There are three families of endogenous opioid peptides and three families of opioid receptors, comprising the so-called endogenous opioid system in the brain [
9]. Endogenous opioid peptides consist of β-endorphin, enkephalins, and dynorphins, which are derived from precursor proteins encoded by pre-proopiomelanocortin (POMC), preproenkephalin (PENK), and pre-prodynorphin (PDYN), respectively [
10]. Each precursor undergoes complex post-translational modifications and proteolytic cleavage, giving rise to multiple active peptides [
11,
12]. For instance, PENK is the precursor for two extended forms of Methionine (Met)-enkephalin and a single form of Leucine (Leu)-enkephalin. Opioid receptors can be divided into μ, δ, and κ three families, encoded by OPRM, OPRD, and OPRK genes [
4,
13,
14]. While they are all G protein–coupled receptors, their extracellular loops are less conserved and responsible for the differential binding affinities to different opioid peptides [
4,
13,
15‐
17]. All three subtypes of opioid receptors are coupling with the downstream G
i or G
o-mediated inhibitory intracellular signaling transduction pathways [
18]. Furthermore, endogenous opioid peptides and receptors exhibit uneven distribution in different brain regions and cell types, and can act either pre- or post-synaptically. Therefore, the opioid system exerts a variety of modulatory roles in multiple neural processes, including pain sensation, reward and drug addiction, as well as seizure and PD [
11].