Biomedical subjects

W D Willis

Publications and source records attributed to W D Willis.

At least 37 records · Page 2Linked to original sources

PubMed2001

Role of neurotransmitters in sensitization of pain responses.

Injection of capsaicin into the skin results in pain, primary heat and mechanical hyperalgesia, and secondary mechanical allodynia and hyperalgesia. Sensory receptors in the area of secondary mechanical allodynia and hyperalgesia are unaffected, and so the sensory changes must be due to central actions of the initial intense nociceptive discharge that follows the capsaicin injection. Central sensitization of the responses of spinothalamic tract neurons lasts several hours, but can be prevented by spinal cord administration of non-NMDA and NMDA glutamate receptor antagonists or NK1 substance P receptor antagonists. The long-lasting increase in excitability of spinothalamic tract cells depends on the activation of several second messenger cascades (PKC, PKA, and NO/PKG signal transduction pathways). The excitability change also depends on activation of calcium/calmodulin-dependent kinase II, which is consistent with the proposal that this central sensitization response is a form of long-term potentiation.

Animals↗

PubMed2001

Cerebellar cortical stimulation increases spinal visceral nociceptive responses.

The role of the cerebellum in modulating nociceptive phenomena is unclear. In this study, we focus on the effects of cerebellar cortical stimulation on the responses of midline neurons of the lumbosacral spinal cord to graded nonnoxious and noxious visceral (colorectal distension) as well as somatic (brush, pressure, pinch) stimuli. Extracellular recording was used for the isolation and recording of spinal nociceptive neurons, while electrical current pulses and chemical injection of D, L-homocysteic acid were used to stimulate the cortex of the posterior cerebellar vermis. Cerebellar cortical stimulation increased the responses of all isolated cells to colorectal distension, whereas the effect on the responses to somatic stimuli was variable. These findings indicate that the posterior cerebellar vermis may exert a pro-nociceptive effect on spinal visceroceptive neurons.

Animals↗

PubMed2001

GABA(A) and 5-HT(3) receptors are involved in dorsal root reflexes: possible role in periaqueductal gray descending inhibition.

The dorsal root reflex (DRR) is a measure of the central excitability of presynaptic inhibitory circuits in the spinal cord. Activation of the periaqueductal gray (PAG), a center for descending inhibition of spinal cord nociceptive transmission, induces release of variety of neurotransmitters in the spinal cord, including GABA and serotonin (5-HT). GABA has been shown to be involved in generation of DRRs. In this study, pharmacological agents that influence DRRs and their possible mechanisms were investigated. DRRs were recorded in anesthetized rats from filaments teased from the cut central stump of the left L(4) or L(5) dorsal root, using a monopolar recording electrode. Stimulating electrodes were placed either on the left sciatic nerve or transcutaneously in the left foot. Animals were paralyzed and maintained by artificial ventilation. Drugs were applied topically to the spinal cord. A total of 64 units were recorded in 34 Sprague-Dawley rats. Peripheral receptive fields were found for nine of these units. In these units, DRRs were evoked by brush, pressure, and pinch stimuli. Nine units were tested for an effect of electrical stimulation in the periaqueductal gray on the DRRs. In eight cases, DRR responses were enhanced following PAG stimulation. The background activity was 4.2 +/- 1.9 spikes/s (mean +/- SE; range: 0-97.7; n = 57). The responses to agents applied to the spinal cord were (in spikes/s): artificial cerebrospinal fluid, 7.1 +/- 3.6 (range: 0-86.9; n = 25); 0.1 mM GABA, 16.8 +/- 8.7 (range: 0-191.0; n = 22); 1.0 mM GABA, 116.0 +/- 26.5 (range: 0.05-1001.2; n = 50); and 1.0 mM phenylbiguanide (PBG), 68.1 +/- 25.3 (range: 0-1,073.0; n = 49). Bicuculline (0.5 mM, n = 27) and ondansetron (1.0 mM, n = 10) blocked the GABA and PBG effects, respectively (P < 0.05). Significant cross blockade was also observed. It is concluded that GABA(A) receptors are likely to play a key role in the generation of DRRs, but that 5-HT(3) receptors may also contribute. DRRs can be modulated by supraspinal mechanisms through descending systems.

Animals↗

PubMed2000

Enhanced phosphorylation of NMDA receptor 1 subunits in spinal cord dorsal horn and spinothalamic tract neurons after intradermal injection of capsaicin in rats.

