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1.
Headache ; 61(7): 1051-1059, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34125955

RESUMO

OBJECTIVE: To highlight the emerging understanding of oxytocin (OT) and oxytocin receptors (OTRs) in modulating menstrual-related migraine (MRM). BACKGROUND: MRM is highly debilitating and less responsive to therapy, and attacks are of longer duration than nonmenstrually related migraine. A clear understanding of the mechanisms underlying MRM is lacking. METHODS: We present a narrative literature review on the developing understanding of the role of OT and the OTR in MRM. Literature on MRM on PubMed/MEDLINE database including clinical trials and basic science publications was reviewed using specific keywords. RESULTS: OT is a cyclically released hypothalamic hormone/neurotransmitter that binds to the OTR resulting in inhibition of trigeminal neuronal excitability that can promote migraine pain including that of MRM. Estrogen regulates OT release as well as expression of the OTR. Coincident with menstruation, levels of both estrogen and OT decrease. Additionally, other serum biochemical factors, including magnesium and cholesterol, which positively modulate the affinity of OT for OTRs, both decrease during menstruation. Thus, during menstruation, multiple menstrually associated factors may lead to decreased circulating OT levels, decreased OT affinity for OTR, and decreased expression of the trigeminal OTR. Consistent with the view of migraine as a threshold disorder, these events may collectively result in decreased inhibition promoting lower thresholds for activation of meningeal trigeminal nociceptors and increasing the likelihood of an MRM attack. CONCLUSION: Trigeminal OTR may thus be a novel target for the development of MRM therapeutics.


Assuntos
Estrogênios/metabolismo , Ciclo Menstrual/metabolismo , Distúrbios Menstruais/metabolismo , Transtornos de Enxaqueca/metabolismo , Ocitocina/metabolismo , Receptores de Ocitocina/metabolismo , Feminino , Humanos
2.
Cereb Cortex ; 30(6): 3644-3654, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32108220

RESUMO

Hypnosis is the oldest form of Western psychotherapy and a powerful evidence-based treatment for numerous disorders. Hypnotizability is variable between individuals; however, it is a stable trait throughout adulthood, suggesting that neurophysiological factors may underlie hypnotic responsiveness. One brain region of particular interest in functional neuroimaging studies of hypnotizability is the anterior cingulate cortex (ACC). Here, we examined the relationships between the neurochemicals, GABA, and glutamate, in the ACC and hypnotizability in healthy individuals. Participants underwent a magnetic resonance imaging (MRI) session, whereby T1-weighted anatomical and MEGA-PRESS spectroscopy scans were acquired. Voxel placement over the ACC was guided by a quantitative meta-analysis of functional neuroimaging studies of hypnosis. Hypnotizability was assessed using the Hypnotic Induction Profile (HIP), and self-report questionnaires to assess absorption (TAS), dissociation (DES), and negative affect were completed. ACC GABA concentration was positively associated with HIP scores such that the higher the GABA concentration, the more hypnotizable an individual. An exploratory analysis of questionnaire subscales revealed a negative relationship between glutamate and the absorption and imaginative involvement subscale of the DES. These results provide a putative neurobiological basis for individual differences in hypnotizability and can inform our understanding of treatment response to this growing psychotherapeutic tool.


Assuntos
Ácido Glutâmico/metabolismo , Giro do Cíngulo/metabolismo , Hipnose , Individualidade , Ácido gama-Aminobutírico/metabolismo , Adulto , Feminino , Giro do Cíngulo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Inquéritos e Questionários , Adulto Jovem
3.
Headache ; 58(4): 545-558, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29266199

RESUMO

BACKGROUND: Approximately 1.7 million Americans sustain a traumatic brain injury (TBI) each year and chronic pain is a common complication. OBJECTIVE: We studied the effects of intranasally administered oxytocin as a potential treatment for chronic pain in an animal model of mild TBI. METHODS: The lateral fluid percussion model of mild TBI was chosen for this purpose and after exposure to mild TBI the rats (n = 12) developed hind paw and facial allodynia compared to sham animals (n = 6). Oxytocin or a vehicle was afterwards administered intranasally and reactive pain was assessed by hind paw and facial von Frey testing. Some animals received the oxytocin receptor antagonist, atosiban, in addition to oxytocin/vehicle treatment (n = 12). The effect of oxytocin on ongoing and spontaneous pain was examined through conditioned place preference testing. To determine whether the effects of intranasal oxytocin could be attributed to delivery via the peripheral blood stream, some TBI animals received an intravenous injection of the same oxytocin dose that was given intranasally. ELISA immunoassays were carried out (n = 6) to measure concentrations of oxytocin in the trigeminal ganglia, pons, spinal cord, and olfactory bulb after intranasal administration and evaluate the most likely route of entry. RESULTS: These studies confirmed that the fluid percussion model can be used to study post-TBI facial allodynia. Oxytocin attenuated both reactive and spontaneous, ongoing non-reactive pain following mild TBI for at least 3-4 hours after intranasal administration by binding to OT or VA1-receptors most likely by a peri-trigeminal nerve mediated uptake. CONCLUSIONS: Intranasal oxytocin attenuates measures of reactive and non-reactive pain in a model of mild TBI and may represent a novel treatment for chronic pain in TBI patients.


