A Tacr1 Spinoparabrachial Circuit Encodes Persistent Pain
Barik A, Sathyamurthy A, Thompson J, Seltzer M, Levine A, Chesler A. A spinoparabrachial circuit defined by Tacr1 expression drives pain. Elife 2021;10:e61135. doi: 10.7554/eLife.61135.
Background: Pain perception depends on spinal projection neurons that relay nociceptive information to the brain. Among these, neurons expressing the neurokinin 1 receptor (Tacr1) and its ligand Substance P (Tac1) are known to contribute to pain and itch processing, yet the specific pathways and central targets mediating persistent pain are incompletely understood. Identifying how distinct subsets of these neurons shape behavioral responses to sustained versus acute noxious stimuli is crucial for understanding chronic pain mechanisms.
Hypothesis: This study tested the hypothesis that Tacr1-expressing projection neurons in the spinal cord communicate with Tacr1-expressing neurons in the superior lateral parabrachial nucleus (PBN-SL) to drive behavioral responses associated with persistent pain.
Methods: The authors used Tacr1-Cre transgenic mice combined with viral-mediated chemogenetic and optogenetic tools to selectively activate or silence Tacr1-expressing neurons in the spinal cord and PBN-SL. Fiber photometry (FP3002) measured population calcium activity during nociceptive and pruritic stimuli. Behavioral assays assessed nocifensive, grooming, and itch-related behaviors following manipulation of these circuits.
Results: Chemogenetic activation of spinal Tacr1 neurons induced robust, localized nocifensive behaviors mimicking persistent pain and suppressed itch responses. Tracing experiments identified dense projections to the PBN-SL. PBN-SLTacr1 neurons responded selectively to sustained, but not acute, noxious stimuli. Activation of these neurons heightened pain behaviors and suppressed itch, while their silencing markedly reduced responses to prolonged noxious stimuli without affecting reflexive responses.
Conclusions: This study revealed a defined spinoparabrachial pathway in which spinal and parabrachial Tacr1-expressing neurons cooperate to encode ongoing pain. This circuit amplifies behavioral responses to persistent noxious input while simultaneously inhibiting itch, highlighting its role in chronic pain processing.