The functional enhancement of NMDA receptors after peripheral tissue injury is proposed to contribute to the sensitization of spinothalamic tract (STT) cells and hyperalgesia. Protein phosphorylation is a major mechanism for the regulation of NMDA receptor function. In this study, Western blots, immunofluorescence double labeling, and the retrograde tracing method were used to examine whether phosphorylation of NMDA receptor 1 (NR1) subunits increases in spinal cord tissue and spinal dorsal horn neurons, especially in STT cells, after injection of capsaicin (CAP) into the glabrous skin of one hindpaw of anesthetized rats. Western blots showed that phosphorylated NR1 protein in spinal cord tissue was increased 30 min after CAP injection. Immunofluorescence double-labeling staining showed no significant difference in the number of the NR1-like immunoreactive neurons in laminae I-VII in the lumbosacral segments (L(4)-S(1)) on the ipsilateral and the contralateral sides 30 min after CAP or vehicle injection. However, the numbers of phospho-NR1-like immunoreactive neurons were significantly increased on the ipsilateral side compared with the vehicle injection group. STT cells were labeled by bilateral microinjections of the retrograde tracer fluorogold into the lateral thalamus, including the ventral-posterior lateral nucleus. Immunofluorescence staining was performed at 30, 60, and 120 min after CAP injection or at 30 min after vehicle injection. There was a significant increase in the proportion of STT cells with phosphorylated NR1 subunits compared either with the contralateral side 30 and 60 min after CAP injection or either side of animals after intradermal injection of vehicle. These results provide direct evidence that NMDA receptors in STT cells are phosphorylated after CAP injection.

Animals↗

PubMed2000

Fos expression is induced by increased nitric oxide release in rat spinal cord dorsal horn.

The relationship between exogenous or endogenous nitric oxide and c-fos, an immediate-early gene which can further activate the production of other substances in the central nervous system, was investigated in this study. We found that Fos expression is increased after intradermal capsaicin injection, which also leads to endogenous nitric oxide release in the spinal cord. The increased Fos expression is distributed in neurons of the superficial layers and lamina V of the dorsal horn on the side ipsilateral to the injection. The increased Fos expression is blocked by N(G)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, but not by its inactive isomer N(G)-nitro-D-arginine methyl ester. Fos expression was also increased following the perfusion of 3-morpholino-sydnonimine, a nitric oxide donor, into the dorsal horn through a microdialysis fiber. The increased Fos was distributed within 400 microm from the edge of the microdialysis fiber. Although Fos expression was increased with 3-morpholino-sydnonimine perfusion compared to that seen with artificial cerebrospinal fluid perfusion, there was still some Fos immunostaining in the control sections. Following perfusion of artificial cerebrospinal fluid in the spinal cord of rats pretreated with N(G)-nitro-L-arginine methyl ester, it was found that Fos staining was reduced significantly compared to the control sections from animals without N(G)-nitro-L-arginine methyl ester pretreatment. These results suggest that nitric oxide helps mediate Fos expression induced by an intradermal capsaicin injection. We conclude that both endogenous and exogenous nitric oxide induce Fos expression. Involvement of nitric oxide in the development of central sensitization may affect nociceptive processing by increasing Fos expression. Since many other substances which are related to pain mechanisms can be induced by Fos, it is suggested that nitric oxide may regulate production of these substances through activation of Fos. Nitric oxide is not only involved in the development of central sensitization, but is also involved in the activation of control mechanisms affecting nociception.

Animals↗

PubMed2000

Adelta and C primary afferents convey dorsal root reflexes after intradermal injection of capsaicin in rats.

Antidromic activity was recorded in anesthetized rats from single afferent fibers in the proximal ends of cut dorsal root filaments at the L(4-6) level and tested for responses to acute cutaneous inflammation produced by intradermal injection of capsaicin. This antidromic activity included low-frequency spontaneous firing and dorsal root reflex (DRR) discharges evoked by applying von Frey hairs to the skin of the foot. DRRs could be recorded from both small myelinated (Adelta) and unmyelinated (C) afferent fibers, as well as from large myelinated (Abeta) fibers. After capsaicin was injected intradermally into the plantar skin of the foot, a significant enhancement of DRR activity was seen in Adelta and C fibers but not in Abeta fibers, and this increase lasted for approximately 1 h. This study supports the hypothesis that centrally mediated antidromic activity in Adelta and C primary afferent fibers contributes to the development of neurogenic inflammation, presumably by release of inflammatory substances in the periphery.

