RESUMO
OBJECTIVE: To explore the burdens experienced by family carers who support older relatives to manage their medications at home. METHODS: This study, based on a larger UK medication management study: MEdication Management in Older people: Realist Approaches Based on Literature and Evaluation (MEMORABLE), reports on findings from family carer interviews (n = 16). The five stages of medication management, identified in MEMORABLE, were used to inform the analysis. RESULTS: Family carers described being involved in some or all five of the MEMORABLE stages to help manage older relatives' medications. Their capacity to undertake this role was sometimes limited by the complex workload involved as well personal circumstances such as time, distance and relationships. Family carers perceived that their knowledge and skills in medication management improved with experience, but also described stress associated with information lag and gaps, risk and responsibility, and loss. They described medication management burdens that needed mitigation: ambiguity, concealment, unfamiliarity, fragmentation and in particular exclusion, conflicted interests and expectation of coping. CONCLUSION: To help mitigate these burdens, family carers should receive better information, training and support for this role. PRACTICE IMPLICATIONS: Continued reliance on family carers for medication management requires strategic recognition in policy, funding and practice.
Assuntos
Adaptação Psicológica , Cuidadores , Idoso , Família , Humanos , Resolução de ProblemasRESUMO
BACKGROUND: More older people are living in the community with multiple diagnoses and medications. Managing multiple medications produces issues of unrivalled complexity for those involved. Despite increasing literature on the subject, gaps remain in understanding how, why and for whom complex medication management works, and therefore how best to improve practice and outcomes. MEMORABLE, MEdication Management in Older people: Realist Approaches Based on Literature and Evaluation, aimed to address these gaps. METHODS: MEMORABLE used realism to understand causal paths within medication management. Informed by RAMESES (Realist And Meta-narrative Evidence Synthesis: and Evolving Standards) guidelines, MEMORABLE involved three overlapping work packages: 1) Realist Review of the literature (24 articles on medication management exploring causality); 2) Realist Evaluation (50 realist-informed interviews with older people, family carers and health and care practitioners, explaining their experiences); and 3) data synthesis and theorising from 1) and 2). RESULTS: Medication management was viewed from the perspective of 'implementation' and structured into five stages: identifying a problem (Stage 1), getting a diagnosis and/or medications (Stage 2), starting, changing or stopping medications (Stage 3), continuing to take medications (Stage 4), and reviewing/reconciling medications (Stage 5). Three individual stages (1, 3 and 4) are conducted by the older person sometimes with family carer support when they balance routines, coping and risk. Stages 2 and 5 are interpersonal where the older person works with a practitioner-prescriber-reviewer, perhaps with carer involvement. Applying Normalisation Process Theory, four steps were identified within each stage: 1) sense making: information, clarification; 2) action: shared-decision-making; 3) reflection/monitoring; and 4) enduring relationships, based on collaboration and mutual trust. In a detailed analysis of Stage 5: Reviewing/reconciling medications, adopting the lens of 'burden', MEMORABLE identified five burdens amenable to mitigation: ambiguity, concealment, unfamiliarity, fragmentation and exclusion. Two initial improvement propositions were identified for further research: a risk screening tool and individualised information. CONCLUSIONS: Older people and family carers often find medication management challenging and burdensome particularly for complex regimens. Practitioners need to be aware of this potential challenge, and work with older people and their carers to minimise the burden associated with medication management. TRIAL REGISTRATION: PROSPERO 2016:CRD42016043506.
