Pharmacology/Drug Development

Opioids are the therapeutic agents of choice to manage moderate to severe pain in patients with advanced cancer, however the unpredictable inter-individual response to opioid therapy remains a challenge for clinicians. While studies are few, the KCNJ6 gene is a promising target for investigating genetic factors that contribute to pain and analgesia response. This is the first association study on polymorphisms in KCNJ6 and response to methadone for pain management in advanced cancer. Fifty-four adult patients with advanced cancer were recruited across two study sites in a prospective, open label, dose individualisation study. Significant associations have been previously shown for rs2070995 and opioid response in opioid substitution therapy for heroin addiction and studies in chronic pain, with mixed results seen in postoperative pain. In this study, no associations were shown for rs2070995 and methadone dose or pain score, consistent with other studies conducted in patients receiving opioids for pain in advanced cancer. There are many challenges in conducting studies in advanced cancer with significant attrition and small sample sizes, however it is hoped that the results of our study will contribute to the evidence base and allow for continued development of gene-drug dosing guidelines for clinicians.

Pain is a major problem that burdens the health and economy of societies worldwide. Nonsteroidal anti-inflammatory drugs (NSAIDs) are over-the-counter medications that are widely indicated for mild to moderate pain conditions. Clinically, the selection of a medication among this class is mainly based according to both patient's and doctor's previous experiences. Herein, we studied differences in therapeutic efficacies among the most commonly prescribed NSAIDs and acetaminophen in inflammatory pain rat model. Body stretching and food consumption behaviors were assessed after intraperitoneal administration of lactic acid. Initially, different concentrations of lactic acid were evaluated in adult male rats in both behavioral models. Acid concentrations of 1.8 and 3.2% were selected to assess the effects of ibuprofen, diclofenac, naproxen, and acetaminophen in body stretching and feeding behaviors, respectively. In the feeding study, food restriction for 1-24 h prior to feeding studies was assessed at first, and 24 h was selected for further tests. Acetaminophen (100 mg/kg), diclofenac (10 mg/kg), ibuprofen (10-32 mg/kg), and naproxen (3.2-10 mg/kg) significantly decreased acid-stimulated body stretching. Likewise, acetaminophen (100 mg/kg), diclofenac (10 mg/kg), and ibuprofen (32 mg/kg) increased food consumption significantly after 3.2% lactic acid. There were no significant differences between different test drugs efficacies in both stretching and feeding behaviors. In conclusion, feeding behavior provides a good appraisal for pain and analgesic drugs in preclinical studies. There were comparable efficacies between all tested medications in both lactic acid-stimulated body stretching and -depressed feeding behaviors.

α2δ-1 (encoded by the gene) is a newly discovered NMDA receptor-interacting protein and is the therapeutic target of gabapentinoids (e.g., gabapentin and pregabalin), frequently used for treating patients with neuropathic pain. Nerve injury causes sustained α2δ-1 upregulation in the dorsal root ganglion (DRG), which promotes NMDA receptor synaptic trafficking and activation in the spinal dorsal horn, a hallmark of chronic neuropathic pain. However, little is known about how nerve injury initiates and maintains the high expression level of α2δ-1 to sustain chronic pain. Here, we show that nerve injury caused histone hyperacetylation and diminished enrichment of histone deacetylase-2 (HDAC2), but not HDAC3, at the promoter in the DRG. Strikingly, knockdown or conditional knockout in DRG neurons in male and female mice consistently induced long-lasting mechanical pain hypersensitivity, which was readily reversed by blocking NMDA receptors, inhibiting α2δ-1 with gabapentin, or disrupting the α2δ-1-NMDA receptor interaction at the spinal cord level. deletion in DRG neurons increased histone acetylation levels at the promoter, upregulated α2δ-1 in the DRG, and potentiated α2δ-1-dependent NMDA receptor activity at primary afferent central terminals in the spinal dorsal horn. Correspondingly, knockdown-induced pain hypersensitivity was blunted in knockout mice. Thus, our findings reveal that HDAC2 functions as a pivotal transcriptional repressor of neuropathic pain via constitutively suppressing α2δ-1 expression and ensuing presynaptic NMDA receptor activity in the spinal cord. HDAC2 enrichment levels at the promoter in DRG neurons constitute a unique epigenetic mechanism that governs acute-to-chronic pain transition.Excess α2δ-1 proteins produced after nerve injury directly interact with glutamate NMDA receptors to potentiate synaptic NMDA receptor activity in the spinal cord, a prominent mechanism of nerve pain. Because α2δ-1 upregulation after nerve injury is long-lasting, gabapentinoids relieve pain symptoms only temporarily. Our study demonstrates for the first time the unexpected role of intrinsic HDAC2 at the α2δ-1 gene promoter in limiting α2δ-1 gene transcription, NMDA receptor-dependent synaptic plasticity, and chronic pain development after nerve injury. These findings challenge the prevailing view about the role of general HDAC activity in promoting chronic pain. Restoring the repressive HDAC2 function and/or reducing histone acetylation at the α2δ-1 gene promoter in primary sensory neurons could lead to long-lasting relief of nerve pain.

Postoperative pain occurs in as many as 70% of the over 230 million surgeries performed annually worldwide. Postoperative pain management still relies on opioids despite their negative consequences, resulting in a public health crisis. Therefore, it is of utmost importance to develop alternative therapies to treat chronic pain. Natural products derived from medicinal plants are potential sources of novel and biologically active compounds for development of safe analgesics. Hence, in this study, we screened a library of natural products to identify small molecules that target the activity of voltage-gated sodium and calcium channels which have important roles in nociceptive sensory processing.

Dysregulation of circular RNAs (circRNAs) has been reported to be functionally associated with chronic pain, but it is unknown whether and how circRNAs participate in visceral hypersensitivity. The expression of circKcnk9 was increased in spinal neurons of IBS-like rats. ShcircKcnk9 attenuated visceral hypersensitivity and inhibited c-Fos expression in IBS-like rats, whereas overexpression of spinal circKcnk9 induced visceral hypersensitivity and increased c-Fos expression in control rats. Furthermore, circKcnk9 was found to act as a miR-124-3p sponge. MiR-124-3p antagomir restored pain responses downregulated by shcircKcnk9 in IBS-like rats. Finally, the signal transducer and activator of transcription 3 (STAT3), validated as a target of miR-124-3p, could play a critical role in visceral hypersensitivity by regulating NSF/GluR2. Perspective. Spinal circKcnk9 functions as a miR-124-3p sponge to promote visceral hypersensitivity by regulating the STAT3/NSF/GluR2 pathway. This pathway might provide a novel epigenetic mechanism of visceral hypersensitivity and a potential circRNA therapeutic target to IBS.

Evaluate the efficacy, safety, and tolerability of zavegepant nasal spray in the acute treatment of migraine.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5-7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain (p = 0.7479), HPT (p = 0.7501), area of PMH (p = 0.1052) or flare size (p = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller (p < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.