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

The responses of primate spinothalamic tract (STT) neurons to innocuous and noxious mechanical stimuli applied to the skin can be enhanced for more than an hour following prolonged noxious stimulation. This increased responsiveness is thought to reflect sensitization of dorsal horn neurons and may help account for secondary hyperalgesia and mechanical allodynia. The proposal that central sensitization is due to the activation of second messenger system was tested in this study by examining the effect of trans-ACPD (trans-D,L-1-amino-1,3-cyclopentanedicarboxylic acid), an agonist of metabotropic excitatory amino acid (EAA) receptors, introduced into the dorsal horn by microdialysis. A low dose of trans-ACPD resulted in an increase in the responses of STT cells to an innocuous mechanical stimulus (BRUSH), but no increase in the responses to noxious mechanical and thermal stimuli or in the excitation produced by iontophoretically applied EAAs. A high dose of trans-ACPD caused a transient increase in background activity, but no change in the responsiveness of spinothalamic cells to any of the test stimuli. It is concluded that low doses of trans-ACPD can selectively enhance transmission through interneuronal pathways mediating tactile inputs to spinothalamic cells.

• MeSH
• akční potenciály účinky léků   MeSH
• aminokyseliny farmakologie   MeSH
• cykloleucin analogy a deriváty   aplikace a dávkování   farmakologie   MeSH
• fyzikální stimulace MeSH
• Macaca fascicularis MeSH
• mícha * cytologie   účinky léků   MeSH
• mikrodialýza MeSH
• nervové dráhy cytologie   účinky léků   MeSH
• neurony * účinky léků   MeSH
• neurotoxiny aplikace a dávkování   farmakologie   MeSH
• receptory metabotropního glutamátu * účinky léků   MeSH
• thalamus * cytologie   účinky léků   MeSH
• vysoká teplota MeSH
• zvířata MeSH
• Check Tag
• 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

Sensitization of dorsal horn neurons following injury may underlie the generation of secondary hyperalgesia and so the chemical basis of sensitization is now receiving considerable attention. The present study used microiontophoretic applications of excitatory amino acids (EAA's) and substance P (SP) to test their roles in the sensitization of primate spinothalamic tract (STT) neurons. Of 70 STT cells examined in laminae I-VI of the dorsal horn, 40 showed an increase in responses to one or more EAA's following their co-application with SP. The increased responses were usually specific to either N-methyl-D-aspartate (NMDA) or to the non-NMDA agonists, quisqualate (QUIS) or D,L-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA). The enhancement of EAA responses was long-lasting (> 15 min) in 18 cases, was accompanied by similarly long-lasting increases in responses to mechanical stimulation of the receptive field in 14 cases and was accompanied by an increase in responses to either glutamate (Glu) or aspartate (Asp) in eleven cases. A global decrease in all EAA responses tested was produced in 26 other STT neurons. The inhibition, unlike the increases, was generalized to both NMDA and non-NMDA ligands, was long-lasting in only six cases and was never accompanied by a change in the responses to mechanical stimuli. The excitatory and inhibitory effects of SP on the responses to NMDA were uniformly reversed by the NK-1 receptor selective antagonist, CP96345. In contrast, only the inhibitory effects of SP on the responses to QUIS or AMPA were reversed by CP96345. The long-lasting enhancement of EAA responses by SP may follow the combined synaptic release of the natural ligands in vivo, resulting in the sensitization of dorsal horn neurons and secondary hyperalgesia. However, the reductions in EAA responses produced by SP are problematic for this hypothesis and need further elucidation.

• MeSH
• aminokyseliny * farmakologie   MeSH
• bifenylové sloučeniny farmakologie   MeSH
• časové faktory MeSH
• chemická stimulace MeSH
• fyzikální stimulace MeSH
• Macaca fascicularis MeSH
• neurony * účinky léků   MeSH
• reakční čas MeSH
• substance P * farmakologie   MeSH
• tractus spinothalamicus cytologie   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

