Dynorphin a Analogs for the Treatment of Chronic Neuropathic Pain

Abstract

Chronic pain is one of the most ubiquitous diseases in the world, but treatment is difficult with conventional methods, due to undesirable side effects of treatments and unknown mechanisms of pathological pain states. The endogenous peptide, dynorphin A has long been established as a target for the treatment of pain. Interestingly, this unique peptide has both inhibitory (opioid in nature) and excitatory activities (nonopioid) in the CNS. Both of these effects have been found to play a role in pain and much work has been done to develop therapeutics to enhance the inhibitory effects. Here we will review the dynorphin A compounds that have been designed for the modulation of pain and will discuss where the field stands today.

The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent κ-Opioid Agonistic Activities

“…In order to avoid the opioid-like adverse effects (e.g., addiction, respiratory depression, and constipation) mainly from the binding of MOR with opioids, 1,2 recent research efforts are focused on the design of potent and selective KOR agonists. 5,6 Early efforts led to the discovery of KOR-selective agonists as spiradoline 7 and enadoline 8,9 (Chart 1). However, these two KOR-selective agonists have failed to survive clinical trials of analgesia due to their negative benefit−risk ratios.…”

Bulleyaconitine A Inhibits Visceral Nociception and Spinal Synaptic Plasticity through Stimulation of Microglial Release of Dynorphin A

“…(3) Particularly, the pretreatment with intrathecal injection of dynorphin A antiserum entirely attenuated subcutaneous BAA-induced visceral antinociception. (4) Dynorphin A is known to be an endogenous ligand of κ-opioid receptors [49,50]. Pretreatment with subcutaneous injection of the κopioid receptor antagonist nor-BNI totally blocked BAAinduced visceral antinociception.…”

Protopanaxadiol alleviates neuropathic pain by spinal microglial dynorphin A expression following glucocorticoid receptor activation

“…Dynorphin A analogues and κ‐receptor agonists have been synthesised as putative analgesics over decades, but no such class of drugs are available clinically. This is probably a result of psychotomimetic effects such as dysphoria ocurring at higher doses (Brust et al, 2016; Hall et al, 2016). Indeed, intrathecal injection of exogenous dynorphin A (0.3 μg) induced reversible mechanical antiallodynia in neuropathy (Li, Fan, et al, 2016), similar to that produced by protopanaxadiol and its spinal concentration was 4.3 ± 0.2‐ng·mg −1 protein, 134‐fold higher than that induced by protopanaxadiol (32‐pg·mg −1 protein).…”

“…These aconitines have been prescribed in China for the treatment of chronic pain over decades. Chronic pain is a severe clinical syndrome, with prevalence more than cancers, coronary heart diseases and diabetes mellitus combined (Hall et al, 2016). Particularly, neuropathic pain and cancer pain are still an unmet medical need and the discovery and development of painkillers with new target molecules and mechanisms are desperately needed.…”

“…Dexamethasone and methylprednisolone have been clinically employed in various chronic pain syndromes including low back pain (Bani‐Hashem et al, 2011; Rijsdijk et al, 2014). The metastatic bone cancer pain and neuropathic pain have also been treated with steroids as adjunct therapy with opioids (Hall et al, 2016). Our present study demonstrated that the glucocorticoid receptor antagonist RU‐486 completely blocked protopanaxadiol gavage‐induced mechanical antiallodynia in neuropathic pain, whereas the oestrogen receptor subtype GPR30 antagonist G15 or mineralocorticoid receptor antagonist had no effect in blocking protopanaxadiol effects.…”