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The present study investigated the impact of advanced age on morphine modulation of persistent inflammatory pain in male and female rats. The impact of age, sex, and pain on μ-opioid receptor (MOR) expression and binding in the ventrolateral periaqueductal gray (vlPAG) was also examined using immunohistochemistry and receptor autoradiography. Intraplantar administration of complete Freund's adjuvant induced comparable levels of edema and hyperalgesia in adult (2-3 mos) and aged (16-18 mos) male and female rats. Morphine potency was highest in adult males, with a greater than two-fold increase in morphine EC observed in adult versus aged males (3.83 mg/kg vs. 10.16 mg/kg). Adult and aged female rats also exhibited significantly higher EC values (7.76 mg/kg and 8.74 mg/kg, respectively) than adult males. The upward shift in EC from adult to aged males was paralleled by a reduction in vlPAG MOR expression and binding. The observed age-related reductions in morphine potency and vlPAG MOR expression and binding have significant implications in pain management in the aged population.
Learn More >Migraine is caused by hyperactivity of the trigeminovascular system, where trigeminal ganglia (TG) play an important role. This hyperactivity might originate from an underfunctional GABAergic system in TG. To investigate this possibility, we adapted a mouse model of migraine by inducing migraine-like grimaces in male mice via repeated injections of nitroglycerin (NTG, 10 mg/kg, i.p.), once every 2 days, for up to 5 sessions. Migraine-like facial pain scores were measured using the mouse grimace scale. Repeated NTG treatments in mice caused significant increases in migraine-like grimaces that were aborted and prevented by two anti-migraine agents sumatriptan and topiramate, respectively. After 5 sessions of NTG injections, the GABA-synthesizing enzyme, 65-kDa glutamate decarboxylase (GAD65), but not the GABA transporter 1 (GAT1) or the α6 subunit-containing GABA receptors (α6GABARs), was downregulated in mouse TG tissues. Taking advantage of the unaffected TG α6GABAR expression in NTG-treated mice, we demonstrated that an α6GABAR-selective positive allosteric modulator (PAM), DK-I-56-1, exhibited both abortive and prophylactic effects, comparable to those of sumatriptan and topiramate, respectively, in this migraine-mimicking mouse model. The brain-impermeable furosemide significantly prevented the effects of DK-I-56-1, suggesting its peripheral site of action, likely via preventing α6GABAR modulation in TG. Results suggest that a decreased GABA synthesis caused by the reduced GAD65 expression in TG contributes to the trigeminovascular activation in this repeated NTG-induced migraine-mimicking model and that the unaltered α6GABARs in TG are potential targets for migraine treatment. Thus, α6GABAR-selective PAMs are potential anti-migraine agents for both abortive and preventive therapies.
Learn More >The effective and safe treatment of pain is an unmet health-care need. Current medications used for pain management are often only partially effective, carry dose-limiting adverse effects and are potentially addictive, highlighting the need for improved therapeutic agents. Most common pain conditions originate in the periphery, where dorsal root ganglion and trigeminal ganglion neurons feed pain information into the CNS. Voltage-gated sodium (Na) channels drive neuronal excitability and three subtypes – Na1.7, Na1.8 and Na1.9 – are preferentially expressed in the peripheral nervous system, suggesting that their inhibition might treat pain while avoiding central and cardiac adverse effects. Genetic and functional studies of human pain disorders have identified Na1.7, Na1.8 and Na1.9 as mediators of pain and validated them as targets for pain treatment. Consequently, multiple Na1.7-specific and Na1.8-specific blockers have undergone clinical trials, with others in preclinical development, and the targeting of Na1.9, although hampered by technical constraints, might also be moving ahead. In this Review, we summarize the clinical and preclinical literature describing compounds that target peripheral Na channels and discuss the challenges and future prospects for the field. Although the potential of peripheral Na channel inhibition for the treatment of pain has yet to be realized, this remains a promising strategy to achieve non-addictive analgesia for multiple pain conditions.
Learn More >OnabotulinumtoxinA (OBTA) is approved for treating chronic headaches and migraines in adults, but there is limited scientific literature on the outcomes in pediatric patients. The aim of this study was to determine if subjects treated with OBTA reported a statistically significant improvement in the primary features (frequency, intensity, duration and disability scoring) associated with migraines compared with placebo at follow-up visits.
Learn More >Peripheral neuropathic pain is a highly disabling condition for patients and a challenge for physicians. Although many drugs have been assessed in scientific studies, few have demonstrated clear clinical efficacy against neuropathic pain. Moreover, the paucity of data regarding their safety raises the question of the benefit-risk ratio when used in patients experiencing peripheral neuropathies.