Action Potentials↗

PubMed2000

Groups II and III metabotropic glutamate receptors differentially modulate brief and prolonged nociception in primate STT cells.

The heterogeneous family of G-protein-coupled metabotropic glutamate receptors (mGluRs) provides excitatory and inhibitory controls of synaptic transmission and neuronal excitability in the nervous system. Eight mGluR subtypes have been cloned and are classified in three subgroups. Group I mGluRs can stimulate phosphoinositide hydrolysis and activate protein kinase C whereas group II (mGluR2 and 3) and group III (mGluR4, 6, 7, and 8) mGluRs share the ability to inhibit cAMP formation. The present study examined the roles of groups II and III mGluRs in the processing of brief nociceptive information and capsaicin-induced central sensitization of primate spinothalamic tract (STT) cells in vivo. In 11 anesthetized male monkeys (Macaca fascicularis), extracellular recordings were made from 21 STT cells in the lumbar dorsal horn. Responses to brief (15 s) cutaneous stimuli of innocuous (brush), marginally and distinctly noxious (press and pinch, respectively) intensity were recorded before, during, and after the infusion of group II and group III mGluR agonists into the dorsal horn by microdialysis. Different concentrations were applied for at least 20 min each (at 5 microliter/min) to obtain cumulative concentration-response relationships. Values in this paper refer to the drug concentrations in the microdialysis fibers; actual concentrations in the tissue are about three orders of magnitude lower. The agonists were also applied at 10-25 min after intradermal capsaicin injection. The group II agonists (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (LCCG1, 1 microM-10 mM, n = 6) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4, 6-dicarboxylate (LY379268; 1 microM-10 mM, n = 6) had no significant effects on the responses to brief cutaneous mechanical stimuli (brush, press, pinch) or on ongoing background activity. In contrast, the group III agonist L(+)-2-amino-4-phosphonobutyric acid (LAP4, 0. 1 microM-10 mM, n = 6) inhibited the responses to cutaneous mechanical stimuli in a concentration-dependent manner, having a stronger effect on brush responses than on responses to press and pinch. LAP4 did not change background discharges significantly. Intradermal injections of capsaicin increased ongoing background activity and sensitized the STT cells to cutaneous mechanical stimuli (ongoing activity > brush > press > pinch). When given as posttreatment, the group II agonists LCCG1 (100 microM, n = 5) and LY379268 (100 microM, n = 6) and the group III agonist LAP4 (100 microM, n = 6) reversed the capsaicin-induced sensitization. After washout of the agonists, the central sensitization resumed. Our data suggest that, while activation of both group II and group III mGluRs can reverse capsaicin-induced central sensitization, it is the actions of group II mGluRs in particular that undergo significant functional changes during central sensitization because they modulate responses of sensitized STT cells but have no effect under control conditions.

Action Potentials↗

PubMed2000

Punctate midline myelotomy for the relief of visceral cancer pain.

OBJECT: This study offers clinical support for the concept that neurosurgical interruption of a midline posterior column pathway by performing a punctate midline myelotomy (PMM) provides significant pain relief without causing adverse neurological sequelae in cancer patients with visceral pain refractory to other therapies. METHODS: A PMM of the posterior columns was performed in six cancer patients in whom visceral pain had been refractory to other therapies. The cause of the visceral pain was related to residual, progressive, or recurrent local cancer or postirradiation effects. Clinical efficacy of the procedure was examined by comparing patient pain ratings and narcotic usage pre- and post-PMM. Follow-up periods ranged from 3 to 31 months. Examination of the results indicates a significant reduction in pain ratings as well as a significant reduction in daily narcotic use. No adverse neurological effects were observed. One spinal cord has been recovered for postmortem examination. CONCLUSIONS: These findings provide corroborating clinical evidence for the existence of a newly recognized midline posterior column pathway that mediates the perception of visceral pelvic and abdominal pain. Preliminary data indicate that significant pain relief can be obtained following PMM with minimal neurological morbidity and suggest that the procedure may provide an alternative treatment modality for cancer-related pain in patients in whom adequate pain control with narcotics cannot be achieved or narcotic side effects cannot be tolerated.

