Accepted

We recently showed that the mesolimbic dopaminergic system was tonically suppressed during chronic pain by enhanced corticotropin releasing factor (CRF) signaling within the dorsolateral bed nucleus of the stria terminalis (dlBNST), and that inhibition of intra-dlBNST CRF signaling restored the mesolimbic dopaminergic system function. Specifically, bilateral intra-dlBNST injections of the CRF type 1 receptor antagonist NBI27914 increased intra-nucleus accumbens dopamine release and induced reward-related behaviors in rats with chronic pain. Here, we used a conditioned place preference (CPP) test to explore whether intra-dlBNST injections of neuropeptide Y (NPY) restored the mesolimbic reward system function in chronic pain rats, because we previously showed that NPY had an effect opposite to that of CRF in dlBNST neurons. Specifically, CRF depolarized type II dlBNST neurons whereas NPY hyperpolarized them. However, unexpectedly, intra-dlBNST NPY injections had no effect on CPP test outcomes. Then, we compared the effects of NPY on the membrane potentials of type II dlBNST neurons of sham-operated control rats and those of chronic pain animals. Whole-cell patch-clamp electrophysiology revealed that NPY hyperpolarized type II dlBNST neurons in the sham-operated group. By contrast, in the chronic pain group, NPY did not hyperpolarize, but rather depolarized, type II dlBNST neurons. These results indicate that NPY no longer hyperpolarize type II dlBNST neurons in rats with chronic pain, therefore it does not reverse the excitatory effects of CRF. This may be why intra-dlBNST injections of NPY into chronic pain rats did not exhibit a rewarding effect in the CPP test, whereas intra-dlBNST injections of NBI27914 did. This is the first study to demonstrate a chronic pain-induced neuroplastic change in NPY signaling in the dlBNST. Such a change may be involved in the dysfunction of the mesolimbic reward system under the chronic pain condition.

Neonatal tissue damage induces long-term deficits in inhibitory synaptic transmission within the spinal superficial dorsal horn (SDH) that include a reduction in primary afferent-evoked, feedforward inhibition onto adult projection neurons. However, the subpopulations of mature GABAergic interneurons which are compromised by early life injury have yet to be identified. The present research illuminates the persistent effects of neonatal surgical injury on the function of inhibitory SDH interneurons derived from the prodynorphin (DYN) lineage, a population which synapses directly onto lamina I spinoparabrachial neurons and is known to suppress mechanical pain and itch in adults. The results demonstrate that hindpaw incision at postnatal day (P) 3 significantly decreased the strength of primary afferent-evoked glutamatergic drive onto DYN neurons within the adult mouse SDH, while increasing the appearance of afferent-evoked inhibition onto the same population. Neonatal injury also dampened the intrinsic membrane excitability of mature DYN neurons, and reduced their action potential discharge in response to sensory input, compared to naïve littermate controls. Furthermore, P3 incision decreased the efficacy of inhibitory DYN synapses onto adult spinoparabrachial neurons, which reflected a prolonged reduction in the probability of GABA release. Collectively, the data suggest that early life tissue damage may persistently constrain the ability of spinal DYN interneurons to limit ascending nociceptive transmission to the adult brain. This is predicted to contribute to the loss of feedforward inhibition onto mature projection neurons, and the 'priming' of nociceptive circuits in the developing spinal cord, following injuries during the neonatal period.Neonatal injury has lasting effects on pain processing in the adult CNS, including a reduction in feedforward inhibition onto ascending projection neurons in the spinal dorsal horn. While it is clear that spinal GABAergic interneurons are comprised of multiple subpopulations that play distinct roles in somatosensation, the identity of those interneurons which are compromised by tissue damage during early life remains unknown. Here we document persistent deficits in spinal inhibitory circuits involving dynorphin-lineage (DYN) interneurons previously implicated in gating mechanical pain and itch. Notably, neonatal injury reduced the strength of DYN inhibitory synapses onto mature lamina I spinoparabrachial neurons, a major output of the spinal nociceptive network, which could contribute to the priming of pain pathways by early tissue damage.

The lateral parabrachial nucleus (lPBN) is a major target of spinal projection neurons conveying nociceptive input into supraspinal structures. However, the functional role of distinct lPBN efferents in diverse nocifensive responses have remained largely uncharacterized. Here we show that that the lPBN is required for escape behaviors and aversive learning to noxious stimulation. In addition, we find that two populations of efferent neurons from different regions of the lPBN collateralize to distinct targets. Activation of efferent projections to the ventromedial hypothalamus (VMH) or lateral periaqueductal gray (lPAG) drives escape behaviors, whereas activation of lPBN efferents to the bed nucleus stria terminalis (BNST) or central amygdala (CEA) generates an aversive memory. Finally, we provide evidence that dynorphin-expressing neurons, which span cytoarchitecturally distinct domains of the lPBN, are required for aversive learning.