In the mammalian autonomic nervous system, tonic and phasic neurons can be differentiated on firing patterns in response to long depolarizing current pulse. However, the similar firing patterns in the somatic primary sensory neurons and their functional significance are not well investigated. Here, we identified two types of neurons innervating somatic sensory in rat dorsal root ganglia (DRG). Tonic neurons fire action potentials (APs) in an intensity-dependent manner, whereas phasic neurons typically generate only one AP firing at the onset of stimulation regardless of intensity. Combining retrograde labeling of somatic DRG neurons with fluorescent tracer DiI, we further find that these neurons demonstrate distinct changes under inflammatory pain states induced by complete Freund's adjuvant (CFA) or bee venom toxin melittin. In tonic neurons, CFA and melittin treatments significantly decrease rheobase and AP durations (depolarization and repolarization), enhance amplitudes of overshoot and afterhyperpolarization (AHP), and increase the number of evoked action potentials. In phasic neurons, however, the same inflammation treatments cause fewer changes in these electrophysiological parameters except for the increased overshoot and decreased AP durations. In the present study, we find that tonic neurons are more hyperexcitable than phasic neurons after peripheral noxious inflammatory stimulation. The results indicate the distinct contributions of two types of DRG neurons in inflammatory pain.
- MeSH
- akční potenciály fyziologie MeSH
- bolest chemicky indukované patofyziologie psychologie MeSH
- chování zvířat fyziologie MeSH
- elektrofyziologické jevy MeSH
- Freundovo adjuvans MeSH
- krysa rodu rattus MeSH
- metoda terčíkového zámku MeSH
- neurony fyziologie MeSH
- potkani Sprague-Dawley MeSH
- spinální ganglia fyziologie MeSH
- zánět chemicky indukované patofyziologie psychologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: The cytokine tumor necrosis factor α (TNFα) is an established pain modulator in both the peripheral and central nervous systems. Modulation of nociceptive synaptic transmission in the spinal cord dorsal horn (DH) is thought to be involved in the development and maintenance of several pathological pain states. Increased levels of TNFα and its receptors (TNFR) in dorsal root ganglion (DRG) cells and in the spinal cord DH have been shown to play an essential role in neuropathic pain processing. In the present experiments the effect of TNFα incubation on modulation of primary afferent synaptic activity was investigated in a model of peripheral neuropathy. METHODS: Spontaneous and miniature excitatory postsynaptic currents (sEPSC and mEPSCs) were recorded in superficial DH neurons in acute spinal cord slices prepared from animals 5 days after sciatic nerve transection and in controls. RESULTS: In slices after axotomy the sEPSC frequency was 2.8 ± 0.8 Hz, while neurons recorded from slices after TNFα incubation had significantly higher sEPSC frequency (7.9 ± 2.2 Hz). The effect of TNFα treatment was smaller in the slices from the control animals, where sEPSC frequency was 1.2 ± 0.2 Hz in slices without and 2.0 ± 0.5 Hz with TNFα incubation. Tetrodotoxin (TTX) application in slices from axotomized animals and after TNFα incubation decreased the mEPSC frequency to only 37.4 ± 6.9% of the sEPSC frequency. This decrease was significantly higher than in the slices without the TNFα treatment (64.4 ± 6.4%). TTX application in the control slices reduced the sEPSC frequency to about 80% in both TNFα untreated and treated slices. Application of low concentration TRPV1 receptors endogenous agonist N-oleoyldopamine (OLDA, 0.2 μM) in slices after axotomy induced a significant increase in mEPSC frequency (175.9 ± 17.3%), similar to the group with TNFα pretreatment (158.1 ± 19.5%). CONCLUSIONS: Our results indicate that TNFα may enhance spontaneous transmitter release from primary afferent fibres in the spinal cord DH by modulation of TTX-sensitive sodium channels following sciatic nerve transection. This nerve injury also leads to enhanced sensitivity of presynaptic TRPV1 receptors to endogenous agonist. Modulation of presynaptic receptor activity on primary sensory terminals by TNFα may play an important role in neuropathic pain development.