Assuntos
Comportamento Animal/efeitos dos fármacos , Concussão Encefálica/complicações , Dor Crônica/tratamento farmacológico , Dor Facial/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Ocitocina/farmacologia , Administração Intranasal , Administração Intravenosa , Animais , Dor Crônica/etiologia , Modelos Animais de Doenças , Dor Facial/etiologia , Antagonistas de Hormônios/farmacologia , Hiperalgesia/etiologia , Masculino , Ocitocina/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores de Ocitocina/antagonistas & inibidores , Vasotocina/análogos & derivados , Vasotocina/farmacologia
4.
Mol Pain ; 13: 1744806917730212, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28845733

RESUMO

Abstract: Chronic pain after traumatic brain injury (TBI) is very common, but the mechanisms linking TBI to pain and the pain-related interactions of TBI with peripheral injuries are poorly understood. Chemokine receptors play an important role in both pain and brain injury. In the current work, we pursued the hypothesis that the epigenetically regulated CXC chemokine receptor 2 (CXCR2) is a crucial modulator of nociceptive sensitization induced by TBI. For these studies, we used the rat lateral fluid percussion model of TBI. Histone actyltransferase activity was blocked using anacardic acid beginning immediately following injury, or delayed for seven days prior to administration. The selective CXCR2 antagonist SCH527123 administered systemically or intrathecally was used to probe the role of chemokine signaling on mechanical hindpaw sensitization after TBI. The expression of the CXCR2 receptor was accomplished using real-time PCR, immunohistochemistry, and Western blotting, while epigenetic regulation was assessed using chromatin immunoprecipitation assay. The spinal levels of several pain-related mediators including CXCL1, an endogenous ligand for CXCR2, as well as brain-derived neurotrophic factor and prodynorphin were measured by enzyme-linked immunosorbent assay. We observed that anacardic acid potently blocked and reversed mechanical hindpaw sensitization after TBI. The same drug was able to prevent the upregulation of CXCR2 after TBI, but did not affect the spinal expression of other pain mediators. On the other hand, both systemically and intrathecally administered SCH527123 reversed hindpaw allodynia after TBI. Most of the spinal CXCR2 appeared to be expressed by spinal cord neurons. Chromatin immunoprecipitation experiments demonstrated TBI-enhanced association of the CXCR2 promoter with acetylated-H3K9 histone protein that was also reversible using anacardic acid. Taken together, our findings suggested that TBI causes the upregulation of spinal CXCR2 through an epigenetic mechanism ultimately supporting nociceptive sensitization. The use of CXCR2 antagonists may, therefore, be useful in pain resulting from TBI.


Assuntos
Benzamidas/farmacologia , Lesões Encefálicas Traumáticas/metabolismo , Ciclobutanos/farmacologia , Hiperalgesia/metabolismo , Receptores de Interleucina-8B/metabolismo , Ácidos Anacárdicos/farmacologia , Animais , Lesões Encefálicas Traumáticas/complicações , Quimiocina CXCL1/metabolismo , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Masculino , Ratos Sprague-Dawley , Receptores de Interleucina-8B/efeitos dos fármacos , Medula Espinal/metabolismo , Regulação para Cima
5.
Mol Pain ; 13: 1744806917727917, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28814144

RESUMO

Background: Nociception is maintained by genome-wide regulation of transcription in the dorsal root ganglia­spinal cord network. Hence, transcription factors constitute a promising class of targets for breakthrough pharmacological interventions to treat chronic pain. DNA decoys are oligonucleotides and specific inhibitors of transcription factor activities. A methodological series of in vivo­in vitro screening cycles was performed with decoy/transcription factor couples to identify targets capable of producing a robust and long-lasting inhibition of established chronic pain. Decoys were injected intrathecally and their efficacy was tested in the spared nerve injury and chronic constriction injury models of chronic pain in rats using repetitive von Frey testing. Results: Results demonstrated that a one-time administration of decoys binding to the Kruppel-like transcription factors (KLFs) 6, 9, and 15 produces a significant and weeks­month long reduction in mechanical hypersensitivity compared to controls. In the spared nerve injury model, decoy efficacy was correlated to its capacity to bind KLF15 and KLF9 at a specific ratio, while in the chronic constriction injury model, efficacy was correlated to the combined binding capacity to KLF6 and KLF9. AYX2, an 18-bp DNA decoy binding KLF6, KLF9, and KLF15, was optimized for clinical development, and it demonstrated significant efficacy in these models. Conclusions: These data highlight KLF6, KLF9, and KLF15 as transcription factors required for the maintenance of chronic pain and illustrate the potential therapeutic benefits of AYX2 for the treatment of chronic pain.


