Kappa opioid receptors in the central amygdala modulate spinal nociceptive processing through an action on amygdala CRF neurons

Abstract

The amygdala plays an important role in the emotional-affective aspects of behaviors and pain, but can also modulate sensory aspect of pain (“nociception”), likely through coupling to descending modulatory systems. Here we explored the functional coupling of the amygdala to spinal nociception. We found that pharmacological activation of neurons in the central nucleus of the amygdala (CeA) increased the activity of spinal dorsal horn neurons; and this effect was blocked by optogenetic silencing of corticotropin releasing factor (CRF) positive CeA neurons. A kappa opioid receptor (KOR) agonist (U-69,593) was administered into the CeA by microdialysis. KOR was targeted because of their role in averse-affective behaviors through actions in limbic brain regions. Extracellular single-unit recordings were made of CeA neurons or spinal dorsal horn neurons in anesthetized transgenic Crh-Cre rats. Neurons responded more strongly to noxious than innocuous stimuli. U-69,593 increased the responses of CeA and spinal neurons to innocuous and noxious mechanical stimulation of peripheral tissues. The facilitatory effect of the agonist was blocked by optical silencing of CRF-CeA neurons though light activation of halorhodopsin expressed in these neurons by viral-vector. The CRF system in the amygdala has been implicated in aversiveness and pain modulation. The results suggest that the amygdala can modulate spinal nociceptive processing in a positive direction through CRF-CeA neurons and that KOR activation in the amygdala (CeA) has pro-nociceptive effects.

Optogenetic Manipulations of Amygdala Neurons Modulate Spinal Nociceptive Processing and Behavior Under Normal Conditions and in an Arthritis Pain Model

“…CRF output neurons in the CeA are known to project to hypothalamic nuclei, the basal forebrain and several brainstem areas involved in behaviors and pain modulation such as the periaqueductal gray (PAG), locus coeruleus (LC) and PB ( Pomrenze et al, 2015 ; Neugebauer et al, 2020 ) regions. Several lines of research show that CRF projecting neurons in the CeA promote averse–affective behaviors ( Fendt et al, 1997 ; Mccall et al, 2015 ; Pomrenze et al, 2015 ; Pomrenze et al, 2019 ) and that the CRF system in the amygdala is endogenously activated in pain conditions and is critically involved in amygdala pain mechanisms ( Mcnally and Akil, 2002 ; Ji et al, 2007 ; Ji and Neugebauer, 2007 ; Fu and Neugebauer, 2008 ; Ji and Neugebauer, 2020 ; Hein et al, 2021 ). The BLA–CeA network is known to convey highly integrated polymodal information from thalamus and cortex and encodes averse-affective aspects of pain ( Veinante et al, 2013 ; Corder et al, 2019 ; Thompson and Neugebauer, 2019 ; Neugebauer, 2020 ).…”

“…This study also showed that optical (eNpHR 3.0 ) silencing of BLA–CeA terminals and CeA–CRF neurons decreased the increased activity of spinal WDR neurons ( Figures 3 , 5 ) and vocalizations ( Figure 3 ) in the arthritis pain model, suggesting a significant contribution of amygdala activity to pain–related neuronal changes at the spinal cord level and to emotional pain-like behaviors. Optogenetic stimulation of eNpHR 3.0 has been used before to silence CRF neurons in the amygdala ( De Guglielmo et al, 2019 ; Ji and Neugebauer, 2020 ). The fact that optogenetic manipulations of the BLA–CeA and CeA–CRF elements had similar effects may suggest that excitatory BLA input to CeA targets CRF neurons or that both engage similar CeA circuits.…”

“…The effects of optogenetic BLA–CeA or CeA–CRF modulations were similar arguing against significant differences in amygdala circuitry in these strains. Previous studies from our group ( Ji and Neugebauer, 2020 ; Hein et al, 2021 ) and others ( De Guglielmo et al, 2019 ) successfully used the pulsed optical protocol to manipulate the activity of specific pathways. Patch-clamp analysis validated the optogenetic protocol parameters used in the in vivo studies ( Supplementary Figures S1, S2 ).…”

“…CRF cell bodies are found mostly in the lateral division (CeL) of the CeA and their projections target several nuclei of the hypothalamus, the bed nucleus of the stria terminalis and different areas of the brainstem, including periaqueductal gray (PAG) and PB ( Pomrenze et al, 2015 ; De Guglielmo et al, 2019 ). CeA–CRF neurons have been linked to the pain modulatory effects of kappa opioid receptors ( Ji and Neugebauer, 2020 ; Hein et al, 2021 ).…”

Electroacupuncture Attenuates Neuropathic Pain and Comorbid Negative Behavior: The Involvement of the Dopamine System in the Amygdala

“…The amygdala displays adaptive changes in activity and neuroplasticity during chronic pain, which subsequently affect pain modulation and the emotional-affective dimension of pain, and facilitates neuropathic pain processing (Rouwette et al, 2012). Lesions or inhibition of special amygdala neurons alleviated mechanical allodynia and pain affective-motivational behaviors induced in NeuP models (Arimura et al, 2019;Corder et al, 2019;Ji and Neugebauer, 2020). It is well known that excessive neuroinflammation is one of the key mechanisms for generating and sustaining chronic pain (Ji et al, 2014).…”