Background & Aims
The anterior cingulate cortex (ACC) has been identified as a key pain structure due to its role in top-down somatosensory modulation and its dysfunction in chronic pain states. The high prevalence of chronic pain in hypodopaminergic disorders points to dopamine (DA) as a prime suspect in mediating ACC dysfunction (Blanchet et al, 2018; Defazio et al, 2008). We have shown that DA is a critical inhibitory modulator of ACC pyramidal neurons and boosting DA signaling in the ACC induces analgesia (Lançon et al, 2021). However, which interneuron populations are involved in DAergic inhibition of pyramidal cells and whether their functionality is impaired in neuropathic conditions has not been investigated.
Methods
To test whether the onset of neuropathic pain significantly affects DA release and dopaminoceptive circuits in the ACC, we used in vivo fiber photometry in freely-moving mice expressing the DA biosensor dLight1.1 and the calcium indicator jRCaMP1b, selectively expressed in PV+, SOM+, or CaMKII+ neurons. Isobestic fluorescence (calcium- and dopamine-independent) was measured with a 405 nm LED oscillating at 208 Hz. Calcium-dependent (jRCaMP1b) and dopamine-dependent (dLight1.1) fluorescence was measured with 470 nm and 568 nm LEDs oscillating at 470 Hz and 333 Hz, respectively. Reporter-guided electrophysiological recordings were performed in acute ACC slices. All experiments were performed in male and female mice to detect potential sex differences and the spared nerve injury (SNI) model was used to induce chronic neuropathic pain.
Results
We observed that D1R activation significantly inhibits pyramidal neurons in L5 of the ACC by promoting GABA release in SHAM but not in SNI mice. Defective SNI-induced D1R-mediated inhibition of pyramidal neurons in neuropathic conditions is linked to a reduction in IPSC amplitude following stimulation of PV+ interneurons specifically. Our in vivo photometry results suggest that the onset of neuropathic pain both increases pain-evoked pyramidal neuron activity and reduces reward-evoked DA release in the ACC. Furthermore, we show that acute pain activates both SOM+ and PV+ interneurons while neuropathic pain onset decreases the activation of PV+, but not SOM+, interneurons. Finally, we used the eGRASP approach to determine which neuronal populations are receiving direct inputs from the VTA.
Conclusions
Our results indicate that the inhibitory effect of D1R activation in the ACC is reduced in neuropathic conditions, contributing to the pathological hyperexcitability of pyramidal neurons. Our electrophysiological data suggest this mechanism is tied to a reduction in the inhibitory potential of PV+ interneurons on pyramidal cells. Our in vivo results also confirm PV+ interneurons are significantly less activated by aversive stimuli in neuropathic states. Furthermore, we show that neuropathic pain significantly reduces phasic DA release in the ACC.
We conclude that neuropathic pain conditions promote a dysregulation of DAergic mesocortical projections and this dysregulation drives direct and indirect potentiation of pyramidal output from the ACC, driving typical sensory, cognitive, and affective symptoms of chronic pain (Lançon and Séguéla, 2023).
References
Blanchet PJ and Brefel-Courbon C. (2018). Chronic pain and pain processing in Parkinson’s disease. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 87: 200-206.
Defazio G, Berardelli A, Fabbrini G, Martino D, Fincati E, Fiaschi A, Moretto G, Abbruzzese G, Marchese R, Bonuccelli U, and Del Dotto P. (2008). Pain as a nonmotor symptom of Parkinson disease: evidence from a case-control study. Archives of neurology 65: 1191-1194.
Lançon K and Séguéla P. (2023). Dysregulated neuromodulation in the anterior cingulate cortex in chronic pain. Frontiers in Pharmacology, 14.
Lançon K, Qu C, Navratilova E, Porreca F, and Séguéla P. (2021). Decreased dopaminergic inhibition of pyramidal neurons in anterior cingulate cortex maintains chronic neuropathic pain. Cell Reports 37:109933.
Reckziegel D, Tétreault P, Ghantous M, Wakaizumi K, Petre B, Huang L, Jabakhanji R, Abdullah T, Vachon-Presseau E, Berger S, and Baria A. (2021). Sex-specific pharmacotherapy for back pain: a proof-of-concept randomized trial. Pain and therapy 10: 1375-1400.
Presenting Author
Kevin Lançon
Poster Authors
Topics
- Models: Chronic Pain - Neuropathic