4.6 Article

Chronic pain susceptibility is associated with anhedonic behavior and alterations in the accumbal ubiquitin-proteasome system

Journal

PAIN
Volume 162, Issue 6, Pages 1722-1731

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/j.pain.0000000000002192

Keywords

Neuropathic pain; Allodynia; Proteomic screening; Nucleus accumbens; Resistance; Proteasome

Funding

  1. European Regional Development Fund (FEDER) through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation
  2. Northern Portugal Regional Operational Programme (NORTE 2020) under the Portugal 2020 Partnership Agreement [NORTE-01-0145-FEDER-000013, NORTE-01-0145-FEDER-000023]
  3. FCT-FundacAo para a Ciencia e a Tecnologia, I.P., OE FCT/MCTES (PIDDAC) [POCI-01-0145-FEDER-007038, PTDC/NEU-SCC/5301/2014, POCI-01-0145-FEDER-007440, UIDB/04539/2020, POCI-01-0145-FEDER-029311, PTDC/BTM-TEC/29311/2017, POCI-01-0145-FEDER-016428, SAICTPAC/0010/2015]
  4. National Mass Spectrometry Network (RNEM) [POCI-01-0145-FEDER-402-022125, ROTEIRO/0028/2013]
  5. FCT [PD/BD/114117/2015, SFRH/BD/109111/2015, SFRH/BD/52291/2013]
  6. IASP Early Career Research Grant 2015
  7. Fundação para a Ciência e a Tecnologia [PTDC/NEU-SCC/5301/2014, SAICTPAC/0010/2015, PTDC/BTM-TEC/29311/2017, PD/BD/114117/2015, SFRH/BD/109111/2015] Funding Source: FCT

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The study found that a small subset of rats with peripheral neuropathy showed high thresholds to mechanical allodynia and exhibited higher hedonic behavior. Proteomic analysis revealed differences in protein expression related to the proteasome pathway between animals with low and high thresholds, suggesting an overactivation of the accumbal proteasome pathway in animals manifesting pain and depressive-like behaviors after a neuropathic injury.
It remains unknown why on similar acute/subacute painful conditions, pain persists in some individuals while in others it resolves. Genetic factors, mood, and functional alterations, particularly involving the mesolimbic network, seem to be key. To explore potential susceptibility or resistance factors, we screened a large population of rats with a peripheral neuropathy and we isolated a small subset (<15%) that presented high thresholds (HTs) to mechanical allodynia (reduced pain manifestation). The phenotype was sustained over 12 weeks and was associated with higher hedonic behavior when compared with low-threshold (LT) subjects. The nucleus accumbens of HT and LT animals were isolated for proteomic analysis by Sequential Window Acquisition of All Theoretical Mass Spectra. Two hundred seventy-nine proteins displayed different expression between LT and HT animals or subjects. Among several protein families, the proteasome pathway repeatedly emerged in gene ontology enrichment and KEGG analyses. Several alpha and beta 20S proteasome subunits were increased in LT animals when compared with HT animals (eg, PSM alpha 1, PSM alpha 2, and PSM beta 5). On the contrary, UBA6, an upstream ubiquitin-activating enzyme, was decreased in LT animals. Altogether these observations are consistent with an overactivation of the accumbal proteasome pathway in animals that manifest pain and depressive-like behaviors after a neuropathic injury. All the proteomic data are available through ProteomeXchange with identifier PXD022478.

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