, spatial attention, and musical and artistic functions (Joseph 1988; Dehaene et al. 1999; Levy et al. 1999; Mesulam 1999; Toga and Thompson 2003; Craig 2005; Gazzaniga 2005; Bever and Chiarello 2009; Gier et al. 2010) . According to “the right hemisphere hypothesis,” emotions are predominantly processed in the RH. The left side of the face is emotionally more expressive (Sackeim et al. 1978). Similarly, the emotional intonation ( prosody) of words is more easily recognized if stimuli are presented to the left ear (Erhan et al. 1998) , and stimuli presented to the left visual field are perceived with greater emotion (Levine and Levy 1986) and elicit greater autonomic response (Spence et al. 1996) . Consistently, patients with frontal damage to the RH demonstrate deficits both in prosody (Ross and Mesulam 1979) and in the recognition of emotional facial expressions (Weddell 1994; Mandal et al. 1999) . The alternative, “valence hypothesis” postulates that emotions are lateralized depending on their valence. The RH is dominant for negative emotions and pain, whereas the LH predominantly processes positive emotions (Sackeim et al. 1982; Davidson 1992) . Patients who suffered trauma to the left frontal lobe are more frequently depressed (Sackeim et al. 1982; Morris et al. 1996) , while those with right frontal damage show inappropriate signs of cheerfulness and mania (Starkstein et al. 1989) . The valence hypothesis is supported by behavioral, neuroimaging, and electrophysiological evidence (Lugo et al. 2002; Symonds et al. 2006; Carrasquillo and Gereau 2008; Ji and Neugebauer 2009) . Yet, a number of studies did not support both the right hemisphere and valence hypotheses and, instead, proposed region-specific contralateral processing of positive and negative emotions (Demaree et al. 2005; Barber et al. 201 (...truncated)


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Hiroyuki Watanabe, Sylvia Fitting, Muhammad Z. Hussain, Olga Kononenko, Anna Iatsyshyna, Takashi Yoshitake, Jan Kehr, Kanar Alkass, Henrik Druid, Henrik Wadensten, Per E. Andren, Ingrid Nylander, Douglas H. Wedell, Oleg Krishtal, Kurt F. Hauser, Fred Nyberg, Victor M. Karpyak, Tatjana Yakovleva, Georgy Bakalkin. Asymmetry of the Endogenous Opioid System in the Human Anterior Cingulate: a Putative Molecular Basis for Lateralization of Emotions and Pain, Cerebral Cortex, 2015, pp. 97-108, 25/1, DOI: 10.1093/cercor/bht204