Abdominal Neoplasms↗

PubMed1999

Ascending projections from the area around the spinal cord central canal: A Phaseolus vulgaris leucoagglutinin study in rats.

A single small iontophoretic injection of Phaseolus vulgaris leucoagglutinin labels projections from the area surrounding the spinal cord central canal at midthoracic (T6-T9) or lumbosacral (L6-S1) segments of the spinal cord. The projections from the midthoracic or lumbosacral level of the medial spinal cord are found: 1) ascending ipsilaterally in the dorsal column near the dorsal intermediate septum or the midline of the gracile fasciculus, respectively; 2) terminating primarily in the dorsal, lateral rim of the gracile nucleus and the medial rim of the cuneate nucleus or the dorsomedial rim of the gracile nucleus, respectively; and 3) ascending bilaterally with slight contralateral predominance in the ventrolateral quadrant of the spinal cord and terminating in the ventral and medial medullary reticular formation. Other less dense projections are to the pons, midbrain, thalamus, hypothalamus, and other forebrain structures. Projections arising from the lumbosacral level are also found in Barrington's nucleus. The results of the present study support previous retrograde tract tracing and physiological studies from our group demonstrating that the neurons in the area adjacent to the central canal of the midthoracic or lumbosacral level of the spinal cord send long ascending projections to the dorsal column nucleus that are important in the transmission of second-order afferent information for visceral nociception. Thus, the axonal projections through both the dorsal and the ventrolateral white matter from the CC region terminate in many regions of the brain providing spinal input for sensory integration, autonomic regulation, motor and emotional responses, and limbic activation.

Animals↗

PubMed1999

A visceral pain pathway in the dorsal column of the spinal cord.

A limited midline myelotomy at T10 can relieve pelvic cancer pain in patients. This observation is explainable in light of strong evidence in support of the existence of a visceral pain pathway that ascends in the dorsal column (DC) of the spinal cord. In rats and monkeys, responses of neurons in the ventral posterolateral thalamic nucleus to noxious colorectal distention are dramatically reduced after a lesion of the DC at T10, but not by interruption of the spinothalamic tract. Blockade of transmission of visceral nociceptive signals through the rat sacral cord by microdialysis administration of morphine or 6-cyano-7-nitroquinoxaline-2,3-dione shows that postsynaptic DC neurons in the sacral cord transmit visceral nociceptive signals to the gracile nucleus. Retrograde tracing studies in rats demonstrate a concentration of postsynaptic DC neurons in the central gray matter of the L6-S1 spinal segments, and anterograde tracing studies show that labeled axons ascend from this region to the gracile nucleus. A similar projection from the midthoracic spinal cord ends in the gracile and cuneate nuclei. Behavioral experiments demonstrate that DC lesions reduce the nocifensive responses produced by noxious stimulation of the pancreas and duodenum, as well as the electrophysiological responses of ventral posterolateral neurons to these stimuli. Repeated regional blood volume measurements were made in the thalamus and other brain structures in anesthetized monkeys in response to colorectal distention by functional MRI. Sham surgery did not reduce the regional blood volume changes, whereas the changes were eliminated by a DC lesion at T10.

Afferent Pathways↗

PubMed1999

Dorsal root potentials and dorsal root reflexes: a double-edged sword.

The nature of dorsal root reflexes (DRRs) and their possible role in peripheral inflammation and the consequent hyperalgesia are reviewed. The history of DRRs and the relationship of DRRs to primary afferent depolarization and presynaptic inhibition in pathways formed by both large and fine afferents are discussed. Emphasis is placed on the mechanisms underlying primary afferent depolarization, including the anatomical arrangement of the synapses involved, how depolarization can result in inhibition by decreasing transmitter release, the role of excitatory amino acids and GABA, the manner in which the equilibrium potential for chloride ions is determined in primary afferent fibers, and forms of presynaptic inhibition that do not utilize GABA(A) receptors. There is then a discussion of neurogenic inflammation, including the role of the release of neuropeptides such as substance P and calcitonin gene-related peptide from sensory nerve endings. Evidence is reviewed that links DRRs to a substantial part of the swelling of the knee joint in acute experimental arthritis and to the flare reaction in the skin following intradermal injection of capsaicin. Possible mechanisms by which the level of DRR activity might be enhanced following inflammation are suggested. The consequences of this increase in DRRs may include exacerbation of hyperalgesia as well as of peripheral inflammation. The conversion of an inhibitory process, presynaptic inhibition, to an excitatory one by DRRs can thus lead to pathological consequences.

