Background & Aims
Chronic pain (CP) is highly prevalent and entails a great burden of disease, impacting several aspects of patients’ lives, namely in interpersonal relationships. In animal models, CP also decreases social motivation and affects social interactions, including the approach of pain-free conspecifics1. Oxytocin (OXT) is a neuropeptide known to regulate a wide range of social behaviors and exerts analgesic effects, being a potential mediator of CP and social behavior interplay. Indeed, a population of OXT neurons was shown to project directly to the spinal cord where it modulated c-fiber discharges, leading to analgesia in an inflammatory pain model2. Moreover, previous unpublished studies from our group showed that a single systemic OXT injection transiently increased pain threshold in neuropathic rats. Thus here, we aim to understand if OXT tonus is able to modulate pain and/or social behavior of a rat CP model.
Methods
Spared nerve injury (SNI) was used to model chronic neuropathic pain. We used chemogenetics to selectively activate OXTergic neurons during behavior. Thus, an OXTp-hM3Dq virus was injected in the paraventricular nucleus of hypothalamus (PVN), the main OXTergic area of the brain, 1 week post-SNI. Mechanical allodynia (Von Frey) was assessed weekly after SNI, except during social behavioral testing period. Social behavior assessment started 4 weeks after SNI. Free social interaction (SI) was assessed in dyads (SHAM-SHAM, SNI-SNI, SHAM-SNI). Moreover, sociability and social preference (towards pain vs pain-free conspecifics) were assessed using 3-chamber test. Each test was performed 30 minutes after saline or clozapine-N-oxide (CNO) injection, in a cross-over design. Additionally, Von Frey test was also performed upon saline/CNO administration to assess the effect of OXTergic activation on evoked pain. Animals received a saline/CNO injection (1/2 each condition) 120 minutes before sacrifice and the brains were collected for immunofluorescence (IF) staining with OXT, mCherry and cFos.
Results
Viral expression was confirmed in the PVN OXTergic neurons. Female rats showed decreased social interaction compared to males, independently of social context (homophenotypic – SHAM-SHAM or SNI-SNI and heterophenotypic – SHAM-SNI). A significant interaction was observed between sex and phenotype and sex and drug treatment. In females, SNI animals showed decreased social interaction in homophenotypical context and CNO decreased social interaction of both SHAM and SNI animals. In heterophenotypical context no differences were observed. Additionally, CNO injection showed a trend to increase social preference of SNI for SNI in the 3-chamber test. Regarding males, SNI animals show increased social interaction, regardless of the drug (saline/CNO) and social context and CNO showed a trend to further increase social interaction. No significant alterations were found in the 3CH in males. No overall significant CNO effect was observed regarding mechanical allodynia, though SNI rats showed heterogeneous responses.
Conclusions
Altogether, this work shows important sex differences regarding the effect of CP on rats’ social behavior. In addition, the activation of OXTergic neurons via chemogenetic manipulation further highlighted the social behavioral differences observed, despite no effect being observed on pain-related behavior.
References
1. Mogil, J. S. (2015). Social modulation of and by pain in humans and rodents. Pain, 156, S35-S41.
2. Eliava, M., Melchior, M., Knobloch-Bollmann, H. S., Wahis, J., da Silva Gouveia, M., Tang, Y., … & Grinevich, V. (2016). A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing. Neuron, 89(6), 1291-1304.
Presenting Author
Fiúza-Fernandes, Juliana
Poster Authors
Juliana Fiúza-Fernandes
BSc
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal
Lead Author
Anselmo Golmes Faria
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal
Lead Author
Sara Rito-Fernandes
Bsc
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal
Lead Author
Diana Fonseca-Rodrigues
Msc
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal
Lead Author
Joana Pereira-Mendes
Msc
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal
Lead Author
Marco Guimarães
Msc
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal
Lead Author
Hugo Miguel Vale Leite Santos Almeida
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal
Lead Author
Topics
- Gender/Sex Differences