Learn More >Reportedly, cytokine activin C is mainly expressed in small-diameter dorsal root ganglion (DRG) neurons and suppresses inflammatory pain. However, the effects of activin C in neuropathic pain remain elusive.
Learn More >Opioid therapies for chronic pain are undermined by many adverse side effects that reduce their efficacy and lead to dependence, abuse, reduced quality of life, and even death. We have recently reported that sphingosine-1-phosphate (S1P) 1 receptor (S1PR1) antagonists block the development of morphine-induced hyperalgesia and analgesic tolerance. However, the impact of S1PR1 antagonists on other undesirable side effects of opioids, such as opioid-induced dependence, remains unknown. Here, we demonstrate that naloxone-precipitated morphine withdrawal in mice altered de novo sphingolipid metabolism in the dorsal horn of the spinal cord and increased S1P that accompanied the manifestation of several withdrawal behaviors. Blocking de novo sphingolipid metabolism with intrathecal administration of myriocin, an inhibitor of serine palmitoyltransferase, blocked naloxone-precipitated withdrawal. Noteworthy, we found that competitive (NIBR-15) and functional (FTY720) S1PR1 antagonists attenuated withdrawal behaviors in mice. Mechanistically, at the level of the spinal cord, naloxone-precipitated withdrawal was associated with increased glial activity and formation of the potent inflammatory/neuroexcitatory cytokine interleukin-1β (IL-1β); these events were attenuated by S1PR1 antagonists. These results provide the first molecular insight for the role of the S1P/S1PR1 axis during opioid withdrawal. Our data identify S1PR1 antagonists as potential therapeutics to mitigate opioid-induced dependence and support repurposing the S1PR1 functional antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.
Learn More >Previous studies demonstrate decreased pain scores with ziconotide as a first-line agent for intrathecal drug therapy(IDT). Subset analysis suggests that patients with neuropathic pain have greater improvement. Here we prospectively examine the role of first-line ziconotide IDT on the tridimensional pain experience in ziconotide IDT naïve patients with neuropathic pain.
Learn More >The present study examines the possible effect of the novel hybrid molecule JM-20 (3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-411-dihydro-1H-pyrido[2,3-b] [1,5] benzodiazepine) on pain-related behaviours in a persistent pain model (5% formalin test) and in the neutrophil migration events during the inflammatory process. It further introduces JM-20 in a chronic constriction injury (CCI) model to clarify the possible subjacent mechanisms with its consequent clinical relevance. A single administration of JM-20 (20 or 40 mg/kg, per os [p.o.]) decreased licking/biting exclusively in the tonic phase of the formalin test in a GABA/benzodiazepine (BZD) receptor antagonist flumazenil-sensitive manner. JM-20 reduced in vivo neutrophil migration, rolling and adhesion to the endothelium induced by intraperitoneal administration of carrageenan in mice. In addition, plasma extravasation and tumour necrosis factor alpha production in the peritoneal fluid were decreased. Treatment with JM-20 (20 mg/kg, p.o.) for 7 days after CCI reduced mechanical hypersensitivity in a NG-monomethyl-l-arginine (L-NMMA)/methylene blue/glibenclamide-sensitive manner. Histopathological signs of Wallerian degeneration (WD) of the sciatic nerve were also attenuated, as well as interleukin-1 beta release in the spinal cord. The nitrate/nitrite concentration was increased centrally and did not show differences at the peripheral nerve level. The findings of this study suggest JM-20 can decrease persistent pain. A transient activity of its BDZ portion on nociceptive pathways mediated by GABA/BZD receptors in association with its anti-inflammatory properties could be at least partially involved in this effect. JM-20 decreased CCI-induced mechanical hypersensitivity via the l-arginine/nitric oxide (NO)/cyclic GMP-sensitive ATP-sensitive potassium channel pathway. Its neuroprotective ability by preventing WD could be implicated in its anti-neuropathic mechanisms.
Learn More >Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown clinically to be effective treatments for migraine. Zavegepant (BHV-3500, BMS-742413) is a high affinity antagonist of the CGRP receptor (hCGRP K = 0.023 nM) that has demonstrated efficacy in the acute treatment of migraine with intranasal delivery in a Phase 2/3 trial, despite showing low oral bioavailability in rats (F = 1.7%). Using zavegepant as a template, we sought to improve oral bioavailability through a series of azepinones which were designed in an attempt to reduce the number of rotatable bonds. These efforts led to the discovery of compound 21 which was able to mostly maintain high affinity binding (hCGRP K = 0.100 nM) and in vivo efficacy in the marmoset facial blood flow assay, while greatly improving oral bioavailability (rat F = 17%).
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