Assuntos
Cuidadores , Conduta do Tratamento Medicamentoso , Idoso , Idoso de 80 Anos ou mais , HumanosRESUMO
A recent study with Ca++-sensitive-dyes in neurons in whole DRGs (Table 5) found that much lower percentages of nociceptors were polymodal-nociceptors (PMNs) (Emery et al., 2016), than the 50-80% values in many electrophysiological fiber studies. This conflict highlighted the lack of knowledge about percentages of nociceptor-subtypes in the DRG. This was analysed from intracellularly-recorded neurons in rat lumbar DRGs stimulated from outside the skin. Polymodal nociceptors (PMNs) were 11% of all neurons and 19% of all nociceptors. Most PMNs had C-fibers (CPMNs). Percentages of C-nociceptors that were CPMNs varied with receptive field (RF) depths, whether superficial (â¼80%), dermal (25%), deep (0%) or cutaneous (superficial + dermal) (40%). This explains CPMN percentages 40-90%, being highest, in electrophysiological studies using cutaneous nerves, and lowest in studies that also include deep RFs, including ours, and the recent Ca++-imaging studies in whole DRGs. Despite having been originally described in 1967 (Burgess and Perl), both Aß-nociceptors and Aß-moderate pressure receptors (MPRs) remain overlooked. Most A-fiber nociceptors in rodents have Aß-fibers. Of rat lumbar Aß-nociceptors with superficial RFs, 50% were MPRs with variable medium-low trkA-expression. Despite having conduction velocities at the two extremes for nociceptors, both CPMNs and MPRs have relatively low thresholds, superficial/epidermal RFs and low trkA-expression. For abbreviations used see Table 5.
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Ongoing/spontaneous pain behavior is associated with ongoing/spontaneous firing (SF) in adult DRG C-fiber nociceptors (Djouhri et al., 2006). Causes of this SF are not understood. We show here that conducting (sometimes called uninjured) C-nociceptors in neuropathic pain models with more hyperpolarized resting membrane potentials (Ems) have lower SF rates. Understanding the control of their Ems may therefore be important for limiting pathological pain. We report that TREK2, a leak K(+) channel, is selectively expressed in IB4 binding rat C-nociceptors. These IB4(+) C-neurons are â¼10 mV more hyperpolarized than IB4(-) C-neurons in vivo (Fang et al., 2006). TREK2 knockdown by siRNA in these neurons in culture depolarized them by â¼10 mV, suggesting that TREK2 is responsible for this â¼10 mV difference. In vivo, more hyperpolarized C-nociceptor Ems were associated with higher cytoplasmic edge-TREK2 expression (edge-TREK2). Edge-TREK2 decreased in C-neurons 7 d after axotomy, and their Ems depolarized by â¼10 mV. This again supports a contribution of TREK2 to their Ems. These relationships between (1) Em and TREK2, (2) SF rate and Em, and (3) spontaneous pain behavior and C-nociceptor SF rate suggested that TREK2 knockdown might increase spontaneous pain. After CFA-induced inflammation, spontaneous foot lifting (a measure of spontaneous pain) was (1) greater in rats with naturally lower TREK2 in ipsilateral small DRG neurons and (2) increased by siRNA-induced TREK2 knockdown in vivo. We conclude that TREK2 hyperpolarizes IB4 binding C-nociceptors and limits pathological spontaneous pain. Similar TREK2 distributions in small DRG neurons of several species suggest that these role(s) of TREK2 may be widespread.
Assuntos
Potenciais da Membrana/fisiologia , Neuralgia/metabolismo , Nociceptores/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Eletrofisiologia , Feminino , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Gânglios Espinais/microbiologia , Técnicas de Silenciamento de Genes , Imuno-Histoquímica , Ratos , Ratos WistarRESUMO
I(h), which influences neuronal excitability, has recently been measured in vivo in sensory neuron subtypes in dorsal root ganglia (DRGs). However, expression levels of HCN (hyperpolarization-activated cyclic nucleotide-gated) channel proteins that underlie I(h) were unknown. We therefore examined immunostaining of the most abundant isoforms in DRGs, HCN1 and HCN2 in these neuron subtypes. This immunostaining was cytoplasmic and membrane-associated (ring). Ring-staining for both isoforms was in neurofilament-rich A-fiber neurons, but not in small neurofilament-poor C-fiber neurons, although some C-neurons showed cytoplasmic HCN2 staining. We recorded intracellularly from DRG neurons in vivo, determined their sensory properties (nociceptive or low-threshold-mechanoreceptive, LTM) and conduction velocities (CVs). We then injected fluorescent dye enabling subsequent immunostaining. For each dye-injected neuron, ring- and cytoplasmic-immunointensities were determined relative to maximum ring-immunointensity. Both HCN1- and HCN2-ring-immunointensities were positively correlated with CV in both nociceptors and LTMs; they were high in Aß-nociceptors and Aα/ß-LTMs. High HCN1 and HCN2 levels in Aα/ß-neurons may, via I(h), influence normal non-painful (e.g. touch and proprioceptive) sensations as well as nociception and pain. HCN2-, not HCN1-, ring-intensities were higher in muscle spindle afferents (MSAs) than in all other neurons. The previously reported very high I(h) in MSAs may relate to their very high HCN2. In normal C-nociceptors, low HCN1 and HCN2 were consistent with their low/undetectable I(h.) In some C-LTMs HCN2-intensities were higher than in C-nociceptors. Together, HCN1 and HCN2 expressions reflect previously reported I(h) magnitudes and properties in neuronal subgroups, suggesting these isoforms underlie I(h) in DRG neurons. Expression of both isoforms was NT3-dependent in cultured DRG neurons. HCN2-immunostaining in small neurons increased 1 day after cutaneous inflammation (CFA-induced) and recovered by 4 days. This could contribute to acute inflammatory pain. HCN2-immunostaining in large neurons decreased 4 days after CFA, when NT3 was decreased in the DRG. Thus HCN2-expression control differs between large and small neurons.