- MeSH
- excitační postsynaptické potenciály MeSH
- krysa rodu rattus MeSH
- metoda terčíkového zámku MeSH
- mícha patologie fyziologie ultrastruktura MeSH
- nemoci periferního nervového systému chemicky indukované patologie patofyziologie MeSH
- nervový přenos fyziologie MeSH
- neurony aferentní cytologie účinky léků fyziologie MeSH
- nocicepce účinky léků fyziologie MeSH
- potkani Wistar MeSH
- sodíkové kanály metabolismus MeSH
- spinální ganglia cytologie fyziologie MeSH
- synapse fyziologie MeSH
- TNF-alfa farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- abstinenční syndrom MeSH
- astrocyty fyziologie MeSH
- bolest etiologie farmakoterapie MeSH
- chronická nemoc MeSH
- cytokiny fyziologie MeSH
- lidé MeSH
- marihuana pro léčebné účely MeSH
- míšní nervy fyziologie MeSH
- modely nemocí na zvířatech MeSH
- morfin terapeutické užití MeSH
- nervový přenos fyziologie MeSH
- nervový systém - fyziologické jevy MeSH
- neuralgie etiologie farmakoterapie patofyziologie MeSH
- neuroglie fyziologie patologie MeSH
- signální transdukce fyziologie MeSH
- spinální ganglia fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- MeSH
- kapsaicin farmakologie MeSH
- koncentrace vodíkových iontů MeSH
- krysa rodu rattus MeSH
- nociceptory klasifikace účinky léků MeSH
- novorozená zvířata fyziologie MeSH
- spinální ganglia fyziologie účinky léků MeSH
- techniky in vitro MeSH
- teplota MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
1. Activation of neurokinin receptors contributes to the excitation of many dorsal horn neurons by cutaneous sensory stimuli, particularly noxious stimuli. In the present study we investigate the role of neurokinin receptors in the activation of primate spinothalamic tract (STT) neurons by cutaneous mechanical stimuli and by intradermal injection of capsaicin. This was done by testing the responses of these neurons to a battery of cutaneous stimuli before and during infusion by microdialysis of antagonists selective for NK1 and NK2 receptors. 2. The NK1 receptor antagonists cis-3-(2-methoxybenzyl-amino-2-benzhydrylquinuclidine (CP96345) and D-Pro9-[Spiro-y-lactam]-Leu10,Trp11)-Physalaemin(1-11) (GR82334) did not significantly reduce the responses of STT cells to mechanical stimulation of the skin. Both NK1 antagonists did, however, produce a significant reduction in the responses of STT neurons to an intradermal injection of capsaicin. Finally, despite having no effects on responses to mechanical stimuli, both NK1 antagonists prevented the sensitization of the responses to cutaneous stimuli that is usually observed after intradermal injections of capsaicin. 3. The NK2 selective antagonists PhCO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (GR98400) and [Tyr5,D-Trp6,8,9,Lys10]-NKA (4-10) (MEN10376) had effects very similar to those of the NK1 antagonists, but with an important difference. Neither NK2 antagonist affected the responses of STT neurons to noxious or innocuous mechanical stimulation of the skin, but they did reduce the responses to intradermal capsaicin injections. These compounds failed to prevent capsaicin-induced sensitization. In fact, cells exposed to GR98400 or MEN10376 showed unusually sustained increases in the responses to mechanical stimuli after the first capsaicin injection, suggesting that these compounds actually induced sensitization. 4. These results support the contention that both neurokinin receptors participate in the processing of nociceptive information in the dorsal horn, especially responses to strong stimuli such as intradermal injection of capsaicin. NK1 receptors are also involved in the sensitization of STT neurons after peripheral injury. A clearer understanding of the role of NK2 receptors in sensitization requires further studies with improved antagonists.
- MeSH
- antagonisté neurokininových receptorů typu 1 MeSH
- bifenylové sloučeniny farmakologie MeSH
- fysalemin analogy a deriváty farmakologie MeSH
- injekce intradermální MeSH
- kapsaicin * farmakologie MeSH
- kůže * inervace MeSH
- Macaca fascicularis MeSH
- mechanoreceptory účinky léků MeSH
- nervový přenos fyziologie účinky léků MeSH
- neurokinin A analogy a deriváty farmakologie MeSH
- neurony fyziologie účinky léků MeSH
- nociceptory * fyziologie účinky léků MeSH
- peptidové fragmenty farmakologie MeSH
- práh bolesti účinky léků MeSH
- receptory neurokininu-1 * fyziologie MeSH
- receptory neurokininu-2 * antagonisté a inhibitory fyziologie MeSH
- spinální ganglia fyziologie účinky léků MeSH
- tractus spinothalamicus * fyziologie účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
1. Sensitization of dorsal horn neurons is thought to play an important role in pain perception, secondary hyperalgesia, and allodynia. Recent experimental evidence suggests that the sensitization of dorsal horn neurons is induced by combined increased release of excitatory amino acids and peptides in the spinal cord dorsal horn from nociceptive primary afferents due to an injury-caused barrage of impulses. We tested the hypothesis that protein kinase C (PKC) is involved as a second messenger in this process of neuronal sensitization. To activate PKC, infusion of a phorbol ester [12-O-tetradecanoylphorbol-13-acetate (TPA)] into the dorsal horn through a microdialysis fiber was used. During TPA infusion the background activity of spinothalamic (STT) neurons increased substantially. After TPA application, while the background activity of the STT neurons was still increased, the responses evoked by either innocuous or noxious mechanical stimulation of the cutaneous receptive field did not change from the control level. However, 1 h after TPA administration the background activity returned to the control level and responses to innocuous mechanical stimuli were significantly elevated. The responses of STT cells to noxious heat and noxious mechanical stimuli did not change significantly after TPA administration. When a phorbol ester that does not activate PKC was applied (alpha-TPA), no significant changes in background or evoked activity of STT cells were observed. Our results provide evidence that PKC may play an important role in the process of sensitization of dorsal horn neurons to innocuous mechanical stimuli.
- MeSH
- aktivace enzymů účinky léků MeSH
- evokované potenciály fyziologie účinky léků MeSH
- Macaca fascicularis MeSH
- mechanoreceptory * fyziologie účinky léků MeSH
- nervový přenos * fyziologie účinky léků MeSH
- neurony fyziologie účinky léků MeSH
- nociceptory * fyziologie účinky léků MeSH
- proteinkinasa C fyziologie MeSH
- spinální ganglia * fyziologie účinky léků MeSH
- termoreceptory * fyziologie účinky léků MeSH
- tetradekanoylforbolacetát * farmakologie MeSH
- tractus spinothalamicus * fyziologie účinky léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