Afferent Pathways↗

PubMed1999

Branching and/or collateral projections of spinal dorsal horn neurons.

Branching and/or collateral projections of spinal dorsal horn neurons is a common phenomenon. Evidence is presented for the existence of STTm/STTl, STTc/STTi, STT/SMT, STT/SRT, SCT/DCPS, SST/DCPS, SCT/SST, STT/SHT, STeT/SHT, STeTs and other doubly or multiply projecting spinal neurons that have been anatomically and physiologically identified and named based on the locations of the cells of origin and their terminations in the brain. These newly discovered spinal projection neurons are characterized by a single cell body and branched axons and/or collaterals that project to two or more target areas in the brain. These novel populations of neurons seem to be a fuzzy set of spinal projection neurons that function as an intersection set of the corresponding single projection spinal neurons and to be at an intermediate stage phylogenetically. Identification strategies are discussed, and general concluding remarks are made in this review.

Animals↗

PubMed1999

Nitric oxide mediates the central sensitization of primate spinothalamic tract neurons.

Nitric oxide (NO) has been proposed to contribute to the development of hyperalgesia by activating the NO/guanosine 3',5'-cyclic monophosphate (cGMP) signal transduction pathway in the spinal cord. We have examined the effects of NO on the responses of primate spinothalamic tract (STT) neurons to peripheral cutaneous stimuli and on the sensitization of STT cells following intradermal injection of capsaicin. The NO level within the spinal dorsal horn was increased by microdialysis of a NO donor, 3-morpholinosydnonimine (SIN-1). SIN-1 enhanced the responses of STT cells to both weak and strong mechanical stimulation of the skin. This effect was preferentially on deep wide dynamic range STT neurons. The responses of none of the neurons tested to noxious heat stimuli were significantly changed when SIN-1 was administered. Intradermal injection of capsaicin increased dramatically the content of NO metabolites, NO-2/NO-3, within the dorsal horn. This effect was attenuated by pretreatment of the spinal cord with a nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). Sensitization of STT cells induced by intradermal injection of capsaicin was also prevented by pretreatment of the dorsal horn with the NOS inhibitors, L-NAME or 7-nitroindazole. Blockade of NOS did not significantly affect the responses of STT cells to peripheral stimulation in the absence of capsaicin injection. The data suggest that NO contributes to the development and maintenance of central sensitization of STT cells and the resultant mechanical hyperalgesia and allodynia after peripheral tissue damage or inflammation. NO seems to play little role in signaling peripheral stimuli under physiological conditions.

Animals↗

PubMed1999

Nitric oxide-mediated spinal disinhibition contributes to the sensitization of primate spinothalamic tract neurons.

This study concentrated on whether an increase in spinal nitric oxide (NO) diminishes inhibition of spinothalamic tract (STT) cells induced by activating the periaqueductal gray (PAG) or spinal glycinergic and GABAergic receptors, thus contributing to the sensitization of STT neurons. A reduction in inhibition of the responses to cutaneous mechanical stimuli induced by PAG stimulation was seen in wide dynamic range (WDR) STT cells located in the deep layers of the dorsal horn when these neurons were sensitized during administration of a NO donor, 3-morpholinosydnonimine (SIN-1), into the dorsal horn by microdialysis. In contrast, PAG-induced inhibition of the responses of high-threshold (HT) and superficial WDR STT cells was not significantly changed by spinal infusion of SIN-1. A reduction in PAG inhibition when STT cells were sensitized after intradermal injection of capsaicin could be nearly completely blocked by pretreatment of the dorsal horn with a NO synthase inhibitor, 7-nitroindazole. Moreover, spinal inhibition of nociceptive activity of deep WDR STT neurons elicited by iontophoretic release of glycine and GABA agonists was attenuated by administration of SIN-1. This change paralleled the change in PAG-induced inhibition. However, the inhibition of HT and superficial WDR cells induced by glycine and GABA release did not show a significant change when SIN-1 was administered spinally. Combined with our recent results, these data show that the effectiveness of spinal inhibition can be reduced by the NO/cGMP pathway. Thus disinhibition may constitute one mechanism underlying central sensitization.

