Table 2.
Classes of novel peripheral visceral analgesics
| Class of Peripheral Visceral Analgesic | Examples | Summary of Mechanism of Action |
|---|---|---|
| Novel µ-opioid agents | ||
| Novel biased ligand of the μ-opioid receptor | TRV130 and PZM21 | Activates G protein without β-arrestin pathway |
| Targeting μ-opioid receptor under acidic conditions | NFEPP | A fluorinated derivative of fentanyl exclusively activated at acidic sites, e.g., inflammation |
| NOP receptor modulation | SCH 221510 | NOP ligand may reverse a possible deficiency of endogenous nociceptin in IBS |
| Dual action on NOP and μ-opioid receptor | Cebranopadol and BU08070 | Peripherally active mixed μ-opioid peptide-NOP receptor agonist |
| Buprenorphine analogs | ORP-101 | Combines analgesia from μ-opioid receptor agonism and the antiaddictive effects of a κ-opioid receptor antagonist |
| Morphiceptin analog | P-317 | Cyclic pentapeptide derivative of morphiceptin with indirect evidence of peripheral action |
| Novel CB2 agonists | LY3038404, PF-03550096, and APD371 | Selective CB2 agonists; may have superior analgesic effects devoid of the centrally mediated CB1 effects |
| N-methyl-d-aspartate receptor antagonists | Ketamine | Prevent central sensitization to opioid analgesics, improving effectiveness of opioids |
| CGRP-related peptide receptor antagonists | CGRP-(8–37) | Blocks endosomal signaling of the CLR to pain transmission |
| Drugs targeting TRP channels | ||
| TRPV1 | JYL1421 | TRPV1 receptor antagonist reduces mechanical, but not chemical, hyperalgesia |
| TRPV4 | RN1734 | Selective TRPV4 antagonist reduces chemically induced hyperalgesia |
| TRPM8 | Peppermint oil and caraway oil | Agonists that reduce colonic hypersensitivity to mechanical stimuli |
| GPER and ER ligands | G-1 and estradiol | Nonselective GPER agonist and ER ligand inhibit muscle contractility and chemically induced colonic hyperalgesia |
| Adenosine A2B receptor antagonist | Aminophylline | Antagonizes A2B receptors that are involved in control of intestinal secretion, motility, and sensation |
NOP, nociceptin/orphanin FQ opioid peptide; IBS, irritable bowel syndrome; CB2, cannabinoid receptor type 2; CGRP, calcitonin gene-related peptide; CLR, calcitonin receptor-like receptor; TRP, transient receptor potential; GPER, G protein-coupled estrogen receptor; ER, estrogen receptor.