Assuntos
Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Gânglios Espinais/metabolismo , Inflamação/metabolismo , Canais Iônicos/metabolismo , Neurônios/metabolismo , Neurotrofina 3/metabolismo , Nociceptores/metabolismo , Canais de Potássio/metabolismo , Potenciais de Ação/fisiologia , Animais , Feminino , Gânglios Espinais/citologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Inflamação/induzido quimicamente , Condução Nervosa/fisiologia , Neurônios/citologia , Dor/metabolismo , Dor/fisiopatologia , Estimulação Física , Ratos , Ratos Wistar , Pele/metabolismoRESUMO
Partial nerve injury leads to peripheral neuropathic pain. This injury results in conducting/uninterrupted (also called uninjured)sensory fibres, conducting through the damaged nerve alongside axotomised/degenerating fibres. In rats seven days after L5 spinal nerve axotomy (SNA) or modified-SNA (added loose-ligation of L4 spinal nerve with neuroinflammation-inducing chromic-gut),we investigated (a) neuropathic pain behaviours and (b) electrophysiological changes in conducting/uninterrupted L4 dorsal root ganglion (DRG) neurons with receptive fields (called: L4-receptive-field-neurons). Compared to pretreatment, modified-SNA rats showed highly significant increases in spontaneous-foot lifting duration, mechanical-hypersensitivity/allodynia, and heathypersensitivity/hyperalgesia, that were significantly greater than after SNA, especially spontaneous-foot-lifting. We recorded intracellularly in vivo from normal L4/L5 DRG neurons and ipsilateral L4-receptive-field-neurons. After SNA or modified-SNA, L4-receptive-field-neurons showed the following: (a) increased percentages of C-, Aδ-, and Aß-nociceptors and cutaneous Aα/ß-low-thresholdmechanoreceptors with ongoing/spontaneous firing; (b) spontaneous firing in C-nociceptors that originated peripherally; this was ata faster rate in modified-SNA than SNA; (c) decreased electricalthresholds in A-nociceptors after SNA; (d) hyperpolarised membrane potentials in A-nociceptors and Aα/-low-thresholdmechanoreceptors after SNA, but not C-nociceptors; (e) decreased somatic action potential rise times in C- and A-nociceptors, not Aα/ß-low-threshold-mechanoreceptors. We suggest that these changes in subtypes of conducting/uninterrupted neurons after partial nerve injury contribute to the different aspects of neuropathic pain as follows: spontaneous firing in nociceptors to ongoing/spontaneous pain; spontaneous firing in Aα/ß-low-threshold-mechanoreceptors to dysesthesias/paresthesias; and lowered A-nociceptor electrical thresholds to A-nociceptor sensitization,and greater evoked pain [corrected].
Assuntos
Potenciais de Ação/fisiologia , Gânglios Espinais/fisiopatologia , Neuralgia/fisiopatologia , Nociceptores/fisiologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Nervos Espinhais/fisiologia , Animais , Axotomia , Comportamento Animal , Feminino , Temperatura Alta , Hiperalgesia/fisiopatologia , Mecanorreceptores/fisiologia , Potenciais da Membrana/fisiologia , Parestesia/fisiopatologia , Ratos , Ratos Wistar , Nervos Espinhais/lesões , Nervos Espinhais/fisiopatologia , TatoRESUMO
Two pore domain potassium (K2P) channels (KCNKx.x) cause K⺠leak currents and are major contributors to resting membrane potential. Their roles in dorsal root ganglion (DRG) neurons normally, and in pathological pain models, are poorly understood. Therefore, we examined mRNA levels for 10 K2P channels in L4 and L5 rat DRGs normally, and 1 day and 4 days after unilateral cutaneous inflammation, induced by intradermal complete Freund's adjuvant (CFA) injections. Spontaneous foot lifting (SFL) duration (spontaneous pain behaviour) was measured in 1 day and 4 day rats <1h before DRG harvest. mRNA levels for KCNK channels and Kv1.4 relative to GAPDH (n=4-6 rats/group) were determined with real-time RT-PCR. This study is the first to demonstrate expression of THIK1, THIK2 and TWIK2 mRNA in DRGs. Abundance in normal DRGs was, in descending order: Kv1.4>TRESK(KCNK18)>TRAAK(KCNK4)>TREK2(KCNK10)=TWIK2(KCNK6)>TREK1 (KCNK2)=THIK2(KCNK12)>TASK1(KCNK3)>TASK2(KCNK5)>THIK1(KCNK13)=TASK3(KCNK9). During inflammation, the main differences from normal in DRG mRNA levels were bilateral, suggesting systemic regulation, although some channels showed evidence of ipsilateral modulation. By 1 day, bilateral K2P mRNA levels had decreased (THIK1) or increased (TASK1, THIK2) but by 4 days they were consistently decreased (TASK2, TASK3) or tended to decrease (excluding TRAAK). The decreased TASK2 mRNA was mirrored by decreased protein (TASK2-immunoreactivity) at 4 days. Ipsilateral mRNA levels at 4days compared with 1 day were lower (TRESK, TASK1, TASK3, TASK2 and THIK2) or higher (THIK1). Ipsilateral SFL duration during inflammation was positively correlated with ipsilateral TASK1 and TASK3 mRNAs, and contralateral TASK1, TRESK and TASK2 mRNAs. Thus changes in K2P mRNA levels occurred during inflammation and for 4 K2P channels were associated with spontaneous pain behaviour (SFL). K2P channels and their altered expression are therefore associated with inflammation-induced pain.
Assuntos
Gânglios Espinais/metabolismo , Inflamação/metabolismo , Neurônios/metabolismo , Dor/metabolismo , Canais de Potássio/genética , RNA Mensageiro/metabolismo , Animais , Feminino , Adjuvante de Freund/metabolismo , Inflamação/complicações , Neurônios/fisiologia , Dor/etiologia , Potássio/metabolismo , RNA Mensageiro/análise , Ratos , Ratos WistarRESUMO
Binding to isolectin-B4 (IB4) and expression of tyrosine kinase A (trkA) (the high-affinity NGF receptor) have been used to define two different subgroups of nociceptive small dorsal root ganglion (DRG) neurons. We previously showed that only nociceptors have high trkA levels. However, information about sensory and electrophysiological properties in vivo of single identified IB4-binding neurons, and about their trkA expression levels, is lacking. IB4-positive (IB4+) and small dark neurons had similar size distributions. We examined IB4-binding levels in >120 dye-injected DRG neurons with sensory and electrophysiological properties recorded in vivo. Relative immunointensities for trkA and two TTX-resistant sodium channels (Nav1.8 and Nav1.9) were also measured in these neurons. IB4+ neurons were classified as strongly or weakly IB4+. All strongly IB4+ neurons were C-nociceptor type (C-fiber nociceptive or unresponsive). Of 32 C-nociceptor-type neurons examined, approximately 50% were strongly IB4+, approximately 20% were weakly IB4+ and approximately 30% were IB4-. Adelta low-threshold mechanoreceptive (LTM) neurons were weakly IB4+ or IB4-. All 33 A-fiber nociceptors and all 44 Aalpha/beta-LTM neurons examined were IB4-. IB4+ compared with IB4- C-nociceptor-type neurons had longer somatic action potential durations and rise times, slower conduction velocities, more negative membrane potentials, and greater immunointensities for Nav1.9 but not Nav1.8. Immunointensities of IB4 binding in C-neurons were positively correlated with those of Nav1.9 but not Nav1.8. Of 23 C-neurons tested for both trkA and IB4, approximately 35% were trkA+/IB4+ but with negatively correlated immunointensities; 26% were IB4+/trkA-, and 35% were IB4-/trkA+. We conclude that strongly IB4+ DRG neurons are exclusively C-nociceptor type and that high Nav1.9 expression may contribute to their distinct membrane properties.
