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Biomedical subjects

K Hole

Publications and source records attributed to K Hole.

At least 19 recordsLinked to original sources
PubMed2001

Activation of spinal serotonin(2A/2C) receptors augments nociceptive responses in the rat.

The role of spinal 5-HT(2A/2C) receptors in the regulation of spinal nociceptive transmission was studied. The 5-HT(2A/2C) agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the antagonist ketanserin tartrate were administered intrathecally immediately before the formalin test. Activation of spinal 5-HT(2A/2C) receptors increased the pain-like behavioural response in both the early and late phases. The findings support the hypothesis that spinal 5-HT(2A/2C) receptors augment the spinal afferent nociceptive impulses induced by peripheral inflammation.

Amphetamines↗
PubMed2000

Inhibition of spinal nociceptive responses after intramuscular injection of capsaicin involves activation of noradrenergic and opioid systems.

Extracellular recordings of wide dynamic range neurones in the dorsal horn driven by electrical stimulation of the sciatic nerve were performed in intact urethane-anaesthetized Sprague-Dawley rats. The electrically evoked neuronal responses were defined as A- and C-fibres responses according to latencies, and the effect of a deep nociceptive conditioning stimulus induced by 200 microg capsaicin (8-methyl-N-vanillyl-6-noneamide) injected into the contralateral gastrocnemius-soleus muscle was studied for at least 30 min. Independent of the size and location of the receptive field of the neurone under study, a clear inhibition of the neuronal responses was observed. The electrically evoked C-fibre responses were inhibited to 53% of baseline 15-30 min after injection of capsaicin. This inhibition was only slightly attenuated by 125 nmol of the alpha-adrenoceptor antagonist phentolamine or 250 nmol of the opioid receptor antagonist naloxone applied directly onto the spinal cord when the two compounds were administered separately 5 min before capsaicin. In contrast, when a mixture of the two compounds was given 5 min before capsaicin, the effect of capsaicin was completely abolished. These results indicate that activation of the capsaicin-sensitive afferents in the gastrocnemius-soleus muscle inhibits the electrically evoked C-fibre responses in the dorsal horn by activating noradrenergic and opioidergic inhibitory systems. Moreover, our data indicate that the activation of these two systems following injection of capsaicin has a sub-additive inhibitory effect on the wide dynamic range neurones in the spinal cord. We conclude that only one of these systems is sufficient for the inhibition to occur.

Adrenergic alpha-Antagonists↗
PubMed1999

Long term potentiation of single WDR neurons in spinalized rats.

We report long-term potentiation (LTP) in single spinal wide dynamic range (WDR) neurons in urethane-anaesthetized spinalized rats with a complete neuromuscular blockade. Peripheral influences were excluded by a complete lidocaine block distal to the stimulation site on the sciatic nerve. As previously shown A-beta fibre evoked responses were not increased by the tetanic stimulation when there was a neuromuscular blockade during the experiment. Spinalization, excluding influences from supraspinal structures, increased all firing responses, and the LTP of C-fibre evoked responses when calculated in number of action potentials compared to intact animals and to previous studies. Furthermore, an LTP of the post discharge was observed after spinalization. An LTP of the post discharge has previously not been reported. Therefore, we conclude that LTP in the dorsal horn normally seems to be inhibited by descending pathways.

Analysis of Variance↗
PubMed1999

Expression of long-term potentiation in single wide dynamic range neurons in the rat is sensitive to blockade of glutamate receptors.

