Cellular Characterisation of Endogenous Analgesic Systems

Abstract

Pain places a great burden upon society, and a better understanding of pain circuitry will be critical to developing new therapies. Of interest is the connection between the medial nucleus of the central amygdala (CeM) and periaqueductal gray (PAG), due to its role in producing analgesia. Opioid and cannabinoid analgesics act upon this pathway, though their specific sites of action within amygdala pain circuitry has not been fully determined. Therefore, the present study aimed to address this using tract tracing and whole cell patch clamp electrophysiology. Retrograde tracer was injected into the rat PAG, and the effects of opioids and cannabinoids on inhibitory inputs to labelled and unidentified CeM neurons was recorded. Notably, while DAMGO reduced inhibitory input to the CeM in both unidentified and labelled projection neurons, deltorphin inhibited inputs to unidentified neurons alone, and U69593 to only projection neurons. DHPG also produced short-term inhibition of inhibitory inputs to CeM neurons, which was abolished by AM251 in unidentified but not labelled neurons. This inhibition was associated with an extended recovery time, which was reduced by AM251 in both populations. These findings suggest that pain processing amygdala circuitry is differentially modulated by opioid receptor agonists. DHPG also modulates this circuitry, however in projection neurons, short-term inhibition seemed to be cannabinoid-independent and longer-term inhibition to be cannabinoid-dependent, potentially indicative of cannabinoid-dependent long-term depression (LTD). Overall, this study is the first to electrophysiologically demonstrate a role for cannabinoids in modulating inputs to PAG-projecting CeM neurons, as well as for κ-receptor agonists in preferentially inhibiting these inputs. This broadens our understanding of how these analgesics interact with pain circuitry via the amygdala, and may lead to more successful manipulation of this pathway to effectively manage pain.