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Paclitaxel-induced neuropathic pain (PINP) is a dose-limiting side effect and is refractory to widely used analgesic drugs. Previous studies have demonstrated a protective role of peroxisome proliferator-activated receptor gama (PPARγ) in neuropathic pain. However, whether PPARγ activation could alleviate PINP remains to be elucidated. Our previous study has validated the analgesic effect of oltipraz, an nuclear factor erythroid-2 related factor 2 (Nrf2) activator, in a rat model of PINP. In this study, we tested the hypothesis that rosiglitazone, a selective agonist of PPARγ, could attenuate PINP through induction of Nrf2/heme oxygenase-1 (HO-1) signaling pathway. Paclitaxel was injected intraperitoneally on four alternate days to induce neuropathic pain. Paw withdrawal threshold was used to evaluate mechanical allodynia. Western blot and immunofluorescence were used to examine the expression and distribution of PPARγ, Nrf2 and HO-1 in the spinal cord. Our results showed that rosiglitazone attenuated established PINP and delayed the onset of PINP via activation of PPARγ, which were reversed by PPARγ antagonist GW9662. Moreover, rosiglitazone inhibited downregulation of PPARγ in the spinal cord of PINP rats. Furthermore, the analgesic effect of rosiglitazone against PINP was abolished by trigonelline, an Nrf2 inhibitor. Finally, rosiglitazone significantly increased expression of Nrf2 and HO-1 in the spinal cord of PINP rats. Collectively, these results indicated that PPARγ activation might mitigate PINP through activating spinal Nrf2/HO-1 signaling pathway. Our results may provide an alternative option for PINP patients.
Learn More >Focused ultrasound (FUS) is a promising technology for facilitating treatment of brain diseases including chronic pain. Focused ultrasound is a unique modality for delivering therapeutic levels of energy into the body, including the central nervous system (CNS). It is non-invasive and can target spatially localized effects through the intact skull to cortical or subcortical regions of the brain. FUS can achieve three different mechanisms of action in the brain that are relevant for chronic pain treatment: (1) localized thermal ablation of neural tissue; (2) localized and transient disruption of the blood-brain barrier for targeted drug delivery to CNS structures; and (3) inhibition or stimulation of neuronal activity in targeted regions. This review provides an in-depth look at the technology of FUS with emphasis placed on applications to CNS-based treatments of chronic pain. While still in the early stages of clinical translation and with some technical challenges remaining, we suggest that FUS has great potential as a novel approach for manipulating CNS networks involved in pain treatment.
Learn More >Transgenic therapy for central neuralgia faces the problems of low expression and weak targeting and affects superficial but not deep neurons. In this study, we generated a lentivirus vector with human preproenkephalin gene (hPPE) expression driven by the transcriptional amplification strategy system (TAS) and established a primary bone marrow-derived mesenchymal stromal cell (BMSC) line stably expressing hPPE for transplantation into a rat model of neuropathic pain rat. The paw thermal withdrawal latency assay and paw mechanical withdrawal threshold assay showed that unlike control BMSCs and BMSCs with hPPE overexpression driven by the CMV or Synapsin 1 (SYN1) promoter, TAS-hPPE BMSCs had a robust and lasting analgesic effect. The TAS-hPPE BMSC-treated group exhibited higher expression of TAS-driven hPPE and a higher ratio of BMSCs in the midbrain, spinal cord and cortex then the CMV-hPPE BMSC- and SYN1-hPPE BMSC-treated groups. Moreover, we also observed that TAS-hPPE BMSCs displayed a greater tendency to differentiate into neurons and exhibit neuronal-like distribution than CMV-hPPE or SYN1-hPPE BMSCs. In conclusion, our study shows that the TAS improves BMSC transgenic therapy for neuropathic pain treatment.
Learn More >This review intends to characterize the recent literature pertaining to the role of aerobic exercise in the prevention of migraine. Areas of consensus within that literature may be used to guide clinical practice, allowing for the promulgation of evidence-based practice recommendations.