Plasticity in pain control systems may play an important role in clinical pain and some mechanisms of plasticity may be similar to those involved in learning. In this study we investigate the importance of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors for the maintenance of long-term potentiation (LTP) in wide dynamic range (WDR) neurons. Doses of 6-nitro-7-sulphomoylbenzoylquinoxaline-2,3-dione disodium (NBQX) and D-Q-amino-5-phosphonopentanoic acid (D-AP5) equipotent in reducing C-fiber mediated responses in controls, reduced the established LTP by about 50 and 80%, respectively. The drug effect lasted less than 1 h in controls. After induction of LTP, NBQX caused a reversible reduction of the potentiation. D-AP5, however, caused a stronger attenuation of the LTP, outlasting the effect of the drug in controls. We suggest that both pre-emptive analgesia preventing LTP induction and an early reduction of the excitation of neurons is important for the inhibition of LTP and central sensitization. Thus, it is possible that an early antinociceptive treatment preventing an excessive excitation of neurons in the dorsal horn may be of importance in preventing longlasting and pathological pain states.

2-Amino-5-phosphonovalerate↗
PubMed1999

Mammaglobin, a potential marker of breast cancer nodal metastasis.

The Mammaglobin gene, a breast-specific member of the uteroglobin gene family, has been previously identified as being overexpressed in some breast tumours, but the cellular origin and relationship to tumour progression are unknown. Using a subtractive hybridization approach, mammaglobin mRNA has also been found to be overexpressed in the in situ compared to the invasive element within an individual breast tumour. Further study by in situ hybridization performed in 13 breast tumours, selected to include normal, in situ, and invasive primary tumour elements, and in most cases axillary lymph node metastases, revealed that mammaglobin expression occurs in all elements, is restricted to epithelial cells, and is significantly increased in tumour cells compared with normal cells ( p< 0.04). Analysis of mammaglobin expression within 20 independent primary breast tumours and their corresponding axillary lymph nodes revealed that all 13 lymph nodes positive and none of the seven nodes negative for metastatic breast carcinoma by histology were mammaglobin-positive by reverse transcription-polymerase chain reaction (RT-PCR) ( p=0.0001). These results suggest that mammaglobin could be a marker of axillary lymph node breast metastases.

Adult↗
PubMed1999

Psoriasin (S100A7) expression and invasive breast cancer.

Alteration of psoriasin (S100A7) expression has previously been identified in association with the transition from preinvasive to invasive breast cancer. In this study we have examined persistence of psoriasin mRNA and protein expression in relation to prognostic factors in a cohort of 57 invasive breast tumors, comprising 34 invasive ductal carcinomas and 23 other invasive tumor types (lobular, mucinous, medullary, tubular). We first developed an IgY polyclonal chicken antibody and confirmed specificity for psoriasin by Western blot in transfected cells and tumors. The protein was localized by immunohistochemistry predominantly to epithelial cells, with both nuclear and cytoplasmic staining, as well as occasional stromal cells in psoriatic skin and breast tumors; however, in situ hybridization showed that psoriasin mRNA expression was restricted to epithelial cells. In breast tumors, higher levels of psoriasin measured by reverse transcriptase-polymerase chain reaction and Western blot (93% concordance) were significantly associated with estrogen and progesterone receptor-negative status (P < 0.0001, P = 0.0003), and with nodal metastasis in invasive ductal tumors (P = 0. 035), but not with tumor type or grade. Psoriasin expression also correlated with inflammatory infiltrates (all tumors excluding medullary, P = 0.0022). These results suggest that psoriasin may be a marker of aggressive behavior in invasive tumors and are consistent with a function as a chemotactic factor.

Blotting, Western↗
PubMed1999

Inhibition of evoked C-fibre responses in the dorsal horn after contralateral intramuscular injection of capsaicin involves activation of descending pathways.

