Biomedicines | Free Full-Text | Glycine Transporter 1 Inhibitors: Predictions on Their Possible Mechanisms in the Development of Opioid Analgesic Tolerance

Biomedicines | Free Full-Text | Glycine Transporter 1 Inhibitors: Predictions on Their Possible Mechanisms in the Development of Opioid Analgesic Tolerance

Looking for safe analgesics and adjuncts and repurposing existing medications to treat different pain entities are still challenges in pain research. The medicinal arsenal for treating mild to severe forms of acute pain includes non-steroidal anti-inflammatory drugs (NSAIDs), minor analgesics, such as paracetamol, and opioid agonists. In this regard, the general guide known as the WHO ladder, which can assist clinicians in treating cancer pain, includes these analgesics; however, opioid types are indispensable medications in this ladder, specifically when the intensity and frequency of pain is increased and cannot be adequately controlled by NSAIDs or other minor analgesics. Indeed, there is no debate on the effectiveness of opioid analgesics in relation to the management of cancer pain or noncancer chronic pain at the initiation of therapy. In the short-term treatment of pain, adverse effects related to the gastrointestinal tract develop, but generally, they are treatable with antiemetics, laxatives, and other drugs [1]). However, with long-term opioid analgesic treatment, the development of analgesic tolerance creates an obstacle, and to overcome it, dose escalation is required. Undoubtedly, further dose escalation results in benefits and risks for patients. Opioid tolerance occurs after long and repeated treatment with opioid agonists and is defined as a decrease in opioid potency, which is reflected by an increase in ED50 or EC50 values. These values are indicative of a pharmacological shift to the right in the dose/concentration–response curves of test opioid agonists, such as morphine [2,3]. In noncancer chronic pain, opioid analgesic tolerance does also occur, and the consequence of opioid dose escalation is that the patient is exposed to the risk of adverse events, including overdose and opioid use disorders (OUD) as well as other opioid side effects, as mentioned above [4,5,6]. Many preclinical and clinical studies have been conducted to understand the underlying mechanisms of opioid analgesic tolerance. In fact, µ-opioid receptors (MORs) mediate the analgesic effect of the most used opioid agonists in clinical practice. These indices indicate that opioid analgesic tolerance mediated through MORs is a clinical drawback hindering long-term opioid treatment. Furthermore, pharmacological blockade of spinal MORs with opioid antagonists, such as naloxone or H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) (a highly selective MOR antagonist), abolishes the analgesic effect of systemic morphine and fentanyl [7]. This means that elucidating spinal mechanisms that contribute to opioid analgesic tolerance can provide new knowledge that might lead to developing novel drug classes or at least adjuvants to taper off opioid doses. Indeed, there are several proposed mechanisms of opioid analgesic tolerance development, but none of them have brought significant value in the clinical setting. However, the diverse mechanisms related to opioid analgesic tolerance offer future research avenues that might ultimately unlock the solution to opioid tolerance. At the signal transduction level, MORs cause desensitization and downregulation (see Table 1), yet compensatory/opponent processes, such as neuroadaptations, occurred upon long-term exposure to opioid analgesics, such as morphine [3,8]. These processes encompass consequences related to opioid analgesic efficacy and homeostatic adaptation changes (opposite effect e.g., hyperalgesia). In this regard, the dose escalation effect is not only limited to the above-mentioned side effects, including opioid analgesic tolerance, but also can precipitate or exacerbate opioid-induced hyperalgesia [3]. The most promising achievements related to counteracting opioid analgesic tolerance was the application of competitive and non-competitive antagonists of ionotropic N-methyl-D-aspartate acid glutamate receptors (NMDARs), namely, MK-801 (dizocilpine), ketamine, and phencyclidine (PCP). In this regard, a large amount of evidence on the contribution of these receptors to opioid analgesic tolerance has been published in recent decades [9]. Alongside these studies, additional papers have also focused on the impact of spinal glutamate receptors in opioid analgesic tolerance, particularly with NMDARs, which are located on the pre- and postsynaptic membrane [10]. Furthermore, there are studies describing compounds that inhibit opioid analgesic tolerance by blocking GluN2A-2D receptor-operated ion channels, such as MK-801 [11,12]. However, these inhibitors bear several side effects, including cognitive impairment and dissociative behaviors [13,14]. Drugs devoid of these side effects that directly or indirectly affect the function of GluN2A-2D-receptor-operated ion channels in relation to opioid analgesic tolerance might be worth investigating in the future.

In this review, we shed light on undiscovered targets in opioid analgesic tolerance, namely glycine transporter type 1 (GlyT1). The prediction is supported by the following evidence from the literature: (i) GlyT1 regulates extrasynaptic glycine concentrations; (ii) glycine acts as a co-agonist at GluN2A-2DRs; (iii) GluN2B is predominantly found in the extrasynaptic region; and (iv) GluN2BR plays a crucial role in the development of opioid analgesic tolerance.

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