Assuntos
Gânglios Espinais/fisiologia , Fibras Nervosas Amielínicas/metabolismo , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Nociceptores/metabolismo , Canais de Sódio/metabolismo , Potenciais de Ação/fisiologia , Animais , Eletrofisiologia , Feminino , Gânglios Espinais/citologia , Imuno-Histoquímica , Lectinas/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8 , Canal de Sódio Disparado por Voltagem NAV1.9 , Fibras Nervosas Mielinizadas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/ultraestrutura , Ratos , Ratos Wistar , Receptor trkA/metabolismoRESUMO
Spontaneous pain, a poorly understood aspect of human neuropathic pain, is indicated in animals by spontaneous foot lifting (SFL). To determine whether SFL is caused by spontaneous firing in nociceptive neurons, we studied the following groups of rats: (1) untreated; (2) spinal nerve axotomy (SNA), L5 SNA 1 week earlier; (3) mSNA (modified SNA), SNA plus loose ligation of the adjacent L4 spinal nerve with inflammation-inducing chromic gut; and (4) CFA (complete Freund's adjuvant), intradermal complete Freund's adjuvant-induced hindlimb inflammation 1 and 4 d earlier. In all groups, recordings of SFL and of spontaneous activity (SA) in ipsilateral dorsal root ganglion (DRG) neurons (intracellularly) were made. Evoked pain behaviors were measured in nerve injury (SNA/mSNA) groups. Percentages of nociceptive-type C-fiber neurons (C-nociceptors) with SA increased in intact L4 but not axotomized L5 DRGs in SNA and mSNA (to 35%), and in L4/L5 DRGs 1-4 d after CFA (to 38-25%). SFL occurred in mSNA but not SNA rats. It was not correlated with mechanical allodynia, extent of L4 fiber damage [ATF3 (activation transcription factor 3) immunostaining], or percentage of L4 C-nociceptors with SA. However, L4 C-nociceptors with SA fired faster after mSNA (1.8 Hz) than SNA (0.02 Hz); estimated L4 total firing rates were approximately 5.0 and approximately 0.6 kHz, respectively. Similarly, after CFA, faster L4 C-nociceptor SA after 1 d was associated with SFL, whereas slower SA after 4 d was not. Thus, inflammation causes L4 C-nociceptor SA and SFL. Overall, SFL was related to SA rate in intact C-nociceptors. Both L5 degeneration and chromic gut cause inflammation. Therefore, both SA and SFL/spontaneous pain after nerve injury (mSNA) may result from cumulative neuroinflammation.
Assuntos
Hiperalgesia/fisiopatologia , Inflamação/complicações , Fibras Nervosas Amielínicas/fisiologia , Neuralgia/fisiopatologia , Dor/fisiopatologia , Potenciais de Ação , Animais , Axotomia , Feminino , Reação a Corpo Estranho/fisiopatologia , Adjuvante de Freund/toxicidade , Gânglios Espinais/fisiologia , Membro Posterior/inervação , Temperatura Alta , Hiperalgesia/etiologia , Ligadura , Fusos Musculares/fisiopatologia , Nociceptores/fisiologia , Dor/etiologia , Estimulação Física , Ratos , Ratos Wistar , Seda , Nervos Espinhais/lesões , Suturas , Degeneração WallerianaRESUMO
To test the hypothesis that trkA (the high-affinity NGF receptor) is selectively expressed in nociceptive dorsal root ganglion (DRG) neurons, we examined the intensity of trkA immunoreactivity in single dye-injected rat DRG neurons, the sensory receptor properties of which were identified in vivo with mechanical and thermal stimuli. We provide the first evidence in single identified neurons that strong trkA expression in DRGs is restricted to nociceptive neurons, probably accounting for the profound influence of NGF on these neurons. Furthermore, we demonstrate that trkA expression is as high in rapidly conducting (Aalpha/beta) as in more slowly conducting (Adelta and C) nociceptors. All Aalpha/beta low-threshold mechanoreceptors (LTMs) are trkA negative, although weak but detectable trkA is present in some C and Adelta LTMs. NGF can influence electrophysiological properties of DRG neurons, probably by binding to trkA. We found positive correlations for single identified Aalpha/beta (but not C or Adelta) nociceptors between trkA immunocytochemical intensity and electrophysiological properties typical of nociceptors, namely long action potential and afterhyperpolarization durations and large action potential amplitudes. Furthermore, for Aalpha/beta (notCorAdelta) nociceptors, trkA intensity is inversely correlated with conduction velocity. Similar relationships, again only in Aalpha/beta nociceptors, between electrophysiological properties and trkA expression exist for sodium channel Nav1.8 but not Nav1.9 immunoreactivities. These findings suggest that in Aalpha/beta nociceptors, influences of NGF on expression levels of Nav1.8 are related to, and perhaps limited by, expression levels of trkA. This view is supported by a positive correlation between immuno-intensities of trkA and Nav1.8 in A-fiber, but not C-fiber, nociceptors.