In this study extracellular recordings of nociceptive dorsal horn neurones driven by electrical stimulation of the sciatic nerve were performed in intact urethane-anaesthetized Sprague-Dawley rats. Spikes 0-40, 40-250 and 250-800 ms after stimulus were defined as A- and C-fibre responses and post-discharge, respectively, and the effect of 200 microg capsaicin (8-methyl-N-vanillyl-6-noneamide) injected into the contralateral gastrocnemius-soleus muscle was investigated. In most cells tested, regardless of the size or location of their receptive fields, the injection of capsaicin caused a clear inhibition of the electrically evoked C-fibre responses. In animals with intact descending pathways the mean C-fibre response was inhibited to 51% of baseline 15 min after injection of capsaicin. In contrast, when capsaicin was given during cold block of the spinal cord between the brainstem and the site of recording in the dorsal horn, the same response was inhibited to 91% of baseline. A significant interaction between cold block and capsaicin was detected. We conclude that stimulation of capsaicin-sensitive afferents in the deep tissue in the hind limb can inhibit the electrically evoked C-fibre responses in the dorsal horn by activating inhibitory descending projections from higher centres. The model presented here may be an important tool for further investigations of the endogenous descending antinociceptive system.

Action Potentials↗
PubMed1999

Recording of long-term potentiation in single dorsal horn neurons in vivo in the rat.

We have published several reports on long-term potentiation (LTP) in single spinal wide dynamic range (WDR) neurons (responding to both innocuous and noxious stimuli) in urethane-anaesthetised rats. The protocol presented here, with single unit recordings of dorsal horn neurons before and after a nociceptive conditioning stimulation, may be useful in many electrophysiological studies of plastic changes in the spinal cord, such as LTP. We invite others to use this protocol for the study of spinal plasticity. Findings using this technique may be relevant for the understanding of changes in nociceptive transmission, induction of central sensitisation and maybe even in mechanisms of pathological pain and chronic pain states. We describe modified and alternative protocols for the study of LTP mechanisms under different conditions in intact and in spinalised animals, and after natural noxious stimuli. We present a novel method minimising peripheral influence of afferent input induced by antidromic neurogenic inflammation or inflammatory changes following a natural noxious stimulation. This is made possible by dissection of the sciatic nerve at two separate locations and local anaesthetic block distal to the stimulation site.

Anesthetics, Local↗
PubMed1999

The medullary dorsal reticular nucleus facilitates pain behaviour induced by formalin in the rat.

The influence of the dorsal reticular nucleus (DRt) on pain behaviour during the formalin test was studied in the rat by lesioning the nucleus through local application of electrical current or quinolinic acid. Animals in which the DRt was lesioned ipsilaterally to the paw injected with formalin spent less time in focused (licking, biting or scratching the injected paw) and total (focused pain behaviour plus protection of the injected paw during movements) pain behaviour, and showed paw-jerks less frequently than non-lesioned animals in both phases 1 and 2 of the test. Animals in which the DRt was lesioned contralaterally to the injected paw presented a decrease in total pain behaviour and number of paw-jerks only during phase 2. The number of superficial (laminae I-II) and deep (laminae III-VI) spinal dorsal horn cells expressing the c-fos proto-oncogene 2 h after subcutaneous injection of formalin was reduced by 34% and 50%, respectively, in animals with an ipsilateral DRt lesion as compared to non-lesioned rats. No differences in c-fos expression were observed after lesioning the DRt contralateral to the formalin injection. The results indicate that the DRt is involved in the facilitation of nociception during the formalin test by enhancing the response capacity of dorsal horn neurons to noxious stimulation. It is suggested that the pronociceptive action of the DRt is mediated by the reciprocal connections it establishes with the spinal dorsal horn.

Animals↗
PubMed1999

Behavioural effects of LTP-inducing sciatic nerve stimulation in the rat.

