Background & Aims
A critical component for the integration of nociception is the anterior cingulate cortex (ACC). It receives nociceptive inputs from several regions and targets cortical and subcortical structures involved in pain processing (1,2). In chronic pain, the excitation/inhibition balance in the ACC is altered and amplifying inhibition alleviates pain hypersensitivity (3,4). It has recently been shown that excitatory projections from the claustrum activate ACC interneurons to effect feed-forward inhibition (5,6). The extent of the involvement of this pathway in acute and chronic pain processing requires further investigation. In this study we characterize the effect of claustrocingulate (CLA-ACC) manipulation reflexive, spontaneous, and cognitive behaviors in acute and chronic pain.
Methods
Cre dependent viral expression of HM3Dq (activation) or caspase 3 (lesion) was limited to CLA-ACC projections using a Cre-encoding retrograde virus in 8 week old male C57BL6J mice. Conditioned place aversion was induced by i.p. injection of 1% acetic acid to evaluate the effect of either manipulation on pain affect. Mechanical thresholds and pain response behaviors were assessed by Von Frey filament before and after hindpaw injection of Complete Freund’s Adjuvant (CFA) to model chronic pain. Separate mice were headplated and electrodes were lowered into the ACC to measure local field potentials during CLA-ACC activation. Mechanical (pinprick) and thermal (laser diode) nociceptive stimuli were then applied to measure changes in evoked activity. Mice then received a hindpaw CFA injection to compare these manipulations in acute and chronic pain conditions.
Results
Local field potentials in the ACC were directly modulated by CLA-ACC activation in both acute and chronic pain. 2 weeks after CFA induction, the amplitude of inhibition induced by CLA-ACC activation was increased. Lesion of CLA-ACC projection neurons induced mechanical allodynia but decreased pain attending. Lesion also prevented the associative aversion to acetic acid. Activation of CLA-ACC projections did not affect acute nociception but did reverse mechanical allodynia in chronic pain. This activation did not alter reflexive pain behavior or pain attendance, but mice displayed a preference for the drug paired chamber over the saline chamber after induction of chronic pain.
Conclusions
Our work demonstrates that CLA-ACC projections restrict nociceptive processing in the ACC and display reduced activity in chronic pain. This identifies a novel mechanism driving ACC hyperactivity activity associated with chronic pain. Chemogenic CLA-ACC activation did not influence acute nociception but did rescue mechanical allodynia and displayed increased cortical responsiveness to feedforward inhibition in chronic pain. This compliments previous findings of CLA-ACC in chronic pain and further indicates a potential target for restoring normal pain processing (7). Claustrum lesion increased nociception while decreasing affective pain behaviors, a dissociation previously shown in lesions of the ACC (8). This indicates that CLA-ACC projections may have diverse and temporally-specific functions in nociceptive and pain processing.
References
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Presenting Author
Christian Faig
Poster Authors
Christian Faig
BSc
University of Alberta
Lead Author
Gloria Kim
University of Alberta
Lead Author
Alison Do BSc
University of Alberta
Lead Author
Zoe Dworsky-Fried MSc
University of Alberta
Lead Author
Jesse Jackson PhD
University of Alberta
Lead Author
Anna Taylor PhD
University of Alberta
Lead Author
Topics
- Mechanisms: Biological-Systems (Physiology/Anatomy)