trk-820 and Pain

Opioid analgesics have been used for thousands of years in the treatment of pain and related disorders, and have become among the most widely prescribed medications. Among opioid analgesics, mu opioid receptor (MOR) agonists are the most commonly used and are indicated for acute and chronic pain management. However, their use results in a plethora of well-described side-effects. From selective delta opioid receptor (DOR) and kappa opioid receptor (KOR) agonists to multitarget MOR/DOR and MOR/KOR ligands, medicinal chemistry provided different approaches aimed at the development of opioid analgesics with an improved pharmacological and tolerability fingerprint. The emergent medicinal chemistry strategy to develop ameliorated opioid analgesics is based upon the concept that functional selectivity for G-protein signalling is necessary for the therapeutic effect, whether β-arrestin recruitment is mainly responsible for the manifestation of side effects, including the development of tolerance after repeated administrations. This review summarises most relevant biased MOR, DOR, KOR and multitarget MOR/DOR ligands synthesised in the last decade and their pharmacological profile in "in vitro" and "in vivo" studies. Such biased ligands could have a significant impact on modern drug discovery and represent a new strategy for the development of better-tolerated drug candidates.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Humans; Molecular Structure; Pain; Pain Management; Receptors, Opioid, mu; Structure-Activity Relationship

Nalfurafine has been used clinically in Japan for treatment of itch in kidney dialysis patients and in patients with chronic liver diseases. A one-year post-marketing study showed nalfurafine to be safe and efficacious without producing side effects of typical KOR agonists such as anhedonia and psychotomimesis. In this chapter, we summarize in vitro characterization and in vivo preclinical studies on nalfurafine. In vitro, nalfurafine is a highly potent and moderately selective KOR full agonist; however, whether it is a biased KOR agonist is a matter of debate. In animals, nalfurafine produced anti-pruritic effects in a dose range lower than that caused side effects, including conditioned place aversion (CPA), hypolocomotion, motor incoordination, consistent with the human data. In addition, nalfurafine showed antinociceptive effects in several pain models at doses that did not cause the side effects mentioned above. It appears to be effective against inflammatory pain and mechanical pain, but less so against thermal pain, particularly high-intensity thermal pain. U50,488H and nalfurafine differentially modulated several signaling pathways in a brain region-specific manners. Notably, U50,488H, but not nalfurafine, activated the mTOR pathway, which contributed to U50,488H-induced CPA. Because of its lack of side effects associated with typical KOR agonists, nalfurafine has been investigated as a combination therapy with an MOR ligand for pain treatment and for its effects on opioid use disorder and alcohol use disorder, and results indicate potential usefulness for these indications. Thus, although in vitro data regarding uniqueness of nalfurafine in terms of signaling at the KOR are somewhat equivocal, in vivo results support the assertion that nalfurafine is an atypical KOR agonist with a significantly improved side-effect profile relative to typical KOR agonists.

Topics: Animals; Humans; Morphinans; Pain; Receptors, Opioid, kappa; Spiro Compounds

Nalfurafine is a G protein signaling-biased kappa opioid receptor (KOR) agonist approved in Japan for second-line treatment of uremic pruritus. Neither nalfurafine nor any other KOR agonist is currently approved anywhere for treatment of pain, but recent evidence suggests that G protein signaling-biased KOR agonists may have promise as candidate analgesics/antipruritics with reduced side effects compared to nonbiased or ß-arrestin-signaling-biased KOR agonists.. This study compared nalfurafine effects in rats using assays of pain-stimulated and pain-depressed behavior used previously to evaluate other candidate analgesics. Nalfurafine effects were also examined in complementary assays of itch-stimulated and itch-depressed behavior.. Intraperitoneal lactic acid (IP acid) and intradermal serotonin (ID 5HT) served as noxious and pruritic stimuli, respectively, in male Sprague Dawley rats to stimulate stretching (IP acid) or scratching (ID 5HT) or to depress positively reinforced operant responding in an assay of intracranial self-stimulation (ICSS; both stimuli).. Nalfurafine was equipotent to decrease IP acid-stimulated stretching and ID 5HT-stimulated scratching; however, doses of nalfurafine that decreased these pain/itch-stimulated behaviors also decreased control ICSS performance. Moreover, nalfurafine failed to alleviate either IP acid- or ID 5HT-induced depression of ICSS.. These results suggest that nalfurafine-induced decreases in pain/itch-stimulated behaviors may reflect nonselective decreases in motivated behavior rather than analgesia or antipruritus against the noxious and pruritic stimuli used here. This conclusion agrees with the absence of clinical data for nalfurafine analgesia and the weak clinical data for nalfurafine antipruritus. Nalfurafine bias for G protein signaling may not be sufficient for clinically safe and reliable analgesia or antipruritus.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Depression; Dose-Response Relationship, Drug; Japan; Male; Morphinans; Pain; Pruritus; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Self Stimulation; Spiro Compounds

κ-Opioid receptor agonists with high selectivity over the μ-opioid receptor and peripheral selectivity are attractive targets in the development of drugs for pain. We have previously attempted to create novel analgesics with peripheral selective κ-opioid receptor agonist on the basis of TRK-820. In this study, we elucidated the biological properties of 17-hydroxy-cyclopropylmethyl and 10α-hydroxy derivatives. These compounds were found to have better κ-opioid receptor selectivity and peripheral selectivity than TRK-820.