Learn More >To describe the core elements of a Whole Health Primary Care Pain Education and Opioid Monitoring Program (PC-POP) and examine its effectiveness at increasing adherence to six of the Veteran Affairs/Department of Defense (VA/DoD) recommended guidelines for long-term opioid therapy (LOT) among chronic noncancer patients seen in primary care (i.e., urine drug screens [UDS], prescription drug monitoring program [PDMP] queries, informed consent, naloxone education/prescriptions, morphine equivalent daily dose [MEDD], and referrals to nonpharmacological pain interventions).
Learn More >An epileptic seizure can trigger a headache during (ictal) or after (postictal) the termination of the event. Little is known about the pathophysiology of seizure-induced headaches. In the current study, we determined whether a seizure can activate nociceptive pathways that carry pain signals from the meninges to the spinal cord, and if so, to what extent and through which classes of peripheral and central neurons. To achieve these goals, we used single-unit recording techniques and an established animal model of seizure (picrotoxin) to determine the effects of epileptic seizure on the activity of trigeminovascular Aδ-, C-, wide-dynamic range, and high-threshold neurons in male and female rats. Occurrence of seizure activated 54%, 50%, 68%, and 39% of the Aδ-, C-, wide-dynamic range, and high-threshold neurons, respectively. Regardless of their class, activated neurons exhibited a twofold to fourfold increase in their firing, which started immediately (1 min) or up to 90 min after seizure initiation, and lasted as short as 10 min or as long as 120 min. Administration of lidocaine to the dura prevented activation of all neuronal classes but not the initiation or maintenance of the seizure. These findings suggest that all neuronal classes may be involved in the initiation and maintenance of seizure-induced headache, and that their activation patterns can provide a neural substrate for explaining the timing and duration of ictal and possibly postictal headaches. By using seizure, which is evident in humans, this study bypasses controversies associated with cortical spreading depression, which is less readily observed in humans.This preclinical study provides a neural substrate for ictal and postictal headache. By studying seizure effects on the activity of peripheral (C and Aδ) and central (wide dynamic range and high-threshold) trigeminovascular neurons in intact and anesthetized dura, the findings help resolve two outstanding questions about the pathophysiology of headaches of intracranial origin. The first is that abnormal brain activity (i.e., seizure) that is evident in human (unlike cortical spreading depression) gives rise to specific and selective activation of the different components of the trigeminovascular system, and the second is that the activation of all components of the trigeminovascular pathway (i.e., peripheral and central neurons) depends on activation of the meningeal nociceptors from their receptors in the dura.
Learn More >To determine the prevalence of and risk factors associated with opioid use in the treatment of migraine, we examined demographics and clinical characteristics of 867 individuals who reported using opioids for the treatment of migraine.
Learn More >Chronic, pathological pain remains a global health problem and a challenge to basic and clinical sciences. A major obstacle to preventing, treating or reverting chronic pain has been that the nature of neural circuits underlying the diverse components of the complex, multidimensional experience of pain is not well understood. Moreover, chronic pain involves diverse maladaptive plasticity processes, which have not been decoded mechanistically in terms of involvement of specific circuits and cause-effect relationships. This review aims to discuss recent advances in our understanding of circuit connectivity in the mammalian brain at the level of regional contributions and specific cell types in acute and chronic pain. A major focus is placed on functional dissection of sub-neocortical brain circuits using optogenetics, chemogenetics and imaging technological tools in rodent models with a view towards decoding sensory, affective and motivational-cognitive dimensions of pain. The review summarizes recent breakthroughs and insights on structure-function properties in nociceptive circuits and higher order sub-neocortical modulatory circuits involved in aversion, learning, reward and mood and their modulation by endogenous GABAergic inhibition, noradrenergic, cholinergic, dopaminergic, serotonergic and peptidergic pathways. The knowledge of neural circuits and their dynamic regulation via functional and structural plasticity will be beneficial towards designing and improving targeted therapies.
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