Assuntos
Dor Crônica/tratamento farmacológico , Fator 6 Semelhante a Kruppel/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/efeitos dos fármacos , Animais , Dor Crônica/metabolismo , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Oligonucleotídeos/metabolismo , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
6.
Mol Pain ; 13: 1744806917703112, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28394696

RESUMO

Background AYX1 is an unmodified DNA-decoy designed to reduce acute post-surgical pain and its chronification with a single intrathecal dose at the time of surgery. AYX1 inhibits the transcription factor early growth response protein 1, which is transiently induced at the time of injury and triggers gene regulation in the dorsal root ganglia and spinal cord that leads to long-term sensitization and pain. This work characterizes the AYX1 dose-response profile in rats and the link to AYX1 pharmacokinetics and metabolism in the cerebrospinal fluid, dorsal root ganglia, and spinal cord. Results The effects of ascending dose-levels of AYX1 on mechanical hypersensitivity were measured in the spared nerve injury model of chronic pain and in a plantar incision model of acute post-surgical pain. AYX1 dose-response profile shows that efficacy rapidly increases from a minimum effective dose of ∼ 0.5 mg to a peak maximum effective dose of ∼ 1 mg. With further dose escalation, the efficacy paradoxically appears to decrease by ∼ 30% and then returns to full efficacy at the maximum feasible dose of ∼ 4 mg. The reduction of efficacy is associated to doses triggering a near-saturation of AYX1 metabolism by nucleases in the cerebrospinal fluid and a paradoxical reduction of AYX1 exposure during the period of early growth response protein 1 induction. This effect is overcome at higher doses that compensate for the effect of metabolism. Discussion AYX1 is a competitive antagonist of early growth response protein 1, which is consistent with the overall increased efficacy observed as dose-levels initially escalate. Chemically, AYX1 is unprotected against degradation by nucleases. The sensitivity to nucleases is reflected in a paradoxical reduction of efficacy in the dose-response curve. Conclusions These findings point to the importance of the nuclease environment of the cerebrospinal fluid to the research and development of AYX1 and other intrathecal nucleotide-based therapeutics.


Assuntos
Dor Aguda/prevenção & controle , Analgésicos , Dor Crônica/prevenção & controle , DNA , Oligonucleotídeos , Dor Aguda/etiologia , Analgésicos/administração & dosagem , Analgésicos/metabolismo , Analgésicos/farmacologia , Animais , Dor Crônica/etiologia , DNA/administração & dosagem , DNA/metabolismo , DNA/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Gânglios Espinais/efeitos dos fármacos , Oligonucleotídeos/metabolismo , Oligonucleotídeos/farmacologia , Oligonucleotídeos/uso terapêutico , Medição da Dor , Dor Pós-Operatória/complicações , Dor Pós-Operatória/prevenção & controle , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos
7.
Br J Psychiatry ; 221(6): 766-767, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36403624
8.
Headache ; 57 Suppl 2: 64-75, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28485846

RESUMO

This article reviews material presented at the 2016 Scottsdale Headache Symposium. This presentation provided scientific results and rationale for the use of intranasal oxytocin for the treatment of migraine headache. Results from preclinical experiments are reviewed, including in vitro experiments demonstrating that trigeminal ganglia neurons possess oxytocin receptors and are inhibited by oxytocin. Furthermore, most of these same neurons contain CGRP, the release of which is inhibited by oxytocin. Results are also presented which demonstrate that nasal oxytocin inhibits responses of trigeminal nucleus caudalis neurons to noxious stimulation using either noxious facial shock or nitroglycerin infusion. These studies led to testing the analgesic effect of intranasal oxytocin in episodic migraineurs-studies which did not meet their primary endpoint of pain relief at 2 h, but which were highly informative and led to additional rat studies wherein inflammation was found to dramatically upregulate the number of oxytocin receptors available on trigeminal neurons. This importance of inflammation was supported by a series of in vivo rat behavioral studies, which demonstrated a clear craniofacial analgesic effect when a pre-existing inflammatory injury was present. The significance of inflammation was further solidified by a small single-dose clinical study, which showed analgesic efficacy that was substantially stronger in chronic migraine patients that had not taken an anti-inflammatory drug within 24 h of oxytocin dosing. A follow-on open label study examining effects of one month of intranasal oxytocin dosing did show a reduction in pain, but a more impressive decrease in the frequency of headaches in both chronic and high frequency episodic migraineurs. This study led to a multicountry double blind, placebo controlled study studying whether, over 2 months of dosing, "as needed" dosing of intranasal oxytocin by chronic and high frequency migraineurs would reduce the frequency of their headaches compared to a 1-month baseline period. This study failed to meet its primary endpoint, due to an extraordinarily high placebo rate in the country of most of the patients (Chile), but was also highly informative, showing strong results in other countries and strong post hoc indications of efficacy. The results provide a strong argument for further development of intranasal oxytocin for migraine prophylaxis.


