Opioid preparations such as morphine are clinically effective in relieving acute, chronic and intractable pain etc; however, long-term use of opioids can induce adverse effects such as respiratory depression, constipation and so on[1–5]. Among them, constipation, also known as opioid-induced constipation (OIC), is characterized by decreased frequency of bowel movements, changes in stool characteristics and incomplete excretion. OIC, can seriously impact the patient's quality of life, resulting in discontinuation of medication by patients, which affects the desired analgesic effect[6–8]. Statistically, about 90% of patients experience gastrointestinal dysfunction such as constipation after taking opioid analgesics[9–12].
The effect of opioid preparations such as morphine on the body include the central nervous system and the peripheral nervous system; the µ-opioid receptor (MOR) is the main action site of opioid preparations in the periphery[13–16]. It has been reported that OIC is mainly due to the activation of the MOR in the gastrointestinal tract, thereby reducing the sensitivity of sensory information transmission in the colon defecation reflex pathway, and inhibiting the release of inhibitory neurotransmitters in colonic nerve cells. This in turn inhibits long-distance transport of the colon, causing intestinal contents to stay in the intestinal cavity of the colon for too long, resulting in excessive absorption of water and electrolytes[7, 8, 13, 17, 18].
The biological actions of purine signaling have been recognized since 1929. The purine receptors include subsets of P1 and P2. P2 receptors can be further sub-classified into two major families: P2X and P2Y[4, 19]. The P2Y receptor family is subdivided into the P2Y1-like receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11) and the P2Y12 -like receptor subtypes (P2Y12 − 14)[19, 20]. Among them, P2Y1 is widely expressed in the enteric nervous system of the gastrointestinal tract, and is closely related to the diastolic function of gastrointestinal smooth muscle induced by non-cholinergic and non-adrenergic neurotransmitters[1, 10, 11, 21]. It has been reported that the inhibitory neurotransmitters involved in the regulation of gastrointestinal motility are mainly non-cholinergic and non-adrenergic inhibitory neurotransmitters, such as adenosine triphosphate (ATP), nitric oxide (NO) etc, which can stimulate the hyperpolarization of smooth muscle cells, leading to relaxation of smooth muscles[13, 22].
In vitro experiments have shown that electrical stimulation of colonic circular muscle cells can record two different functional potentials: excitatory neuromuscular junction potential (EJP) and inhibitory neuromuscular junction potential (IJP). EJP can cause colonic smooth muscle contraction, while IJP is mainly induced by inhibitory neurotransmitters such as ATP, NO etc. Further, IJP comprises fast inhibitory junction potential (fIJP) and the following slow-acting neuromuscular junction potential (sIJP)[11, 22, 23]. Experimental studies have shown that purine-dependent fIJP induces transient phase relaxation of gastrointestinal smooth muscle, while NO-dependent sIJP induces sustained relaxation of gastrointestinal smooth muscle[9, 22]. The literature reports that fIJP is highly sensitive to MRS2500, which is a selective antagonist for the P2Y1 receptor, while sIJP is more sensitive to the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME)[10, 22].
Endomorphin-2 (Tyr-Pro-Phe-Phe-Nh2, EM2), the endogenous ligands of MOR, which is selectively bind to MOR at a high affinity and involved in the regulation of visceral information transmission.The previous experimental study of our group found that the endogenous receptor agonist endomorphine-2 (EM2) of MOR has no obvious effect on the sIJP of colonic circular muscle cells, but it can completely block fIJP, which is similar to the effect of the P2Y1 receptor selective receptor antagonist MRS2500 on the colon fragment.
Therefore, this study was designed to determine the correlation of P2Y1 and OIC by observing the distribution characteristics of P2Y1 in the distal colonic submucosal plexus and its expression changes in the distal colonic submucosa of OIC rats.