Animals↗

PubMed1999

Inhibition of primate spinothalamic tract neurons by spinal glycine and GABA is modulated by guanosine 3',5'-cyclic monophosphate.

Our recent work has suggested that the nitric oxide/guanosine 3', 5'-cyclic monophosphate (NO/cGMP) signal transduction system contributes to central sensitization of spinothalamic tract (STT) neurons in part by influencing the descending inhibition of nociception resulting from stimulation in the periaqueductal gray. This study was designed to examine further whether activation of the NO/cGMP cascade reduces the inhibition of the activity of STT neurons mediated by spinal inhibitory amino acid (IAA) receptors. Responses of STT cells to noxious cutaneous stimuli were inhibited by iontophoresis of glycine and GABA agonists in anesthetized monkeys. Administration of 8-bromoguanosine-3',5'-cyclophosphate sodium (8-bromo-cGMP), a membrane permeable analogue of cGMP, either by microdialysis or by iontophoresis reduced significantly the IAA-induced inhibition of wide dynamic range (WDR) STT cells in the deep layers of the dorsal horn. The reduction in inhibition lasted for up to 1-1.5 h after the cessation of drug infusion. In contrast, IAA-induced inhibition of WDR STT cells in the superficial dorsal horn and high-threshold (HT) cells in superficial or deep layers was not significantly changed during 8-bromo-cGMP infusion. Iontophoresis of 8-bromo-cGMP onto STT cells produced the same actions as produced by microdialysis of this agent, but the effect was not as long-lasting nor as potent. Finally, an attenuation of the IAA receptor-mediated inhibition of STT cells produced by iontophoretic release of a NO donor, 3-morpholinosydnonimine, could be blocked by pretreatment of the spinal cord with a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. These results suggest that an increased spinal cGMP level contributes to the sensitization of WDR STT neurons in the deep dorsal horn in part by down-regulating spinal IAA receptors. However, no evidence is provided in this study that the NO/cGMP cascade regulates IAA receptors on HT and superficial WDR neurons. Combined with the preceding studies, our data support the view that NO and cGMP function in the same signal transduction cascade and play an important role in central sensitization.

Animals↗

PubMed1999

Role of metabotropic glutamate receptor subtype mGluR1 in brief nociception and central sensitization of primate STT cells.

G-protein coupled metabotropic glutamate receptors (mGluRs) are important modulators of synaptic transmission in the mammalian CNS and have been implicated in various forms of neuroplasticity and nervous system disorders. Increasing evidence also suggests an involvement of mGluRs in nociception and pain behavior although the contribution of individual mGluR subtypes is not yet clear. Subtypes mGluR1 and mGluR5 are classified as group I mGluRs and share the ability to stimulate phosphoinositide hydrolysis and activate protein kinase C. The present study examined the role of group I mGluRs in nociceptive processing and capsaicin-induced central sensitization of primate spinothalamic tract (STT) cells in vivo. In 10 anesthetized male monkeys (Macaca fascicularis) extracellular recordings were made from 20 STT cells in the lumbar dorsal horn. Responses to brief (15 s) cutaneous stimuli of innocuous (BRUSH) and barely and substantially noxious (PRESS and PINCH, respectively) intensity were recorded before, during, and after the infusion of group I mGluR agonists and antagonists into the dorsal horn by microdialysis. Cumulative concentration-response relationships were obtained by applying different concentrations for at least 20 min each (at 5 microl/min). The actual concentrations reached in the tissue are 2-3 orders of magnitude lower than those in the microdialysis fibers (values in this paper refer to the latter). The group I antagonists were also applied at 10-25 min after capsaicin injection. S-DHPG, a group I agonist at both mGluR1 and mGluR5, potentiated the responses to innocuous and noxious stimuli (BRUSH > PRESS > PINCH) at low concentrations (10-100 microM; n = 5) but had inhibitory effects at higher concentrations (1-10 mM; n = 5). The mGluR5 agonist CHPG (1 microM-100 mM; n = 5) did not potentiate but inhibited all responses (10-100 mM; n = 5). AIDA (1 microM-100 mM), a mGluR1-selective antagonist, dose-dependently depressed the responses to PINCH and PRESS but not to BRUSH (n = 6). The group I (mGluR1 > mGluR5) antagonist CPCCOEt (1 microM-100 mM) had similar effects (n = 6). Intradermal injections of capsaicin sensitized the STT cells to cutaneous mechanical stimuli. The enhancement of the responses by capsaicin resembled the potentiation by the group I mGluR agonist S-DHPG (BRUSH > PRESS > PINCH). CPCCOEt (1 mM) reversed the capsaicin-induced sensitization when given as posttreatment (n = 5). After washout of CPCCOEt, the sensitization resumed. Similarly, AIDA (1 mM; n = 7) reversed the capsaicin-induced sensitization and also blocked the potentiation by S-DHPG (n = 5). These data suggest that the mGluR1 subtype is activated endogenously during brief high-intensity cutaneous stimuli (PRESS, PINCH) and is critically involved in capsaicin-induced central sensitization.

