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W D Willis

Publications and source records attributed to W D Willis.

At least 55 records · Page 3Linked to original sources
PubMed1999

Periaqueductal gray stimulation-induced inhibition of nociceptive dorsal horn neurons in rats is associated with the release of norepinephrine, serotonin, and amino acids.

The stimulation of the periaqueductal gray (PAG) produces behavioral analgesia in rats, cats, monkeys, and humans. This analgesia is believed to be mediated by several neurotransmitter systems, including the serotonergic, noradrenergic, glycinergic, gamma-aminobutyric acidergic, and opiatergic systems. The present study was designed to determine whether PAG stimulation produces the release of serotonin (5-HT), norepinephrine (NE), Gly, and gamma-aminobutyric acid in the spinal cord dorsal horn and whether the release of these neurotransmitters by PAG stimulation is associated with a long-lasting inhibition of the evoked nociceptive responses of dorsal horn neurons. The effect of different frequencies of stimuli on the release of neurotransmitters in the spinal cord was also examined. Microdialysis in combination with HPLC was used to measure the concentrations of neurotransmitters in the lumbar dorsal horn before, during, and after electrical stimulation of the PAG. The PAG was stimulated with electrical pulses at 333 Hz first and then at 67 Hz with the same intensity for 27 min, respectively. Both stimulus frequencies produced a significant increase in the release of 5-HT, NE, Gly, and Asp in the spinal dialysate, but the low-frequency stimulus was more potent in causing the release of neurotransmitters. Low-frequency stimulation also significantly increased the release of Glu. The time course of inhibition of dorsal horn neurons induced by long-lasting PAG stimulation corresponded to the time course of neurotransmitter release. Therefore, the results suggest that the long-lasting inhibition induced by PAG stimulation is mediated in part by the release of 5-HT, NE, and inhibitory amino acids in the spinal cord.

Amino Acids↗
PubMed1998

Increased spinal release of excitatory amino acids following intradermal injection of capsaicin is reduced by a protein kinase G inhibitor.

Second messengers have been shown to play a role in the release of neurotransmitters presynaptically in several brain regions and cell types. This study was designed to test the hypothesis that the increased release of aspartate and glutamate that occurs after injection of capsaicin is dependent on activation of the cAMP and the cGMP transduction cascades. A microdialysis fiber was implanted into the dorsal horn of the spinal cord for collection of extracellular fluid and for administration of drugs to the spinal cord. Dialysate samples were collected before and after injection of capsaicin and after infusion of inhibitors of protein kinase G (PKG; KT5823) or protein kinase A (PKA; H89). KT5823, H89, or artificial cerebrospinal fluid (ACSF; control) were administered after injection of capsaicin to reduce the increased release of aspartate and glutamate. At the time of injection of capsaicin, there is an increase in release of aspartate (191+/-21%) and glutamate (194+/-14%). This increased release is maintained through 2.5 h for both glutamate and aspartate at approximately 125% to 150%. The increase in aspartate and glutamate concentrations that occurs after capsaicin injection was reduced back to baseline after spinal infusion of the PKG inhibitor, KT5823. Blockade of PKA had no effect on the increased release of aspartate and glutamate. Thus, the current data support a role for the cGMP-PKG pathway in the control of neurotransmitter release in vivo.

Alkaloids↗
PubMed1998

Nitric oxide contributes to central sensitization following intradermal injection of capsaicin.

This study provides direct evidence from measurements of its metabolites, NO2- and NO3-, that NO is released in the spinal cord during central sensitization. A microdialysis fiber was implanted in the dorsal horn at L5 for collecting dialysate and administering drugs. Dialysate was pumped through a cadminum reducing column, a post-column derivatizing unit, and then a u.v. detector. After injection of capsaicin into one hind foot, NO2-increased in the dialysate. Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME) significantly reduced NO release induced by a second injection of capsaicin into the opposite foot. This supports the ideas that NO is involved in central sensitization in the spinal cord and contributes to hyperalgesia and allodynia following capsaicin injection.

Analysis of Variance↗
PubMed1998

Changes in nitric oxide synthase isoforms in the spinal cord of rat following induction of chronic arthritis.

Nitric oxide (NO) possibly plays an important role in the events resulting in hyperalgesia. Nitric oxide synthase (NOS) is a key enzyme in the production of NO. In this study, the relationship between NOS and hyperalgesia in a rat chronic arthritis model was tested. Chronic arthritis was induced by injection of incomplete Freund's adjuvant into the knee joint cavity unilaterally. The paw withdrawal latency (PWL) to radiant heat was used to detect secondary thermal hyperalgesia induced by the arthritis. After 1 day the PWL of the arthritic hind-paw decreased and it reached its nadir at 3 days after induction of arthritis. The lumbar and cervical enlargement of the spinal cord were removed in different groups of animals 3, 7, 14, or 21 days after induction of arthritis, and frozen tissue sections were cut. Two series of sections were incubated with polyclonal antibodies to neuronal NOS (nNOS) or to inducible NOS (iNOS). nNOS was found to increase gradually in laminae I-III in the lumbar but not in the cervical enlargement. The change became most obvious 14 days after induction of arthritis as compared to the control animals. Ependymal cells around the central canal of the lumbar enlargement were more densely stained by anti-iNOS after arthritis. A corresponding change was also found in the cervical enlargement. Computer-assisted image analysis revealed that the mean density of the affected areas in the treated group increased significantly compared with the control animals. This study suggests that the expression of both nNOS and iNOS increase following induction of chronic arthritis, which in turn would presumably lead to an increase in the production of NO. This process could be involved in mediation of the secondary thermal hyperalgesia induced by chronic arthritis.