Assuntos
Transtornos de Enxaqueca/prevenção & controle , Ocitócicos/administração & dosagem , Ocitocina/administração & dosagem , Administração Intranasal , Animais , Humanos , Gânglio Trigeminal/efeitos dos fármacos
9.
Curr Opin Anaesthesiol ; 30(4): 458-465, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28590258

RESUMO

PURPOSE OF REVIEW: This article reviews the phenomenon of opioid-induced hyperalgesia (OIH) and its implications for clinical anesthesia. The goal of this review is to give an update on perioperative prevention and treatment strategies, based on findings in preclinical and clinical research. RECENT FINDINGS: Several systems have been suggested to be involved in the pathophysiology of OIH with a focus on the glutaminergic system. Very recently preclinical data revealed that peripheral µ-opioid receptors (MORs) are key players in the development of OIH and acute opioid tolerance (AOT). Peripheral MOR antagonists could, thus, become a new prevention/treatment option of OIH in the perioperative setting. Although the impact of OIH on postoperative pain seems to be moderate, recent evidence suggests that increased hyperalgesia following opioid treatment correlates with the risk of developing persistent pain after surgery. In clinical practice, distinction among OIH, AOT and acute opioid withdrawal remains difficult, especially because a specific quantitative sensory test to diagnose OIH has not been validated yet. SUMMARY: Since the immediate postoperative period is not ideal to initiate long-term treatment for OIH, the best strategy is to prevent its occurrence. A multimodal approach, including choice of opioid, dose limitations and addition of nonopioid analgesics, is recommended.


Assuntos
Analgésicos Opioides/efeitos adversos , Anestesia/efeitos adversos , Hiperalgesia/induzido quimicamente , Tolerância a Medicamentos , Humanos , Hiperalgesia/prevenção & controle , Hiperalgesia/terapia , Síndrome de Abstinência a Substâncias/fisiopatologia
10.
Cephalalgia ; 36(10): 943-50, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26590611

RESUMO

AIMS: Our studies investigated the location of oxytocin receptors in the peripheral trigeminal sensory system and determined their role in trigeminal pain. METHODS: Oxytocin receptor expression and co-localization with calcitonin gene-related peptide was investigated in rat trigeminal ganglion using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the effects of facial electrocutaneous stimulation and adjuvant-induced inflammation of the temporomandibular joint on oxytocin receptor expression in the trigeminal ganglion. Finally, the effects of oxytocin on capsaicin-induced calcitonin gene-related peptide release from dural nociceptors were investigated using isolated rat dura mater. RESULTS: Oxytocin receptor immunoreactivity was present in rat trigeminal neurons. The vast majority of oxytocin receptor immunoreactive neurons co-expressed calcitonin gene-related peptide. Both electrocutaneous stimulation and adjuvant-induced inflammation led to a rapid upregulation of oxytocin receptor protein expression in trigeminal ganglion neurons. Oxytocin significantly and dose-dependently decreased capsaicin-induced calcitonin gene-related peptide release from dural nociceptors. CONCLUSION: Oxytocin receptor expression in calcitonin gene-related peptide containing trigeminal ganglion neurons, and the blockade of calcitonin gene-related peptide release from trigeminal dural afferents suggests that activation of these receptors may provide therapeutic benefit in patients with migraine and other primary headache disorders.


Assuntos
Transtornos da Cefaleia/metabolismo , Nociceptores/metabolismo , Receptores de Ocitocina/biossíntese , Gânglio Trigeminal/metabolismo , Animais , Peptídeo Relacionado com Gene de Calcitonina/análise , Peptídeo Relacionado com Gene de Calcitonina/biossíntese , Peptídeo Relacionado com Gene de Calcitonina/genética , Regulação da Expressão Gênica , Transtornos da Cefaleia/genética , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Ocitocina/análise , Receptores de Ocitocina/genética , Resultado do Tratamento , Gânglio Trigeminal/química
11.
J Am Chem Soc ; 136(17): 6401-5, 2014 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-24708172

RESUMO

Determining permeability of a given compound through human skin is a principal challenge owing to the highly complex nature of dermal tissue. We describe the application of an ambient mass spectrometry imaging method for visualizing skin penetration of sodium channel modulators, including novel synthetic analogs of natural neurotoxic alkaloids, topically applied ex vivo to human skin. Our simple and label-free approach enables successful mapping of the transverse and lateral diffusion of small molecules having different physicochemical properties without the need for extensive sample preparation.


