Reward feedback responses in the brain may be predictive of chronic pain complaints later on, according to results of a multinational European study reported in Pain.1 Furthermore, pain complaint responses come from the same regions in the brain and share the same neural pathways as reward feedback responses, the authors found.
The study, led by Frauke Nees, PhD from the Department of Cognitive and Clinical Neuroscience at Heidelberg University in Mannheim, Germany, indicated that greater engagement of behavioral and planning responses to reward outcomes strongly pointed to a higher propensity for pain complaints 2 years later. Similar responses to anticipation of rewards were not observed, a finding that was consistent with results of another recent study, demonstrating decreased striatal activation on functional magnetic resonance imaging (fMRI) brain mapping during reward anticipation for people with known gambling or substance addictions.2
Dr Nees and colleagues assembled a cohort of 644 healthy 14- to 15- year-old adolescents (n=390 boys; mean age, 14.58 ± 0.39 years) from the Imaging Genetics (IMAGEN) study conducted in the United Kingdom, Ireland, France and Germany for initial evaluation and 2-year follow-up.
The investigators observed that “pain and reward are considered as opponent, yet interacting, processes, which are related to partly similar brain regions, such as the striatum, the prefrontal cortex, the anterior cingulate cortex (ACC), the orbitofrontal cortex, or the amygdala.”
They identified human µ-opioid receptors (OPRM1) in the brain as possible effectors of genetic alterations in pain processing, while testing for a possible role in reward feedback response as well. The study participants gave samples for genotyping of alleles with single nucleotide polymorphisms (SNPs) for OPRM1, specifically rs179991, associated with both higher pain and higher pain thresholds, and rs563649, associated with increased response to noxious stimuli.3-5
Using fMRI to map increases in blood oxygen level-dependent responses in those specific regions of the brain during reward feedback, the investigators observed significant responses in the ventral and dorsal striatum and periaqueductal gray matter of adolescents identified as carrying the rs563649 T-allele, and also in the ACC, amygdala, and insula of C-allele carriers during reward feedback, but not during anticipation. The results indicated that these traits may provide genetic markers of more chronic experiences of pain later in life.
Summary and Clinical Applications
This study was the first to suggest a link between high reward receptor responses in the striatal cortex, possibly partially mitigated by opioid genetic predisposition, and expression of pain complaints 2 years later, suggesting possible risk factors for chronic pain in later life.
Limitations and Disclosures
As the study was conducted in healthy volunteers, pain scores were low and not representative of chronic pain.
Examination of multiple brain regions may reflect overlapping resulting in overestimation.
T. Banaschewski served in an advisory or consultancy role for Actelion, Hexal Pharma, Lilly, Medice, Novartis, Shire, and Vifor Pharma and received conference support or speaker’s fee from Medice, Novartis, and Shire.
J. Gallinat has received research funding from the German Federal Ministry of Education and Research, AstraZeneca, Eli Lilly, Janssen-Cilag, and Bristol-Myers Squibb; he has received speaking fees from AstraZeneca, Janssen-Cilag, and Bristol-Myers Squibb.
- Nees F, Becker S, Millenet S, et al. Brain substrates of reward processing and the μ-opioid receptor: a pathway into pain? Pain 2017;158:212-219.
- Luijten M, Schellekens AF, Kuhn S. Disruption of reward processing in addiction an image-based meta-analysis of functional magnetic resonance imaging studies. JAMA Psychiatry. 2017 Feb 1. doi:10.1001/jamapsychiatry.2016.3084 [epub ahead of print]
- Kolesnikov Y, Gabovits B, Levin A, et al. Chronic pain after lower abdominal surgery: do catechol-O-methyl transferase/opioid receptor m-1 polymorphisms contribute? Mol Pain. 2013;9:19.
- Fillingim RB, Kaplan L, Staud R, et al. The A118G single nucleotide polymorphism of the mu-opioid receptor gene (OPRM1) is associated with pressure pain sensitivity in humans. J Pain. 2005;6:159–67.
- Shabalina SA, Zaykin DV, Gris P. Expansion of the human mu-opioid receptor gene architecture: novel functional variants. Hum Mol Genet. 2009;18:1037–51.