Pharmacology/Drug Development

Bone cancer pain (BCP) remains a difficult clinical problem. This study examined whether pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is effective for attenuating BCP, and investigated the interaction between activation of PPARγ and phosphatase and tensin homolog deleted from chromosome 10 (PTEN) / mammalian target of rapamycin (mTOR) signal in the spinal dorsal horn (SDH) of BCP rats.

The role of peripheral mu-opioid receptors (MOPs) in chronic pain conditions is not well understood. Here, we used a combination of mouse genetics, behavioral assays, and pharmacologic interventions to investigate the contribution of primary afferent MOPs to nociceptive, inflammatory, and neuropathic pain, as well as to opioid analgesia.

The present study was undertaken to further investigate the spinal anti-allodynic effects of endomorphins (EMs) and their C-terminal hydrazide modified analogs EM-1-NHNH and EM-2-NHNH in the spared nerve injury (SNI) model of neuropathic pain in mice. Our results demonstrated that intrathecal (i.t.) administration of endomorphin-1 (EM-1), endomorphin-2 (EM-2), EM-1-NHNH and EM-2-NHNH produced potent anti-allodynic effects ipsilaterally in neuropathic pain model. Judging from the area under the curve (AUC) values, these two analogs exhibited higher antinociception than their parent peptides. Moreover, they also displayed significant antinociceptive effects in the contralateral paw administered intrathecally. Interestingly, EM-1 and its analog EM-1-NHNH displayed their antinociception probably by μ-opioid receptor subtype since the μ-opioid receptor antagonist naloxonazine didn't significantly block the anti-allodynia of EM-1 and EM-1-NHNH, which implied a same opioid mechanism. However, the anti-allodynia induced by EM-2, but not EM-2-NHNH was significantly reduced by both μ-opioid antagonist, naloxonazine and κ-antagonist, nor-binaltorphamine (nor-BNI), indicating multiple opioid receptors were involved in the anti-allodynic effects of EM-2. Most importantly, EM-1-NHNH decreased the antinociceptive tolerance, and EM-2-NHNH displayed non-tolerance-forming antinociception. Therefore, C-terminal amide to hydrazide conversion changed the spinal antinociceptive profiles of EMs in neuropathic pain. The present investigation is of great value in the development of novel opioid therapeutics against neuropathic pain.

Neuropathic pain is a chronic pain state characterized by nerve damage, inflammation, and nociceptive neuron hyperactivity. As the underlying pathophysiology is complex, a more effective therapy for neuropathic pain would be one that targets multiple elements. Here, we generated recombinant adeno-associated viruses (AAVs) encoding three therapeutic genes, namely, , , and , with various combinations. The efficacy for pain relief was evaluated in a rat spared nerve injury model of neuropathic pain. The maximal analgesic effect was achieved when the AAVs expressing all three genes were administered to rats with neuropathic pain. The combination of two virus constructs expressing the three genes was named KLS-2031 and evaluated as a potential novel therapeutic for neuropathic pain. Single transforaminal epidural injections of KLS-2031 into the intervertebral foramen to target the appropriate dorsal root ganglion produced notable long-term analgesic effects in female and male rats. Furthermore, KLS-2031 mitigated the neuroinflammation, neuronal cell death, and dorsal root ganglion hyperexcitability induced by the spared nerve injury. These results suggest that KLS-2031 represents a promising therapeutic option for refractory neuropathic pain.

Cytochrome P450 2D (CYP2D) mediates the activation and inactivation of several classes of psychoactive drugs, including opioids, which can alter drug response. Tramadol is a synthetic opioid with analgesic activity of its own as well as being metabolically activated by CYP2D to O-desmethyltramadol (ODMST) an opioid receptor agonist. We investigated the impact of brain CYP2D metabolism on central tramadol and ODSMT levels, and resulting analgesic response after oral tramadol administration in rats. CYP2D inhibitors propranolol and propafenone were administered intracerebroventricularly prior to oral tramadol administration and analgesia was measured by tail-flick latency. Drug levels of tramadol and its metabolites, ODSMT and N-desmethyltramadol, were assessed in plasma and in brain by microdialysis using LC-ESI-MS/MS. Inhibiting brain CYP2D with propafenone pretreatment increased analgesia after oral tramadol administration (ANOVA p = 0.02), resulting in a 1.5-fold increase in area under the analgesia-time curve (AUC, p < 0.01). This effect was associated with changes in the brain levels of tramadol and its metabolites consistent with brain CYP2D inhibition. In conclusion, under oral tramadol dosing pretreatment with a central administration of the CYP2D inhibitor propafenone increased analgesia (without altering plasma drug or metabolite levels), indicating that tramadol itself (and activity of CYP2D within the brain) contributed to analgesia.

Drugs that block voltage-gated sodium channels (Nas) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics (Lancet Neurol.20109413424; Expert Opin. Ther. Pat.201020755779). The identification of compounds with improved efficacy and safety is a key aim for the discovery of improved Na blocking drugs (Comprehensive Medicinal Chemistry III; (Elsevier, 2017; pp 131-175). We report the identification of a novel class of brain penetrant and voltage-gated sodium channel blockers, leading to the discovery of vixotrigine, a use-dependent sodium channel blocker with activity in models of pain. Vixotrigine has excellent physiocochemical properties for drug development, and both preclinical and clinical data support a safety profile suitable for potential use in neuropathic pain and other conditions. It has shown efficacy in a Phase II study for pain associated with trigeminal neuralgia.