Basal extracellular concentrations of 9 amino acids (AAs: aspartate, Asp; glutamate, Glu; asparagine, Asn; serine, Ser; glycine, Gly; threonine, Thr; alanine, Ala; taurine, Tau; and glutamine, Gln) were determined in the spinal cord dorsal horn of anesthetized rats using microdialysis and HPLC techniques. The concentrations of all measured AAs but Gln increased significantly (P < 0.05) during sciatic nerve stimulation at C-fiber strength. The concentration of Tau remained elevated following stimulation, while the other AAs returned to prestimulation values. Addition of the specific non-NMDA antagonist, CNQX, to the perfusing solution prevented the nerve stimulation-evoked AA release. Since the measured increases in extracellular AA concentrations are probably mainly due to activation of interneurons, these results suggest that blockade of non-NMDA receptors prevented activation of interneurons in the dorsal horn and support a major role of non-NMDA receptors at the first synapse of primary afferent fibers in the dorsal horn. Complete block of AA release and decreased basal levels of Glu after infusion of TTX into the dorsal horn also implies increased neuronal activity as the main source of higher AA levels during nerve stimulation.

• MeSH
• 6-kyano-7-nitrochinoxalin-2,3-dion MeSH
• aminokyseliny * metabolismus   MeSH
• chinoxaliny * farmakologie   MeSH
• elektrická stimulace MeSH
• krysa rodu rattus MeSH
• mícha fyziologie   metabolismus   účinky léků   MeSH
• nervová vlákna fyziologie   MeSH
• nervus ischiadicus * fyziologie   MeSH
• potkani Sprague-Dawley MeSH
• receptory N-methyl-D-aspartátu fyziologie   MeSH
• receptory neurotransmiterů * antagonisté a inhibitory   fyziologie   MeSH
• tetrodotoxin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

• Klíčová slova
• bolest - fyziologie - příručky, neurotransmise - bolest - příručky,

• Konspekt
• Lékařské vědy. Lékařství
• NLK Obory
• neurologie
• patologie
• fyziologie

The role of excitatory amino acids (EAAs) in the excitation of monkey spinothalamic tract (STT) neurons following activation of cutaneous primary afferent fibers by noxious and non-noxious stimuli was investigated. The responses of STT neurons to either NMDA or non-NMDA EAA ligands were blocked by infusion of specific antagonists through a microdialysis fiber into the region surrounding the cells. Our results show that blockade of non-NMDA receptors results in a nearly complete elimination of the responses of STT neurons to all stimuli. Blockade of NMDA receptors results in an attenuation of the responses to noxious stimuli but, in addition, prevents the development of the sensitization of STT neurons that is often observed after intradermal injection of capsaicin. These observations further support a role of EAAs in the transmission of sensory information from primary afferent fibers to dorsal horn neurons and a role for NMDA receptors in the generation of hyperalgesia.

• MeSH
• 2-amino-5-fosfonovalerát * analogy a deriváty   MeSH
• 6-kyano-7-nitrochinoxalin-2,3-dion MeSH
• aminokyseliny antagonisté a inhibitory   farmakologie   MeSH
• chemická stimulace MeSH
• chinoxaliny farmakologie   MeSH
• elektrická stimulace MeSH
• elektrofyziologie MeSH
• fyzikální stimulace MeSH
• kapsaicin farmakologie   MeSH
• Macaca fascicularis MeSH
• míšní kořeny fyziologie   MeSH
• neurony * fyziologie   MeSH
• receptory aminokyselin MeSH
• receptory buněčného povrchu * fyziologie   MeSH
• receptory N-methyl-D-aspartátu * fyziologie   MeSH
• těhotenství MeSH
• tractus spinothalamicus cytologie   fyziologie   MeSH
• vysoká teplota MeSH
• zvířata MeSH
• Check Tag
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

1. Responses of spinothalamic tract (STT) neurons to mechanical and thermal stimulation of skin were recorded under urethane and pentobarbital anesthesia in 12 control rats and in 20 rats with experimental neuropathy. Activity of the STT cells in neuropathic rats was recorded 7, 14, and 28 days after inducing the neuropathy by placing four loose ligatures on the sciatic nerve. 2. All neuropathic animals showed guarding of the injured hindpaw and a shorter withdrawal latency from a radiant heat source of the neuropathic hindpaw than that of the sham-operated paw. 3. STT neurons in neuropathic animals showed the most profound changes 7 and 14 days after the nerve ligation. When compared with STT cells in unoperated animals, approximately half of the neurons had high background activity, responses to innocuous stimuli represented a larger percentage of the total evoked activity in wide dynamic range neurons, and the occurrence and magnitude of afterdischarges to mechanical and thermal stimuli were increased. 4. The mean threshold temperatures of heat-evoked responses of the STT cells in neuropathic animals were not different than those of cells from control animals. However, in neuropathic rats, cells reacting to small heat stimuli usually already had afterdischarges. 5. The increase in the background activity of STT cells is consistent with behavioral observations of spontaneous pain in this model of experimental neuropathy. Furthermore, the afterdischarges of STT cells may parallel the prolonged paw withdrawal in response to noxious stimuli that is seen in these animals and that is evidence for hyperalgesia. However, there was no indication of a lowered threshold for thermal stimuli as might be expected if the animals have thermal allodynia. Mechanical allodynia may have resulted from a relative increase in responsiveness to innocuous mechanical stimuli. However, responses to noxious mechanical stimuli were reduced compared with control, at least at 28 days after the ligation. Peripheral and central mechanisms responsible for the changes in responses of STT cells in neuropathic animals are suggested.