Assuntos
Potenciais de Ação/fisiologia , Gânglios Espinais/citologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia , Nociceptores/fisiologia , Receptor trkA/metabolismo , Canais de Sódio/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Contagem de Células/métodos , Tamanho Celular , Diagnóstico por Imagem/métodos , Feminino , Imuno-Histoquímica/métodos , Técnicas In Vitro , Isoquinolinas , Canal de Sódio Disparado por Voltagem NAV1.8 , Canal de Sódio Disparado por Voltagem NAV1.9 , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Amielínicas/fisiologia , Condução Nervosa/fisiologia , Condução Nervosa/efeitos da radiação , Neurônios/classificação , Neurônios/efeitos dos fármacos , Neuropeptídeos/fisiologia , Compostos Organometálicos , Compostos Organofosforados , Ratos , Ratos Wistar , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/fisiologia , Estatísticas não Paramétricas , Tetrodotoxina/farmacologiaRESUMO
The existence of nociceptors with Abeta-fibers has often been overlooked, and many textbooks endorse the view that all nociceptors have either C- or Adelta-fibers. Here we review evidence starting from the earliest descriptions of A-fiber nociceptors, which clearly indicates that a substantial proportion of cutaneous/somatic afferent A-fiber nociceptors conduct in the Abeta conduction velocity (CV) range in all species in which CV was carefully examined, including mouse, rat, guinea pig, cat and monkey. Reported proportions of A-fiber nociceptors with Abeta-fibers vary from 18% to 65% in different species, usually >50% in rodents. In rat, about 20% of all somatic afferent neurons with Aalpha/beta-fibers were nociceptive. Distributions of CVs of A-fiber nociceptors usually appear unimodal, with a median/peak in the upper Adelta or lower Abeta CV range. We find no evidence to suggest discontinuous differences in electrophysiological or cytochemical properties of Adelta and Abeta nociceptors, rather there are gradual changes in relation to CV. However, some functional differences have been reported. In cat, A-fiber nociceptors with lower mechanical thresholds (moderate pressure receptors) tend to have faster CVs [P.R. Burgess, D. Petit, R.M. Warren. Receptor types in cat hairy skin supplied by myelinated fibers. J. Neurophysiol. 31 (1968) 833-848]. In primate (monkey) A-fiber nociceptors that responded to heat were divided into type I A mechano-heat (AMH) units (Adelta and Abeta CVs) with lower mechanical and higher heat thresholds and may include moderate pressure receptors, and type II AMH units (Adelta CVs) with higher mechanical/lower heat thresholds. It is important that the existence of Abeta nociceptors is recognised, because assumptions that fast conducting, large diameter afferents are always low threshold mechanoreceptors might lead/have led to misinterpretations of data.
Assuntos
Gânglios Sensitivos/fisiologia , Fibras Nervosas Mielinizadas/fisiologia , Neurônios Aferentes/fisiologia , Nociceptores/fisiologia , Vias Aferentes/citologia , Vias Aferentes/fisiologia , Animais , Gânglios Sensitivos/citologia , Humanos , Mamíferos/fisiologia , Fibras Nervosas Mielinizadas/ultraestrutura , Condução Nervosa/fisiologia , Neurônios Aferentes/citologia , Nociceptores/citologia , Limiar da Dor/fisiologia , Pele/inervaçãoRESUMO
We have examined the distribution of the sensory neuron-specific Na+ channel Nav1.8 (SNS/PN3) in nociceptive and non-nociceptive dorsal root ganglion (DRG) neurons and whether its distribution is related to neuronal membrane properties. Nav1.8-like immunoreactivity (Nav1.8-LI) was examined with an affinity purified polyclonal antiserum (SNS11) in rat DRG neurons that were classified according to sensory receptive properties and by conduction velocity (CV) as C-, Adelta- or Aalpha/beta. A significantly higher proportion of nociceptive than low threshold mechanoreceptive (LTM) neurons showed Nav1.8-LI, and nociceptive neurons had significantly more intense immunoreactivity in their somata than LTM neurons. Results showed that 89, 93 and 60% of C-, Adelta- and Aalpha/beta-fibre nociceptive units respectively and 88% of C-unresponsive units were positive. C-unresponsive units had electrical membrane properties similar to C-nociceptors and were considered to be nociceptive-type neurons. Weak positive Nav1.8-LI was also present in some LTM units including a C LTM, all Adelta LTM units (D hair), about 10% of cutaneous LTM Aalpha/beta-units, but no muscle spindle afferent units. Nav1.8-LI intensity was negatively correlated with soma size (all neurons) and with dorsal root CVs in A- but not C-fibre neurons. Nav1.8-LI intensity was positively correlated with action potential (AP) duration (both rise and fall time) in A-fibre neurons and with AP rise time only in positive C-fibre neurons. It was also positively correlated with AP overshoot in positive neurons. Thus high levels of Nav1.8 protein may contribute to the longer AP durations (especially in A-fibre neurons) and larger AP overshoots that are typical of nociceptors.
Assuntos
Proteínas do Tecido Nervoso/biossíntese , Neurônios Aferentes/fisiologia , Nociceptores/fisiologia , Canais de Sódio/biossíntese , Tetrodotoxina/farmacologia , Potenciais de Ação/fisiologia , Animais , Western Blotting , Tamanho Celular , Eletrofisiologia , Feminino , Corantes Fluorescentes , Gânglios Espinais/citologia , Gânglios Espinais/fisiologia , Imuno-Histoquímica , Mecanorreceptores/fisiologia , Potenciais da Membrana/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.8 , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Mielinizadas/ultraestrutura , Fibras Nervosas Amielínicas/fisiologia , Fibras Nervosas Amielínicas/ultraestrutura , Proteínas do Tecido Nervoso/efeitos dos fármacos , Condução Nervosa , Neurônios Aferentes/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Canais de Sódio/efeitos dos fármacosRESUMO
The TTX-sensitive Na(v)1.7 (PN1) Na(+) channel alpha subunit protein is expressed mainly in small dorsal root ganglion (DRG) neurones. This study examines immunocytochemically whether it is expressed exclusively or preferentially in nociceptive primary afferent DRG neurones, and determines the electrophysiological properties of neurones that express it. Intracellular somatic action potentials (APs) evoked by dorsal root stimulation were recorded in L6/S1 DRG neurones at 30 +/- 2 degrees C in vivo in deeply anaesthetised young guinea-pigs. Each neurone was classified, from its dorsal root conduction velocity (CV) as a C-, Adelta- or Aalpha/beta-fibre unit and from its response to mechanical and thermal stimuli, as a nociceptive, low threshold mechanoreceptive (LTM) or unresponsive unit. Fluorescent dye was injected into the soma and Na(v)1.7-like immunoreactivity (Na(v)1.7-LI) was examined on sections of dye-injected neurones. All C-, 90 % of Adelta- and 40 % of Aalpha/beta-fibre units, including both nociceptive and LTM units, showed Na(v)1.7-LI. Positive units included 1/1 C-LTM, 6/6 C-nociceptive, 4/4 C-unresponsive (possible silent nociceptive) units, 5/6 Adelta-LTM (D hair), 13/14 Adelta-nociceptive, 2/9 Aalpha/beta-nociceptive, 10/18 Aalpha/beta-LTM cutaneous and 0/9 Aalpha/beta-muscle spindle afferent units. Overall, a higher proportion of nociceptive than of LTM neurones was positive, and the median relative staining intensity was greater in nociceptive than LTM units. Na(v)1.7-LI intensity was clearly positively correlated with AP duration and (less strongly) negatively correlated with CV and soma size. Since nociceptive units tend overall to have longer duration APs, slower CVs and smaller somata, these correlations may be related to the generally greater expression of Na(v)1.7 in nociceptive units.