Assuntos
Espectrometria de Massas/métodos , Absorção Cutânea , Pele/metabolismo , Bloqueadores dos Canais de Sódio/farmacocinética , Administração Tópica , Alcaloides/administração & dosagem , Alcaloides/química , Alcaloides/farmacocinética , Animais , Humanos , Permeabilidade , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/administração & dosagem , Bloqueadores dos Canais de Sódio/química , Canais de Sódio/metabolismo
12.
Pharmaceutics ; 16(6)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38931882

RESUMO

OBJECTIVE: Following a mild traumatic brain injury (mTBI), the most prevalent and profoundly debilitating occurrence is the emergence of an acute and persistent post-traumatic headache (PTH), for which there are presently no approved treatments. A crucial gap in knowledge exists regarding the consequences of an mTBI, which could serve as a foundation for the development of therapeutic approaches. The activation of trigeminal sensory nerve terminals that innervate the calvarial periosteum (CP)-a densely innervated tissue layer covering the calvarial skull-has been implicated in both migraines and PTHs. We have previously shown that trigeminal oxytocin receptors (OTRs) may provide a therapeutic target for PTHs. This study examined the expression of oxytocin receptors on trigeminal nerves innervating the periosteum and whether these receptors might serve as a therapeutic target for PTHs using a direct application of oxytocin to the periosteum in a rodent model of PTH. METHODS: We used retrograde tracing and immunohistochemistry to determine if trigeminal ganglion (TG) neurons innervating the periosteum expressed OTRs and/or CGRPs. To model the impact of local inflammation that occurs following an mTBI, we applied chemical inflammatory mediators directly to the CP and assessed for changes in immediate-early gene expression as an indication of neuronal activation. We also determined whether mTBI would lead to expression changes to OTR levels. To determine whether these OTRs could be a viable therapeutic target, we assessed the impact of oxytocin injections into the CP in a mouse model of PTH-induced periorbital allodynia. RESULTS: The results of these experiments demonstrate the following: (1) the cell bodies of CP afferents reside in the TG and express both OTRs and CGRPs; (2) inflammatory chemical stimulation of the periosteum leads to rapid activation of TG neurons (phospho-ERK (p-ERK) expression), (3) mTBI-induced inflammation increased OTR expression compared to the sham group; and (4) administration of oxytocin into the periosteum on day 2 and day 40 blocked cutaneous allodynia for up to one hour post-administration for both acute and persistence phases in the PTH model-an effect that was preventable by the administration of an OTR antagonist. CONCLUSION: Taken together, our observations suggest that periosteal trigeminal afferents contribute to post-TBI craniofacial pain, and that periosteum tissue can be used as a potential local target for therapeutics such as oxytocin.

13.
J Pers Med ; 14(2)2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38392617

RESUMO

Sex hormones and migraine are closely interlinked. Women report higher levels of migraine symptoms during periods of sex hormone fluctuation, particularly during puberty, pregnancy, and perimenopause. Ovarian steroids, such as estrogen and progesterone, exert complex effects on the peripheral and central nervous systems, including pain, a variety of special sensory and autonomic functions, and affective processing. A panel of basic scientists, when challenged to explain what was known about how sex hormones affect the nervous system, focused on two hormones: estrogen and oxytocin. Notably, other hormones, such as progesterone, testosterone, and vasopressin, are less well studied but are also highlighted in this review. When discussing what new therapeutic agent might be an alternative to hormone therapy and menopause replacement therapy for migraine treatment, the panel pointed to oxytocin delivered as a nasal spray. Overall, the conclusion was that progress in the preclinical study of hormones on the nervous system has been challenging and slow, that there remain substantial gaps in our understanding of the complex roles sex hormones play in migraine, and that opportunities remain for improved or novel therapeutic agents. Manipulation of sex hormones, perhaps through biochemical modifications where its positive effects are selected for and side effects are minimized, remains a theoretical goal, one that might have an impact on migraine disease and other symptoms of menopause. This review is a call to action for increased interest and funding for preclinical research on sex hormones, their metabolites, and their receptors. Interdisciplinary research, perhaps facilitated by a collaborative communication network or panel, is a possible strategy to achieve this goal.

