Pharmacology/Drug Development

Chronic pain is a public health problem as current treatments are unsatisfactory with small therapeutic index. Although pregabalin is effective for treating chronic pain, the clinical use is limited due to its side effects. Therefore, improving its therapeutic index is essential. In this study, HSK16149 was found to be a novel ligand of voltage-gated calcium channel (VGCC) αδ subunit. HSK16149 inhibited [H]gabapentin binding to the αδ subunit and was 23 times more potent than pregabalin. In two rat models of neuropathic pain, the minimum effective dose (MED) of HSK16149 was 10 mg/kg and the efficacy was similar to that of 30 mg/kg pregabalin. Moreover, the efficacy of HSK16149 could persist up to 24 h post-administration at 30 mg/kg, while the efficacy of pregabalin lasted only for 12 h at 30 mg/kg in streptozotocin-induced diabetic neuropathy model, indicating that HSK16149 might be a longer-acting drug candidate. HSK16149 could also inhibit mechanical allodynia in intermittent cold stress model and decrease phase II pain behaviors in formalin-induced nociception model. In addition, the locomotor activity test showed that the MED of HSK16149 was similar to that of pregabalin, while in the rotarod test, the MEDs of HSK16149 and pregabalin were 100 mg/kg and 30 mg/kg, respectively. These finding indicated that HSK16149 might have a better safety profile on the central nervous system. In summary, HSK16149 is a potent ligand of VGCC αδ subunit with a better therapeutic index than pregabalin. Hence, it could be an effective and safe drug candidate for treating chronic pain. As a novel potent ligand of VGCC αδ subunit, HSK16149 has the potential to be an effective and safe drug candidate for the treatment of chronic pain.

The primary aim of this study was to examine sex differences in acute antinociceptive and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in rats. Complete Freund's adjuvant (CFA) was administered to adult Sprague-Dawley rats to induce pain and inflammation in one hindpaw; 2.5 h later, vehicle or a single dose of the NSAIDs ibuprofen (1.0-32 mg/kg) or ketoprofen (0.1-10 mg/kg), or the COX-2-preferring inhibitor celecoxib (1.0-10 mg/kg) was injected i.p. Mechanical allodynia, heat hyperalgesia, biased weight-bearing, and hindpaw thickness were assessed 0.5-24 h after drug injection. Ibuprofen and ketoprofen were more potent or efficacious in females than males in reducing mechanical allodynia and increasing weight-bearing on the CFA-injected paw, and celecoxib was longer-acting in females than males on these endpoints. In contrast, ketoprofen and celecoxib were more potent or efficacious in males than females in reducing hindpaw edema. When administered 3 days rather than 2.5 h after CFA, ketoprofen (3.2-32 mg/kg) was minimally effective in attenuating mechanical allodynia and heat hyperalgesia, and did not restore weight-bearing or significantly decrease hindpaw edema, with no sex differences in any effect. Neither celecoxib nor ketoprofen effects were significantly attenuated by cannabinoid receptor 1 or 2 (CB1 or CB2) antagonists in either sex. These results suggest that common NSAIDs administered shortly after induction of inflammation are more effective in females than males in regard to their antinociceptive effects, whereas their anti-inflammatory effects tend to favor males; effect sizes indicate that sex differences in NSAID effect may be functionally important in some cases.

In this brief report, we demonstrate that the Ca3.3 T-type voltage-gated calcium channel subtype is involved in our FRICT-ION model of chronic trigeminal neuropathic pain. We first showed that the gene encoding Ca3.3 is significantly upregulated in whole trigeminal ganglia of FRICT-ION mice compared to controls at week 10 post-injury. We confirmed protein upregulation of Ca3.3 compared to controls using Western blot analysis of whole trigeminal ganglia tissues. Finally, we demonstrated that intraperitoneal injection of a selective TAT-based Ca3.3 blocking peptide in FRICT-ION mice significantly reduces Ca3.3 protein expression at the peak anti-allodynic effect (4 hrs post-injection) of the attenuated neuropathic pain behavior. We also suggest that blockade of Ca3.3 may be more effective in attenuating trigeminal neuropathic pain in female than male FRICT-ION mice. Therefore, blocking or attenuating Ca3.3 function may be an effective strategy for treatment of trigeminal neuropathic pain.

Benzodiazepines bind to and act on α1-3 and α5-containing GABAA receptors. Previous studies suggest that different GABAA receptor α-subtypes mediate the various behavioral effects of benzodiazepines, which raises the possibility of combining benzodiazepines with subtype-selective GABAA receptor antagonists to improve the therapeutic profiles of benzodiazepines. This study examined the GABAA receptor subtype mediation of the tolerance to midazolam-induced antinociception in rats. Midazolam (3.2 mg/kg) significantly reduced the locomotion in rats which was prevented by the selective α1-preferring GABAA receptor antagonist β-carboline-3-carboxylate-t-butyl ester (βCCt) (3.2 mg/kg). Midazolam increased the paw withdrawal threshold as tested by the von Frey filament assay in the complete Freund's adjuvant-induced inflammatory pain model in rats, and this effect was not altered by βCCt or another α1-preferring GABAA receptor antagonist 3-propoxy-β-carboline hydrochloride (3PBC). Repeated treatment with midazolam in combination with vehicle, βCCt or 3PBC (twice daily) for 7 days led to a progressive increase of the ED50 values in the midazolam- and vehicle-treated rats, but not in other rats, suggesting the development of tolerance to midazolam but not to the combination of midazolam with α1-preferring GABAA receptor antagonists. These results suggest the essential role of the α1-subtype of GABAA receptors in mediating the development of tolerance to midazolam-induced antinociceptive effects and raise the possibility of increasing therapeutic profiles of benzodiazepines by selectively blocking specific α-subtypes of GABAA receptors.