Multifunctional Opioid-Derived Hybrids in Neuropathic Pain: Preclinical Evidence, Ideas and Challenges

Abstract

When the first- and second-line therapeutics used to treat neuropathic pain (NP) fail to induce efficient analgesia—which is estimated to relate to more than half of the patients—opioid drugs are prescribed. Still, the pathological changes following the nerve tissue injury, i.a. pronociceptive neuropeptide systems activation, oppose the analgesic effects of opiates, enforcing the use of relatively high therapeutic doses in order to obtain satisfying pain relief. In parallel, the repeated use of opioid agonists is associated with burdensome adverse effects due to compensatory mechanisms that arise thereafter. Rational design of hybrid drugs, in which opioid ligands are combined with other pharmacophores that block the antiopioid action of pronociceptive systems, delivers the opportunity to ameliorate the NP-oriented opioid treatment via addressing neuropathological mechanisms shared both by NP and repeated exposition to opioids. Therewith, the new dually acting drugs, tailored for the specificity of NP, can gain in efficacy under nerve injury conditions and have an improved safety profile as compared to selective opioid agonists. The current review presents the latest ideas on opioid-comprising hybrid drugs designed to treat painful neuropathy, with focus on their biological action, as well as limitations and challenges related to this therapeutic approach.

The Downregulation of Opioid Receptors and Neuropathic Pain

“…Nevertheless, in most treatment guidelines for NP, opioids (e.g., morphine and oxycodone) are only suggested for use as third-line treatment drugs because of drug safety considerations and their low analgesic effect in NP [ 49 , 52 , 53 , 54 ]. In this context, multitargeted treatment of opioid receptors can improve the drug tolerance and safety profile [ 55 , 56 ], and previous studies have shown that simultaneous activation of MOR and DOR with bivalent agonist ligands delivers potent analgesia in experimental NP [ 57 , 58 , 59 ]. For example, the benzomorphan ligand LP2, a multitarget MOR-DOR agonist, can significantly ameliorate mechanical allodynia from the early phase of treatment up to 21 days post ligature in unilateral sciatic nerve chronic constriction injury in male Sprague–Dawley (SD) rats [ 57 ].…”

Antinociceptive and Antiallodynic Activity of Some 3-(3-Methylthiophen-2-yl)pyrrolidine-2,5-dione Derivatives in Mouse Models of Tonic and Neuropathic Pain

“…The development of new hybrid compounds for the treatment of neuropathic pain treatment is constantly emerging, especially due to the expected higher efficacy of such molecules in the pharmacotherapy of this complex disease [ 11 , 19 , 26 , 27 ]. Therefore, our research was focused on a group of hybrid compounds characterized by a multimodal mechanism of action and the ability to alleviate neuropathic pain caused by various factors, i.e., chemotherapy and diabetes.…”

The Multimodal MOPr/DOPr Agonist LP2 Reduces Allodynia in Chronic Constriction Injured Rats by Rescue of TGF-β1 Signalling

“…Direct coupling of MOPr-DOPrs in the form of heterooligomers has been demonstrated in the spinal cord tissue and it was proposed to underlie the anti-nociceptive synergy between MOPr and DOPr agonists (Gomes et al, 2004). Thus, simultaneous activation of MOPr and DOPr with a dual target compound delivers potent analgesia in experimental models of chronic pain with strongly reduced dependence and tolerance development on the course of repeated administration (Starnowska-Sokół and Przewłocka, 2020). Nevertheless, the molecular mechanisms underlying the analgesic effects of DOPr agonists are still unclear as well as the different contribute of glial cells and neurons in the allodynic effects of these compounds.…”