Animals↗

PubMed1999

Comparative study of viscerosomatic input onto postsynaptic dorsal column and spinothalamic tract neurons in the primate.

The purpose of the present investigation was to examine, in the primate, the role of the postsynaptic dorsal column (PSDC) system and that of the spinothalamic tract (STT) in viscerosensory processing by comparing the responses of neurons in these pathways to colorectal distension (CRD). Experiments were done on four anesthetized male monkeys (Macaca fascicularis). Extracellular recordings were made from a total of 100 neurons randomly located in the L(6)-S(1) segments of the spinal cord. Most of these neurons had cutaneous receptive fields in the perineal area, on the hind limbs or on the rump. Forty-eight percent were PSDC neurons activated antidromically from the upper cervical dorsal column or the nucleus gracilis, 17% were STT neurons activated antidromically from the thalamus, and 35% were unidentified. Twenty-one PSDC neurons, located mostly near the central canal, were excited by CRD and three were inhibited. Twenty-four PSDC neurons, mostly located in the nucleus proprius, did not respond to CRD. Of the 17 STT neurons, 7 neurons were excited by CRD, 4 neurons were inhibited, and 6 neurons did not respond to CRD. Of the unidentified neurons, 23 were excited by CRD, 7 were inhibited, and 5 did not respond. The average responses of STT and PSDC neurons excited by CRD were comparable in magnitude and duration. These results suggest that the major role of the PSDC pathway in viscerosensory processing may be due to a quantitative rather than a qualitative neuronal dominance over the STT.

Animals↗

PubMed1999

Dorsal root reflexes and cutaneous neurogenic inflammation after intradermal injection of capsaicin in rats.

The role of dorsal root reflexes (DRRs) in acute cutaneous neurogenic inflammation induced by intradermal injection of capsaicin (CAP) was examined in anesthetized rats. Changes in cutaneous blood flow (flare) on the plantar surface of the foot were measured using a laser Doppler flowmeter, and neurogenic edema was examined by measurements of paw thickness. To implicate DRRs in neurogenic inflammation after CAP injection, the ipsilateral sciatic and femoral nerves were sectioned, dorsal rhizotomies were performed at L(3-)-S(1), and antagonists of GABA or excitatory amino acid receptors were administered intrathecally. Intradermal injection of CAP evoked a flare response that was largest at 15-20 mm from the injection site and that spread >30 mm. Acute transection of the sciatic and femoral nerves or dorsal rhizotomies nearly completely abolished the blood flow changes 15-20 mm from the CAP injection site, although there was only a minimal effect on blood flow near the injection site. These procedures also significantly reduced neurogenic edema. Intrathecal bicuculline, 6-cyano-7-nitroquinoxaline-2,3-dione, (CNQX) or D(-)-2-amino-7-phosphonoheptanoic acid (AP7), but not phaclofen, also reduced dramatically the increases in blood flow 15-20 mm from the CAP injection site, but had only a minimal effect on blood flow near the injection site. Neurogenic edema was reduced by the same agents that reduced blood flow. Multiunit DRRs recorded from the central stumps of cut dorsal rootlets in the lumbar spinal cord were enhanced after CAP injection. This enhanced DRR activity could be reduced significantly by posttreatment of the spinal cord with bicuculline, CNQX or AP7, but not phaclofen. It is concluded that peripheral cutaneous inflammation induced by intradermal injection of CAP involves central nervous mechanisms. DRRs play a major role in the development of neurogenic cutaneous inflammation, although a direct action of CAP on peripheral nerve terminals or the generation of axon reflexes also may contribute to changes in the skin near the injection site.

Animals↗