Endogenous opioid peptides in the descending pain modulatory circuit

Abstract

The opioid epidemic has led to a serious examination of the use of opioids for the treatment of pain. Opioid drugs are effective due to the expression of opioid receptors throughout the body. These receptors respond to endogenous opioid peptides that are expressed as polypeptide hormones that are processed by proteolytic cleavage. Endogenous opioids are expressed throughout the peripheral and central nervous system and regulate many different neuronal circuits and functions. One of the key functions of endogenous opioid peptides is to modulate our responses to pain. This review will focus on the descending pain modulatory circuit which consists of the ventrolateral periaqueductal gray (PAG) projections to the rostral ventromedial medulla (RVM). RVM projections modulate incoming nociceptive afferents at the level of the spinal cord. Stimulation within either the PAG or RVM results in analgesia and this circuit has been studied in detail in terms of the actions of exogenous opioids, such as morphine and fentanyl. Further emphasis on understanding the complex regulation of endogenous opioids will help to make rational decisions with regard to the use of opioids for pain. We also include a discussion of the actions of endogenous opioids in the amygdala, an upstream brain structure that has reciprocal connections to the PAG that contribute to the brain's response to pain.

Keywords: Amygdala; Beta-endorphin; Enkephalin; Opioid; Pain; Periaqueductal gray; Rostral ventromedial medulla.

Figure 1.

Schematic depicting known endogenous opioids and opioid receptors based on function in the amygdala, PAG and RVM in naïve adult rats. AMYGDALA: Endogenous opioid peptides are released in the medial CeA (CeM). Enkephalin is likely released from lateral CeA (CeL) neurons and the main island of the intercalated cells (Im). While β-endorphin is release from hypothalamic terminals the source of dynorphin is not defined. The predominant opioid receptor expressed in the CeM is the mu opioid receptor (MOR) whose activation inhibits GABA release in the CeM. Kappa opioid receptors (KOR) are also expressed on GABA terminals. PAG: Endogenous opioid peptides are released in the PAG from terminals arising from the amygdala and the hypothalamus. The predominant opioid receptor in the PAG is MOR which is expressed on neurons in the PAG. MORs hyperpolarize neurons via activation of G protein-coupled potassium channels (GIRKs). MORs are also expressed on presynaptic glutamate and GABA terminals arising from outside the PAG and inhibit neurotransmitter release. KOR are also expressed on presynaptic terminals. Delta opioid receptors (DOR) have been observed on enkephalin terminals within the PAG using immunohistochemistry. Output neurons (gray) are both glutamatergic and GABAergic with heterogeneous sensitivity to opioids. RVM: In the RVM, OFF- and ON-cells are defined functionally with in vivo recordings but have been distinguished in in vitro studies as primary cells (OFF-like) that are opioid-insensitive and secondary cells (ON-like) that are directly hyperpolarized by MOR agonists. A proportion of primary cells are inhibited by KOR agonists. Both MOR and KOR receptors inhibit presynaptic glutamate and GABA release onto both cell types. It should be noted that DOR-mediated functions in both the PAG and RVM are increased with chronic morphine treatment or chronic pain. The functions of various endogenous opioids with respect to the spatial and temporal release and heterogeneous expression of opioid receptors in the descending pain circuit are not understood.

Figure 2.

Endogenous opioid actions in the the intercalated cells (ITC) of the amygdala. (1) Low to moderate stimuli at BLA-Intercalated (ITC) synapses promote release of endogenous enkephalins from dense core vesicles (DCV) contained within ITC neurons. Sufficient peptide release through moderate stimulation is required to overcome peptidases and allow enkephalin signaling through DOR. Enkephalin reduces BLA-ITC synaptic activity by decreasing presynaptic glutamate release. (2) Moderate stimuli, together with peptidase inhibition, are required to overcome potential microarchitectural constraints to allow enkephalin-induced MOR activation which reduces presynaptic GABA release at local ITC-ITC synapses. (3) Activation of postsynaptic MORs by endogenously released opioids activates G protein-coupled potassium (GIRK) channels. The resulting efflux of K⁺ ions through these teriaptin Q-sensitive GIRK channels hyperpolarizes ITCs, reducing their excitability. Coincident synaptic activity could also be shunted (e.g. blue arrows) due to decreased input resistance. Both outcomes are expected to reduce total ITC activity and limit feedforward inhibition from the ITC, thus disinhibiting CeA outputs to regions, including the PAG. (Figure adapted from Winters, et al., 2017).