A spinoparabrachial circuit defined by Tacr1 expression drives pain

Abstract

Painful stimuli evoke a mixture of sensations, negative emotions and behaviors. These myriad effects are thought to be produced by parallel ascending circuits working in combination. Here we describe a pathway from spinal cord to brain for ongoing pain. Activation of a defined subset of spinal projection neurons expressing Tacr1 evokes a full repertoire of somatotopically-directed coping behaviors in the absence of noxious input. These cells project to a tiny cluster of Tacr1-positive neurons in the superior lateral parabrachial nucleus (PBN-SL) that themselves are responsive to sustained but not acute noxious stimuli. Activation of these PBN-SLTacr1 neurons alone does not trigger pain responses but instead serves to dramatically heighten nocifensive behaviors and suppress itch. Remarkably, mice with silenced PBN-SLTacr1 neurons ignore long-lasting noxious stimuli. These data reveal a spinoparabrachial pathway that plays a key role in the sensation of ongoing pain.

A harmonized atlas of mouse spinal cord cell types and their spatial organization

“…The mid excitatory (ME)/Lmx1b family was comprised of Excit-21, Excit-22, Excit-23, Excit-24, and Excit-25 and corresponds to cells suggested to be involved in pain 3,83 . These clusters expressed Lmx1b, suggesting a dI5/dIL B embryonic origin.…”

Brain circuits for pain and its treatment

“…These CeA GAB-Aergic neurons include a distinct ensemble of neurons that are activated by general anesthesia and inhibit pain (91). Recent studies have begun to investigate distinct populations of lPB neurons, defined by expression of Calca, Tac1, Nts1, Pdyn, Sst, and/or Tac1r (29,(70)(71)(72)(92)(93)(94)(95). Together, these studies suggest that lPB neurons that receive monosynaptic input from DH projection neurons transmit nociceptive information to the lateral subdivisions of the CeA (CeL) [and the laterocapsular subdivision (CeCL), often referred to as the "nociceptive amygdala"] through two populations of Slc17a6 + (VGLUT2 + ) neurons: (i) Calca + Slc17a6 + lPBe neurons, via Pdyn + lPB neurons (92,93), and (ii) intralaminar (ILN) and midline thalamic (MThal) neurons, via Tac1r + lPB neurons (94,95).…”

Unified neural pathways that gate affective pain and multisensory innate threat signals to the amygdala

“…Nociceptive information is encoded by spinal cord neurons that send a number of specific projections to the brain (Basbaum et al, 2009; Todd, 2010). One example is spinal projection neurons within the superficial layer of the spinal dorsal horn that express the Tacr1 gene (Barik et al, 2020; Chiang et al, 2020; Choi et al, 2020; Deng et al, 2020). To identify direct spino-recipient areas in the brain, we genetically labeled only the spinal Tacr1 neurons with tdTomato fluorescent protein by the triple crossing of Tacr1 Cre , Cdx2 FlpO , and Ai65 (Rosa-CAG-FrtSTOPFrt-LoxSTOPLox-tdTomato; dsTomato ) mice as described previously (Bourane et al, 2015) (Figure S1A).…”

“…Unlike the STT, the SPT has been well-characterized as an affective-motivational pain pathway. Recent studies have shown that the lateral PBN receives direct nociceptive inputs from projection neurons within the spinal dorsal horn (Barik et al, 2020; Chiang et al, 2020; Choi et al, 2020; Deng et al, 2020). The dorsolateral PBN (PBdl) receives predominantly nociceptive inputs from the spinal cord and then projects to multiple limbic structures, such as the PAG, VMH, and ILN, thereby producing emotional and physiological changes in response to pain signals (Chiang et al, 2020; Deng et al, 2020).…”