A short-lasting tetanic sciatic nerve stimulation that previously has been shown to be nociceptive only during the stimulation, induces long-term potentiation (LTP) of nociceptive evoked responses in wide dynamic range neurons in the dorsal horn of rats. The LTP may contribute to the process of central sensitization. We have shown that the tetanic conditioning stimulation with muscular contractions induces LTP of both Abeta- and C-fibre evoked responses. However, the same stimulation during muscular paralysis induces LTP only of C-fibre evoked responses. In the present study, we investigated the effects of this conditioning stimulation with or without muscular paralysis in behavioural tests in rats. Conditioning stimulation with muscular contractions caused a significant reduction of weight borne on the stimulated side, suggesting muscular soreness and peripheral sensitization. Conditioning stimulation during neuromuscular paralysis, which only has given LTP of C-fibre evoked responses in intact animals, caused no change in the weight borne on the stimulated side, suggesting less or even absence of allodynia. However, in these animals the response temperature in the hot plate test was increased both on the stimulated and on the contralateral side compared to sham-operated rats. In view of our recent results indicating that a descending inhibition reduces the expression of LTP in dorsal horn cells, and the suggestion by others that long-term descending inhibition may override a segmental facilitation, it is suggested that an increased long-lasting endogenous nociceptive inhibition is induced after LTP-inducing stimulation. This is an interesting parallel to stimulation-induced analgesia in humans. Copyright 1999 European Federation of Chapters of the International Association for the Study of Pain.

Journal Article↗
PubMed1998

AMPA and NMDA receptor-dependent spinal LTP after nociceptive tetanic stimulation.

LTP is often studied as a model of synaptic plasticity. Plasticity in pain control systems may involve mechanisms similar to those involved in learning. We recently reported LTP of both the A beta and C-fibre evoked responses of single dorsal horn neurons after a tetanic stimulation of the sciatic nerve, lasting for at least 6 h. In the present paper we show that identical stimulation induced LTP only of the C-fibre evoked response after blockade of muscular contractions during the tetanus. The C-fibre evoked response increased significantly less after pretreatment with either the AMPA antagonist NBQX or the NMDA antagonist D-AP5 (mean increase 33%) than in untreated animals (105%, p < 0.001), indicating that both AMPA and NMDA receptor stimulation are involved in the induction of LTP.

2-Amino-5-phosphonovalerate↗
PubMed1998

Expression of lumican in human breast carcinoma.

Lumican mRNA has been identified as being differentially expressed between different regions of the same human breast tumor. In situ hybridization study of 26 independent breast tumors confirmed the presence of lumican mRNA in fibroblast-like cells within stroma and showed a significant increase of its expression in tumor compared to adjacent normal stroma (P < 0.001). Higher lumican expression was associated with higher tumor grade, lower estrogen receptor levels in the tumor, and younger age of the patients (P < 0.05). Reverse transcription-PCR analysis of total RNA extracted from 19 independent breast tissues exhibiting lesions that are thought to parallel tumor progression also suggests that this proteoglycan is differentially expressed during tumor progression.

Adult↗
PubMed1997

LTP of spinal A beta and C-fibre evoked responses after electrical sciatic nerve stimulation.

Plasticity in the central nervous system may play an important role in clinical pain. The present study shows that long-term potentiation (LTP) may be induced in single wide dynamic range (WDR) neurons in the dorsal horn after high-frequency stimulation of the sciatic nerve in intact urethane anaesthetized rats. Extracellular recordings of firing responses after single pulse stimuli were made. The high-frequency conditioning stimulus increased the A beta- and C-fibre-mediated firing responses to single pulse stimuli by 60 and 130%, respectively, for more than 6 h. This finding supports a role for WDR neurons in 'nociceptive memory' in the dorsal horn. The model presented here may be an important tool for further investigations of mechanisms of plasticity within the dorsal horn.

Afferent Pathways↗
PubMed1997

A dual effect of 5-HT1B receptor stimulation on nociceptive dorsal horn neurones in rats.