14.
Br J Pharmacol ; 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715413

RESUMO

BACKGROUND AND PURPOSE: The voltage-gated sodium channel isoform NaV1.7 is a high-interest target for the development of non-opioid analgesics due to its preferential expression in pain-sensing neurons. NaV1.7 is also expressed in autonomic neurons, yet its contribution to involuntary visceral reflexes has received limited attention. The small molecule inhibitor ST-2560 was advanced into pain behaviour and cardiovascular models to understand the pharmacodynamic effects of selective inhibition of NaV1.7. EXPERIMENTAL APPROACH: Potency of ST-2560 at NaV1.7 and off-target ion channels was evaluated by whole-cell patch-clamp electrophysiology. Effects on nocifensive reflexes were assessed in non-human primate (NHP) behavioural models, employing the chemical capsaicin and mechanical stimuli. Cardiovascular parameters were monitored continuously in freely-moving, telemetered NHPs following administration of vehicle and ST-2560. KEY RESULTS: ST-2560 is a potent inhibitor (IC50 = 39 nM) of NaV1.7 in primates with ≥1000-fold selectivity over other isoforms of the human NaV1.x family. Following systemic administration, ST-2560 (0.1-0.3 mg·kg-1, s.c.) suppressed noxious mechanical- and chemical-evoked reflexes at free plasma concentrations threefold to fivefold above NaV1.7 IC50. ST-2560 (0.1-1.0 mg·kg-1, s.c.) also produced changes in haemodynamic parameters, most notably a 10- to 20-mmHg reduction in systolic and diastolic arterial blood pressure, at similar exposures. CONCLUSIONS AND IMPLICATIONS: Acute pharmacological inhibition of NaV1.7 is antinociceptive, but also has the potential to impact the cardiovascular system. Further work is merited to understand the role of NaV1.7 in autonomic ganglia involved in the control of heart rate and blood pressure, and the effect of selective NaV1.7 inhibition on cardiovascular function.

15.
J Am Chem Soc ; 135(48): 18012-5, 2013 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-24261833

RESUMO

Both chronic and neuropathic pain conditions are associated with increased expression of certain voltage-gated sodium ion channel (NaV) isoforms in peripheral sensory neurons. A method for noninvasive imaging of these channels could represent a powerful tool for investigating aberrant expression of NaV and its role in pain pathogenesis. Herein, we describe the synthesis and evaluation of a positron emission tomography (PET) radiotracer targeting NaVs, the design of which is based on the potent, NaV-selective inhibitor saxitoxin. Both autoradiography analysis of sciatic nerves excised from injured rats as well as whole animal PET-MR imaging demonstrate that a systemically administered [(18)F]-labeled saxitoxin derivative concentrates at the site of nerve injury, consistent with upregulated sodium channel expression following axotomy. This type of PET agent has potential use for serial monitoring of channel expression levels at injured nerves throughout wound healing and/or following drug treatment. Such information may be correlated with pain behavioral analyses to help shed light on the complex molecular processes that underlie pain sensation.


Assuntos
Neuralgia/diagnóstico , Saxitoxina/análogos & derivados , Nervo Isquiático/lesões , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Canais de Sódio Disparados por Voltagem/análise , Animais , Radioisótopos de Flúor/química , Imageamento por Ressonância Magnética , Neuralgia/metabolismo , Tomografia por Emissão de Pósitrons , Ratos , Saxitoxina/síntese química , Nervo Isquiático/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Canais de Sódio Disparados por Voltagem/metabolismo
16.
Mol Pain ; 9: 33, 2013 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-23819466

RESUMO

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has shown promise in the alleviation of acute and chronic pain by altering the activity of cortical areas involved in pain sensation. However, current single-coil rTMS technology only allows for effects in surface cortical structures. The ability to affect activity in certain deep brain structures may however, allow for a better efficacy, safety, and tolerability. This study used PET imaging to determine whether a novel multi-coil rTMS would allow for preferential targeting of the dorsal anterior cingulate cortex (dACC), an area always activated with pain, and to provide preliminary evidence as to whether this targeted approach would allow for efficacious, safe, and tolerable analgesia both in a volunteer/acute pain model as well as in fibromyalgia chronic pain patients. METHODS: Part 1: Different coil configurations were tested in a placebo-controlled crossover design in volunteers (N = 16). Tonic pain was induced using a capsaicin/thermal pain model and functional brain imaging was performed by means of H2(15)O positron emission tomography - computed tomography (PET/CT) scans. Differences in NRS pain ratings between TMS and sham treatment (NRS(TMS)-NRS(placebo)) which were recorded each minute during the 10 minute PET scans. Part 2: 16 fibromyalgia patients were subjected to 20 multi-coil rTMS treatments over 4 weeks and effects on standard pain scales (Brief Pain Inventory, item 5, i.e. average pain NRS over the last 24 hours) were recorded. RESULTS: A single 30 minute session using one of 3 tested rTMS coil configurations operated at 1 Hz consistently produced robust reduction (mean 70% on NRS scale) in evoked pain in volunteers. In fibromyalgia patients, the 20 rTMS sessions also produced a significant pain inhibition (43% reduction in NRS pain over last 24 hours), but only when operated at 10 Hz. This degree of pain control was maintained for at least 4 weeks after the final session. CONCLUSION: Multi-coil rTMS may be a safe and effective treatment option for acute as well as for chronic pain, such as that accompanying fibromyalgia. Further studies are necessary to optimize configurations and settings as well as to elucidate the mechanisms that lead to the long-lasting pain control produced by these treatments.


Assuntos
Fibromialgia/fisiopatologia , Giro do Cíngulo/fisiologia , Dor/fisiopatologia , Estimulação Magnética Transcraniana , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Neuromodulation ; 16(4): 318-27; discussion 327, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23252766

RESUMO

OBJECTIVE: The study was performed to test the hypothesis that high-frequency alternating current (HFAC) ranging from 2 to 100 kHz delivered to the spinal dorsal roots reduces activity of spinal wide dynamic range (WDR) dorsal horn neurons (DHNs) during noxious peripheral stimulation. MATERIALS AND METHODS: This hypothesis was tested in both small and large animal in vivo preparations. Single-unit extracellular spinal DHN recordings were performed in seven adult rats and four adult goats while testing various parameters of HFAC delivered to the nerve roots or dorsal root entry zone using various electrode types. Frequencies tested ranged from 2 to 100 kHz but focused on the 3 to 50 kHz range. This study investigated the ability of HFAC to inhibit WDR neuronal activity evoked by noxious mechanical (pinch), and electrical stimuli was tested but was primarily focused on electrical stimulation. RESULTS: Rat Study: Effects of HFAC were successfully tested on 11 WDR neurons. Suppression or complete blockade of evoked activity was observed in all 11 of these neurons. Complete data sets for neurons systematically tested with 15 baseline and post-HFAC stimulus sweeps were obtained in five neurons, the nociceptive activity of which was suppressed by an average of 69 ± 9.7% (p < 0.0001). Goat Study: HFAC was successfully tested on 15 WDR neurons. Conclusive suppression or complete nociceptive blockade was observed for 12/15 and complete data sets with at least 20 baseline and post-HFAC stimulus sweeps were obtained from eight DHNs. For these neurons the mean activity suppression was 70 ± 10% (p < 0.005). CONCLUSIONS: Delivery of HFAC to the region of epidural nerve root or nerve root entry inhibited afferent nociceptive input and therefore may have potential to serve as an alternative to traditional spinal cord stimulation without sensory paresthesia as neuronal activation cannot occur at frequencies in this range.


Assuntos
Estimulação Elétrica , Nociceptores/fisiologia , Medula Espinal/fisiologia , Nervos Espinhais/fisiologia , Potenciais de Ação/fisiologia , Animais , Biofísica , Pressão Sanguínea , Estimulação Elétrica/efeitos adversos , Eletrocardiografia , Eletromiografia , Gânglios Espinais/citologia , Cabras , Masculino , Fibras Nervosas/fisiologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/citologia
18.
J Pain ; 24(10): 1859-1874, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37271350

RESUMO

Traumatic brain injury (TBI) can cause acute and chronic pain along with motor, cognitive, and emotional problems. Although the mechanisms are poorly understood, previous studies suggest disruptions in endogenous pain modulation may be involved. Voluntary exercise after a TBI has been shown to reduce some consequences of injury including cognitive impairment. We hypothesized, therefore, that voluntary exercise could augment endogenous pain control systems in a rodent model of TBI. For these studies, we used a closed-head impact procedure in male mice modeling mild TBI. We investigated the effect of voluntary exercise on TBI-induced hindpaw nociceptive sensitization, diffuse noxious inhibitory control failure, and periorbital sensitization after bright light stress, a model of post-traumatic headache. Furthermore, we investigated the effects of exercise on memory, circulating markers of brain injury, neuroinflammation, and spinal cord gene expression. We observed that exercise significantly reduced TBI-induced hindpaw allodynia and periorbital allodynia in the first week following TBI. We also showed that exercise improved the deficits associated with diffuse noxious inhibitory control and reduced bright light stress-induced allodynia up to 2 months after TBI. In addition, exercise preserved memory and reduced TBI-induced increases in spinal BDNF, CXCL1, CXCL2, and prodynorphin expression, all genes previously linked to TBI-induced nociceptive sensitization. Taken together, our observations suggest that voluntary exercise may reduce pain after TBI by reducing TBI-induced changes in nociceptive signaling and preserving endogenous pain control systems. PERSPECTIVE: This article evaluates the effects of exercise on pain-related behaviors in a preclinical model of traumatic brain injury (TBI). The findings show that exercise reduces nociceptive sensitization, loss of diffuse noxious inhibitory control, memory deficits, and spinal nociception-related gene expression after TBI. Exercise may reduce or prevent pain after TBI.


Assuntos
Concussão Encefálica , Lesões Encefálicas Traumáticas , Dor Crônica , Cefaleia Pós-Traumática , Camundongos , Masculino , Animais , Cefaleia Pós-Traumática/complicações , Hiperalgesia/etiologia , Hiperalgesia/terapia , Lesões Encefálicas Traumáticas/complicações , Dor Crônica/complicações
19.
Reg Anesth Pain Med ; 48(9): 462-470, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-36822815

RESUMO

BACKGROUND: Moderate-to-severe acute pain is prevalent in many healthcare settings and associated with adverse outcomes. Peripheral nerve blockade using traditional needle-based and local anesthetic-based techniques improves pain outcomes for some patient populations but has shortcomings limiting use. These limitations include its invasiveness, potential for local anesthetic systemic toxicity, risk of infection with an indwelling catheter, and relatively short duration of blockade compared with the period of pain after major injuries. Focused ultrasound is capable of inhibiting the peripheral nervous system and has potential as a pain management tool. However, investigations of its effect on peripheral nerve nociceptive fibers in animal models of acute pain are lacking. In an in vivo acute pain model, we investigated focused ultrasound's effects on behavior and peripheral nerve structure. METHODS: Focused ultrasound was applied directly to the sciatic nerve of rats just prior to a hindpaw incision; three control groups (focused ultrasound sham only, hindpaw incision only, focused ultrasound sham+hindpaw incision) were also included. For all four groups (intervention and controls), behavioral testing (thermal and mechanical hyperalgesia, hindpaw extension and flexion) took place for 4 weeks. Structural changes to peripheral nerves of non-focused ultrasound controls and after focused ultrasound application were assessed on days 0 and 14 using light microscopy and transmission electron microscopy. RESULTS: Compared with controls, after focused ultrasound application, animals had (1) increased mechanical nociceptive thresholds for 2 weeks; (2) sustained increase in thermal nociceptive thresholds for ≥4 weeks; (3) a decrease in hindpaw motor response for 0.5 weeks; and (4) a decrease in hindpaw plantar sensation for 2 weeks. At 14 days after focused ultrasound application, alterations to myelin sheaths and nerve fiber ultrastructure were observed both by light and electron microscopy. DISCUSSION: Focused ultrasound, using a distinct parameter set, reversibly inhibits A-delta peripheral nerve nociceptive, motor, and non-nociceptive sensory fiber-mediated behaviors, has a prolonged effect on C nociceptive fiber-mediated behavior, and alters nerve structure. Focused ultrasound may have potential as a peripheral nerve blockade technique for acute pain management. However, further investigation is required to determine C fiber inhibition duration and the significance of nerve structural changes.


Assuntos
Dor Aguda , Anestésicos Locais , Ratos , Animais , Ratos Sprague-Dawley , Fibras Nervosas/fisiologia , Hiperalgesia , Nervo Isquiático , Modelos Animais
20.
NMR Biomed ; 25(4): 563-9, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22447731

RESUMO

The ability of divalent manganese to enter neurons via calcium channels makes manganese an excellent MRI contrast agent for the imaging of nociception, the afferent neuronal encoding of pain perception. There is growing evidence that nociceptive neurons possess increased expression and activity of calcium channels, which would allow for the selective accumulation of manganese at these sites. In this study, we show that oral manganese chloride leads to increased enhancement of peripheral nerves involved in nociception on T(1)-weighted MRI. Oral rather than intravenous administration was chosen for its potentially better safety profile, making it a better candidate for clinical translation with important applications, such as pain diagnosis, therapy and research. The spared nerve injury (SNI) model of neuropathic pain was used for the purposes of this study. SNI rats were given, sequentially, increasing amounts of manganese chloride (lowest, 2.29 mg/100 g weight; highest, 20.6 mg/100 g weight) with alanine and vitamin D(3) by oral gavage. Compared with controls, SNI rats demonstrated increased signal-to-background ratios on T(1)-weighted fast spin echo MRI, which was confirmed by and correlated strongly with spectrometry measurements of nerve manganese concentration. We also found the difference between SNI and control rats to be greater at 48 h than at 24 h after dosing, indicating increased manganese retention in addition to increased manganese uptake in nociceptive nerves. This study demonstrates that oral manganese is a viable method for the imaging of nerves associated with increased nociceptive activity.


Assuntos
Cloretos/administração & dosagem , Imageamento por Ressonância Magnética/métodos , Compostos de Manganês/administração & dosagem , Neuralgia/diagnóstico , Neuralgia/fisiopatologia , Nociceptividade , Administração Oral , Animais , Meios de Contraste/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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