• MeSH
• chování zvířat fyziologie   MeSH
• elektrofyziologie MeSH
• fyzikální stimulace MeSH
• inbrední kmeny potkanů MeSH
• krysa rodu rattus MeSH
• kůže * patofyziologie   MeSH
• nemoci periferního nervového systému * patofyziologie   psychologie   MeSH
• neurony * fyziologie   MeSH
• tractus spinothalamicus patofyziologie   patologie   MeSH
• vysoká teplota * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

• Klíčová slova
• mícha - funkce - mechanismy - monografie,

• Konspekt
• Lékařské vědy. Lékařství
• NLK Obory
• neurologie
• fyziologie
• anatomie

1. An experimental peripheral neuropathy (EPN) was induced in three monkeys (Macaca fascicularis) by ligation of spinal nerve L7. Behavioral responses to innocuous mechanical stimuli were tested before and after the surgery. Two weeks after the nerve ligation, the activity of spinothalamic tract (STT) neurons was recorded on both sides of the spinal cord with the animal under general anesthesia. Responses of the STT neurons to the following stimuli applied to the skin were recorded: graded mechanical stimuli (brush, press, pinch and squeeze), von Frey filaments of different bending forces (0.077-19.05 g), 5-s heat stimuli ranging from 39 to 53 degrees C, and 15 s cold stimuli (32-8 degrees C). 2. Innocuous mechanical stimulation of the foot did not evoke hindlimb withdrawal in the animals before surgery. Within 24-48 h after nerve ligation, the animals showed hindlimb withdrawal to the same innocuous stimuli. This behavior was more pronounced on the side of the ligation than on the sham-operated side and more frequent during the second week after the surgery. 3. Responses of 51 STT neurons recorded on the side of the ligation (EPN all group) were compared with responses of 33 STT cells recorded on the sham-operated side (control group) and with records from STT neurons in unoperated animals obtained earlier (reference group). Neurons from the EPN all group were divided into two sets according to their rostrocaudal location (EPN R, rostral to L6/7 border, n = 40; EPN C, caudal to L6/7 border, n = 11). 4. Neurons from the EPN all and EPN R groups had significantly higher background frequencies than those from the control and reference groups. Innocuous brush stimuli evoked mean discharge frequencies of approximately 35 Hz in EPN R neurons and only approximately 15 Hz in both control and reference groups. Increased responsiveness of EPN R neurons to innocuous stimuli was also demonstrated by lower thresholds and higher discharge frequencies to von Frey filament stimulation and by discriminative analysis of the responses evoked by graded mechanical stimuli. 5. The responses of the EPN R neurons to heat stimulation of the skin showed decreased thresholds and increased responses to suprathreshold stimuli, resulting in a significant leftward shift of the stimulus-response curve compared with both reference and control groups. The neurons from the control group showed responses comparable to reference group values. 6. Neurons from the reference group tested with the cooling stimuli showed no evoked response above background.(ABSTRACT TRUNCATED AT 400 WORDS)

• MeSH
• elektrofyziologie MeSH
• fyzikální stimulace MeSH
• Macaca fascicularis MeSH
• modely nemocí na zvířatech MeSH
• nemoci periferního nervového systému * patofyziologie   MeSH
• nervové dráhy fyziologie   MeSH
• nervus ischiadicus fyziologie   MeSH
• nízká teplota MeSH
• tractus spinothalamicus cytologie   fyziologie   MeSH
• vysoká teplota MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH