The analgesic and anti‐inflammatory effects of Salvinorin A analogue β‐tetrahydropyran Salvinorin B in mice

Abstract

Background Drugs activating the mu opioid receptor are routinely used to treat severe acute and chronic pain. Unfortunately, side effects including nausea, constipation, respiratory depression, addiction and tolerance can limit clinical utility. In contrast, kappa opioid receptor (KOPr) agonists, such as Salvinorin A (SalA), have analgesic properties with little potential for abuse. Methods We evaluated SalA and the novel analogue β-tetrahydropyran Salvinorin B (β-THP SalB) for the ability to modulate pain and inflammation in vivo. The hot water tail-withdrawal assay, intradermal formalin-induced inflammatory pain and paclitaxel-induced neuropathic pain models were used to evaluate analgesic properties in mice. Tissue infiltration of inflammatory cells was measured by histology and flow cytometry. Results β-THP SalB produced a longer duration of action in the tail-withdrawal assay compared to the parent compound SalA, and, like SalA and U50,488, β-THP SalB is a full agonist at the KOPr. In the formalin-induced inflammatory pain model, β-THP SalB and SalA significantly reduced pain score, paw oedema and limited the infiltration of neutrophils into the inflamed tissue. β-THP SalB and SalA supressed both mechanical and cold allodynia in the paclitaxel-induced neuropathic pain model, in a dose-dependent manner. Conclusions Structural modification of SalA at the C-2 position alters its analgesic potency and efficacy in vivo. Substitution with a tetrahydropyran group at C-2 produced potent analgesic and anti-inflammatory effects, including a reduction in paclitaxel-induced neuropathic pain. This study highlights the potential for KOPr agonists as analgesics with anti-inflammatory action and little risk of abuse.

The C-2 derivatives of salvinorin A, ethoxymethyl ether Sal B and β-tetrahydropyran Sal B, have anti-cocaine properties with minimal side effects

“…Both EOM Sal B and Sal A have significantly higher potency (lower EC 50 values) compared to U50,488, although the differences between EOM Sal B and Sal A are not statistically significant. This is consistent with recently reported values for β-THP Sal B which showed no change in Emax values but increased potency (EC 50 values of 1.4 mg/kg compared to Sal A 2.1 mg/kg in B6-SJL mice) (Paton et al 2017). Evaluation of metabolic stability in rat liver microsomes, showed a small but significant increase in CYP450-mediated metabolism.…”

“…2). β-THP Sal B (EC 50, 1.4 mg/kg) has been evaluated previously in this assay with increased potency compared to Sal A (EC 50 =2.1 mg/kg; Emax 107% ± 7%) in male B6-SJL mice (Paton et al 2017). …”

Repeated Morphine Produces Sensitization to Reward and Tolerance to Antiallodynia in Male and Female Rats with Chemotherapy-Induced Neuropathy

“…First, to our knowledge, this is the first study to report tolerance to morphine antiallodynia in paclitaxel-treated rats receiving repeated morphine treatment; however, these findings agree with previous reports of tolerance to morphine antiallodynia in rats studied using other nerve-injury models (Bulka et al, 2002;Ledeboer et al, 2006). It is also important to note that, although antiallodynia in preclinical studies is often interpreted as evidence for potential analgesic effects in humans, there are several examples of poor translation between preclinical antiallodynia and clinical analgesia for treatment of CINP (Xiao et al, 2009;Tatsushima et al, 2011;Paton et al, 2017). Thus, the tolerance to morphine antiallodynia shown here is only suggestive of a potential for tolerance to morphine analgesia in human patients with chemotherapy-induced neuropathic pain.…”

Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability

“…We utilized the known analgesic properties of KOR agonists 13a to investigate the effects of 14 in comparison to 9 . We utilized the warm-water tail-withdrawal assay to induce a spinal cord reflex in mice to evaluate the duration of the analgesic effects (Figure 9a).…”

“…13 The lack of rewarding effects of KOR agonists suggests that they may hold potential for development as pain medications with reduced abuse potential. 14 Additionally, it has been hypothesized that the dysphoric effects of KOR agonism may be the result of different KOR-mediated pathways than the analgesic effects; therefore, it may be possible to decouple the undesirable hallucinogenic/dysphoric properties of agonism at the KOR by the development of functionally selective ligands.…”