Augmented angiotensin II/AT₂R signaling in the DRGs of CCI rats is attenuated by EMA300 to block p38 MAPK and p44/p42 MAPK activation, a mechanism with clinical validity for alleviating neuropathic pain.

Small molecule AT2 R antagonists are worthy of further investigation as novel analgesics for relief of intractable PCIBP and other pain types where hyperalgesia worsens symptoms.

No abstract

Mice with experimental nerve damage can display long‑lasting neuropathic pain behavior. We show here that 4 months and later after nerve injury, male but not female mice displayed telomere length (TL) reduction and p53‑mediated cellular senescence in the spinal cord, resulting in maintenance of pain and associated with decreased lifespan. Nerve injury increased the number of p53‑positive spinal cord neurons, astrocytes, and microglia, but only in microglia was the increase male‑specific, matching a robust sex specificity of TL reduction in this cell type, which has been previously implicated in male‑specific pain processing. Pain hypersensitivity was reversed by repeated intrathecal administration of a p53‑specific senolytic peptide, only in male mice and only many months after injury. Analysis of UK Biobank data revealed sex-specific relevance of this pathway in humans, featuring male‑specific genetic association of the human p53 locus ( TP53 ) with chronic pain and a male-specific effect of chronic pain on mortality. Our findings demonstrate the existence of a biological mechanism maintaining pain behavior, at least in males, occurring much later than the time span of virtually all extant preclinical studies.

Introduction: Neuropathic pain and chronic inflammatory pain are large unmet medical needs. Over the past two decades, numerous 'pain targets' have been identified for analgesic drug discovery. Despite promising results in rodent pain models, many compounds modulating such targets lacked efficacy in clinical trials. An exception is oral EMA401, a small-molecule angiotensin II type 2 receptor (AT 2 R) antagonist. Areas covered: Herein, angiotensin II/AT 2 R signaling-induced hyperexcitability and abnormal sprouting of cultured dorsal root ganglion neurons, together with radioligand binding, pharmacokinetics, analgesic efficacy and mode of action of small-molecule AT 2 R antagonists in rodent models of peripheral neuropathic and chronic inflammatory pain, are reviewed. The findings of a successful Phase IIa clinical trial of EMA401 in patients with neuropathic pain are presented in brief. Expert opinion: The functional importance of angiotensin II/AT 2 R signaling has remained enigmatic for decades, and there are no clinically available medications that target the AT 2 R. However, on the basis of preclinical findings and recent clinical trial data showing that the peripherally restricted, smallmolecule AT 2 R antagonist, EMA401, successfully alleviated neuropathic pain in a Phase II clinical trial, the AT 2 R is receiving considerable attention as a new therapeutic target with human validation for the relief of peripheral neuropathic and chronic inflammatory pain conditions.