Assuntos
Gânglios Espinais/fisiologia , Neurônios Aferentes/fisiologia , Neuropeptídeos/metabolismo , Nociceptores/fisiologia , Canais de Sódio/metabolismo , Potenciais de Ação , Animais , Estimulação Elétrica , Eletrofisiologia , Gânglios Espinais/citologia , Cobaias , Imuno-Histoquímica/métodos , Mecanorreceptores/fisiologia , Condução Nervosa , Coloração e Rotulagem , Fatores de TempoRESUMO
This is the first examination of sensory receptive properties and associated electrophysiological properties in vivo of dorsal root ganglion (DRG) neurons that express the TTX-resistant sodium channel Na(v)1.9 (NaN). Intracellular recordings in lumbar DRGs in Wistar rats enabled units with dorsal root C-, Adelta-, or Aalpha/beta-fibers to be classified as nociceptive, low-threshold mechanoreceptive (LTM), or unresponsive. Intracellular dye injection enabled subsequent immunocytochemistry for Na(v)1.9-like immunoreactivity (Na(v)1.9-LI). Na(v)1.9-LI was expressed selectively in nociceptive-type (C- and A-fiber nociceptive and C-unresponsive) units. Of the nociceptive units, 64, 54, and 31% of C-, Adelta-, and Aalpha/beta-fiber units, respectively, were positive for Na(v)1.9-LI. C-unresponsive units were included in the nociceptive-type group on the basis of their nociceptor-like membrane properties; 91% were positive. Na(v)1.9-LI was undetectable in Adelta- or Aalpha/beta-fiber LTM units and in one C-LTM unit. Na(v)1.9-LI intensity was correlated negatively with soma size and conduction velocity in nociceptive units and with conduction velocity in C-fiber units. There was a positive correlation with action potential rise time in nociceptive-type units with membrane potentials equal to or more negative than -50 mV. The data provide direct evidence that Na(v)1.9 is expressed selectively in (but not in all) C- and A-fiber nociceptive-type units and suggest that Na(v)1.9 contributes to membrane properties that are typical of nociceptive neurons.
Assuntos
Neurônios Aferentes/metabolismo , Neuropeptídeos/metabolismo , Dor/metabolismo , Canais de Sódio/metabolismo , Potenciais de Ação/fisiologia , Animais , Feminino , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Imuno-Histoquímica , Canal de Sódio Disparado por Voltagem NAV1.9 , Fibras Nervosas/fisiologia , Fibras Nervosas Mielinizadas/fisiologia , Condução Nervosa/fisiologia , Neurônios Aferentes/classificação , Neurônios Aferentes/citologia , Neurônios Aferentes/efeitos dos fármacos , Neuropeptídeos/efeitos dos fármacos , Ratos , Ratos Wistar , Canais de Sódio/efeitos dos fármacos , Tetrodotoxina/farmacologiaRESUMO
Capsaicin (0.01-50 microM) was applied to adult rat vagus nerve in vitro to examine the C-fibre conduction block and to compare its time course with that of the depolarisation caused by this drug. The conduction block was assessed by the reduction in the C-wave of the compound action potential. Capsaicin caused a dose-dependent decrease in the height and area under the C-wave; the threshold dose was between 0.01 and 0.3 microM and maximum C-wave reduction of about 85% occurred with doses of 5 microM or above. The C-wave reduction was divided into reversible and irreversible components which differed in dose dependency. The threshold for the reversible block was below 0.3 microM and for the irreversible block it was about 1 microM. The onset of the block took about 5 min. regardless of dose. Where there was more than 50% recovery after the block the reversible component was measured. This was dose dependent and its duration was 10-90 min. Removal of external calcium did not affect the magnitude of the C-wave block, although it did seem to prevent recovery of the C-wave.