In this study the modulatory effects of 5-HT1B receptor activation on wide dynamic range neurones in the spinal cord were studied. Extracellular single unit recordings of dorsal horn neurones were performed in intact urethane-anaesthetized female Sprague-Dawley rats, and the receptive field distally on one hind paw was electrically stimulated with needle electrodes applied to the skin. The 5-HT1B receptor agonist, CP-93,129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one), the 5-HT1A/B receptor antagonist cyanopindolol, and the 5-HT1A receptor antagonist WAY100635 (N-[2-[4-(2-methoxypheny])-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride), were applied directly onto the spinal cord, and single unit responses were counted separately for A beta-, A delta-, C-fibre responses and post-discharge according to the latencies. A dual effect of CP-93,129 was observed: 50 nmol CP-93,129 caused a clear inhibition of the A delta-fibre responses, whereas 50 and 150 nmol CP-93,129 produced a dose-dependent increase in post-discharge without affecting A beta- and C-fibre responses. Application of 50 nmol cyanopindolol or 50 nmol WAY 100635 alone did not affect neither the neuronal A-fibre nor the C-fibre responses, but when 50 nmol cyanopindolol was coadministered with 50 nmol CP-93,129 the effect of CP-93,129 alone was blocked: the A delta-fibre response was not inhibited and the post-discharge was not increased. In contrast, 50 nmol WAY100635 did not block the effect of 50 nmol CP-93,129 when the two drugs were coadministered. These results suggest that stimulation of the 5-HT1B receptors may have both pro- and antinociceptive effects on wide dynamic range neurones in the dorsal horn after repeated electrical stimulation.

Action Potentials↗
PubMed1997

Differential effects of activation of lumbar and thoracic 5-HT2A/2C receptors on nociception in rats.

The role of 5-HT2 receptors in nociceptive behaviour of rats was investigated using spinal administration of the 5-HT2A/2C receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI), the 5-HT2A/2C antagonist ketanserin and the glutamate receptor agonist NMDA. Nociceptive behaviour was scored after injections at upper thoracic or lumbosacral levels. DOI (0.1-10 mM, 15 microl) administered at the upper thoracic level induced pain-like behaviour in a dose-dependent manner and a long-lasting motor depression at the greatest dose. At the lumbosacral level a similar dose-dependent pain-like behaviour was observed, but it was less pronounced. Motor depression was not observed at any dose. Ketanserin injected before DOI blocked both nociceptive and motor effects. Stimulation of both NMDA and 5-HT2A/2C receptors had a mutually potentiating effect. The present results show that the effects of DOI were more pronounced at the upper thoracic than at the lumbosacral level. This is possibly caused by the difference in 5-HT2A/2C receptor density at the two levels. The motor depression induced by the greatest dose of DOI given at the upper thoracic level appears to mask the pain-like behaviour. The nociceptive behaviour seen after DOI injection is further increased following co-injection of NMDA.

Amphetamines↗
PubMed1996

The effect of 5-HT1A receptor stimulation on nociceptive dorsal horn neurones in rats.

Spinal 5-HT1A receptor subtypes are involved in regulation of nociception. This study was performed to investigate the effect of stimulation of these receptors on wide dynamic range neurones in the spinal cord. Extracellular single unit recordings of dorsal horn neurones were performed in intact urethane-anaesthetized female Sprague-Dawley rats. The receptive field distally on one hind paw was electrically stimulated with needle electrodes applied to the skin. The 5-HT1A receptor agonist, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) , and the 5-HT1A receptor antagonist, WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl ]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride), were applied directly onto the spinal cord, and single unit responses were counted separately for Abeta-, Adelta-, C-fibre responses and post-discharge according to the latencies. Only 500 nmol 8-OH-DPAT caused a significant inhibition of all the neuronal responses. Cells with a pronounced wind-up, limited C-fibre response before drug application and relatively large receptive field for pinch in laminae III-IV were most powerfully inhibited by 500 nmol 8-OH-DPAT. 50 nmol WAY100635 alone did not affect the neuronal responses but blocked the effect of 500 nmol 8-OH-DPAT. These results suggest that stimulation of 5-HT1A receptors inhibits the activity in spinal wide dynamic range neurones after repeated electrical stimulation.

8-Hydroxy-2-(di-n-propylamino)tetralin↗