Topics: Acetic Acid; Analgesics; Animals; Dose-Response Relationship, Drug; Drug Discovery; Male; Mice; Mice, Inbred ICR; Models, Molecular; Molecular Conformation; Morphinans; Pain; Receptors, Opioid, kappa; Spiro Compounds; Structure-Activity Relationship

We designed and synthesized pentacyclic propellane derivatives with a 6-amide side chain to afford compounds with higher MOR/KOR ratio and lower sedative effects than nalfurafine. The obtained etheno-bridged derivative with a β-amide side chain, YNT-854, showed a higher MOR/KOR ratio than nalfurafine. YNT-854 also exhibited a higher dose ratio between the sedative effect and the analgesic effect than observed with nalfurafine, which may guide the future design of useful analgesics with a weaker sedative effect than nalfurafine.

Topics: Amides; Analgesics, Opioid; Animals; CHO Cells; Cricetinae; Cricetulus; Guinea Pigs; Male; Mice; Mice, Inbred ICR; Morphinans; Pain; Protein Binding; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spiro Compounds; Structure-Activity Relationship

The analgesic effects of opioid agonists and the expression of mu- and kappa-opioid receptors were compared between mice with herpetic pain and those with postherpetic pain induced by herpetic virus inoculation. Morphine inhibited herpetic pain more effectively than postherpetic pain. Intrathecal injection reduced the analgesic effects of morphine on postherpetic pain, but intracerebroventricular injection did not. The kappa-opioid receptor agonist nalfurafine suppressed herpetic and postherpetic pain to similar degrees. mu-Opioid receptor-like immunoreactivities in the lumbar dorsal horn were markedly decreased at the postherpetic, but not herpetic, stage of pain. In the dorsal root ganglia, the expression of mu-opioid receptor mRNA was significantly decreased in mice with postherpetic pain, whereas the kappa-opioid receptor mRNA level was not altered. These results suggest that specific down-regulation of the mu-opioid receptor in the primary sensory neurons is responsible for the reduced analgesic action of morphine on postherpetic pain. The kappa-opioid receptor may be a useful target for the analgesic treatment of postherpetic neuralgia.

Topics: Analgesics, Opioid; Animals; Down-Regulation; Female; Fluorescent Antibody Technique; Ganglia, Spinal; Herpesvirus 1, Human; Hyperalgesia; Immunohistochemistry; Injections, Intraventricular; Injections, Spinal; Mice; Mice, Inbred BALB C; Morphinans; Morphine; Neuralgia, Postherpetic; Pain; Pain Measurement; Posterior Horn Cells; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spine; Spiro Compounds

(-)-17-Cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6beta-[N-methyl-3-trans-3-(3-furyl) acrylamido] morphinan hydrochloride (TRK-820) is a kappa-opioid receptor agonist that has pharmacological characteristics different from typical kappa-opioid receptor agonists. This study was conducted to determine the antiallodynic and antihyperalgesic effects of TRK-820 in a mouse model of acute herpetic pain and to compare them with those of the kappa-opioid receptor agonist enadoline and the mu-opioid receptor agonist morphine. Percutaneous inoculation with herpes simplex virus type-1 induced tactile allodynia and mechanical hyperalgesia in the hind paw on the inoculated side. TRK-820 (0.01-0.1 mg/kg p.o.), enadoline (1-10 mg/kg p.o.) and morphine (5-20 mg/kg p.o.) dose dependently inhibited the allodynia and hyperalgesia, but the antiallodynic and antihyperalgesic dose of enadoline markedly decreased spontaneous locomotor activity. The antinociceptive action of TRK-820 (0.1 mg/kg) was completely antagonized by pretreatment with norbinaltorphimine, a kappa-opioid receptor antagonist, but not by naltrexone, a mu-opioid receptor antagonist. Repeated treatment with morphine (20 mg/kg, four times) resulted in the reduction of antiallodynic and antihyperalgesic effects, whereas the inhibitory potency of TRK-820 (0.1 mg/kg) was almost the same even after the fourth administration. There was no cross-tolerance in antinociceptive activities between TRK-820 and morphine. Intrathecal and intracerebroventricular, but not intraplantar, injections of TRK-820 (10-100 ng/site) suppressed the allodynia and hyperalgesia. These results suggest that TRK-820 inhibits acute herpetic pain through kappa-opioid receptors in the spinal and supraspinal levels. TRK-820 may have clinical efficacy in acute herpetic pain with enough safety margins.

Topics: Animals; Gene Expression; Mice; Morphinans; Morphine; Pain; Receptors, Opioid, kappa; Receptors, Opioid, mu; RNA, Messenger; Spiro Compounds