Animals↗
PubMed1998

Involvement of the locus coeruleus in analgesic effects of a low dose of naloxone during the inflammatory process.

We evaluated the effects of systemic administration of a low dose of naloxone in rats with bilateral lesions in the area of the locus coeruleus (LC) under conditions of unilateral inflammation, compared with those in sham-operated rats. In each group, rats received a single s.c. injection of carrageenan (6 mg in 0.15 ml saline), and effects of a low dose of naloxone (5 microg/kg, i.p.) on thermal nociception were examined at 4 h and 7 days following the induction of unilateral hindpaw inflammation. The antinociceptive effect was assessed by prolongation of the paw withdrawal latency (PWL) to noxious thermal stimuli. Prior to induction of inflammation, the low dose of naloxone had no significant effect on PWLs in either the sham-operated or the LC-lesioned rats. Four hours after carrageenan injection, the low dose of naloxone produced prolongation of PWLs in the sham-operated rats but failed to induce antinociception in the LC-lesioned rats. Antinociceptive effects were observed in both groups of rats 7 days after carrageenan injection. These results suggest that the LC is involved in naloxone-induced anti-nociception during the early phase of inflammation.

Analgesics↗
PubMed1998

The effects of SDZ NKT 343, a potent NK1 receptor antagonist, on cutaneous responses of primate spinothalamic tract neurones sensitized by intradermal capsaicin injection.

Substance P, acting through neurokinin I receptors, is involved in the processing of nociceptive information in the spinal cord. Sensitization of spinothalamic tract neurons occurs to low-intensity stimuli following capsaicin injection. The current study tested the effects of the novel neurokinin I receptor antagonist, SDZ NKT 343, on the sensitization of spinothalamic tract cells by capsaicin in monkeys. Spinothalamic tract cells from the lumbar enlargement with receptive fields in the hindpaw were isolated and recorded before and after intradermal injection of capsaicin. The background activity and responses to brushing, pressing and pinching the skin were assessed. Thirty minutes after capsaicin injection there was an increase in background activity and responses to brush and pressure applied to the receptive field. Infusion of SDZ NKT 343 (for 30-45 min) significantly reversed the increased response to brushing without affecting the increased background activity or the increased response to pressure. Thus, blockade of neurokinin 1 receptors reduces the sensitized responses to innocuous mechanical stimuli but not to noxious mechanical stimuli.

Action Potentials↗
PubMed1998

Memantine attenuates responses of spinothalamic tract cells to cutaneous stimulation in neuropathic monkeys.

Several lines of evidence indicate that N-methyl-D-aspartate (NMDA) receptors play an important role in nociception in general and in pathological pain in particular. It has been previously demonstrated in behavioral studies that NMDA receptor antagonists attenuate pathological pain in humans and nociceptive behaviors in animals. In the present study, we investigated the effect of the NMDA receptor antagonist memantine (MEM) on the responses of spinothalamic tract (STT) cells in normal and neuropathic monkeys. Memantine was delivered into the spinal cord through a microdialysis fiber acutely implanted into the dorsal horn. Responses of STT cells to peripheral stimulation within their receptive fields were recorded before and after MEM infusion. In normal animals (n = 7), 10 mm MEM did not affect STT cell (n = 7) baseline activity or responses to mechanical stimuli (brush, press or pinch). In neuropathic animals (n = 6), 1.0, 3.0, 10.0 and 100 mm MEM did not affect baseline activity of STT cells (n = 7); however, in a dose-dependent fashion, it significantly reduced responses of these cells to all cutaneous stimuli. The data suggest that MEM can have a direct effect on STT cells, blocking NMDA receptors known to be present on this cell population and, furthermore, may be a therapeutic agent for chronic pain.

Journal Article↗
PubMed1998

Epigastric antinociception by cervical dorsal column lesions in rats.

BACKGROUND: Previous clinical evidence and electrophysiologic studies in the authors' laboratory have implicated the dorsal column (DC) as an important pathway for the transmission of visceral colorectal pain. This study examined, behaviorally and electrophysiologically, the role of the DC in mediating epigastric nociception using a visceral pain model involving duodenal distension in rats. METHODS: For behavioral testing, the writhing-like responses produced in awake rats by graded intraduodenal balloon distension (0.1 to 0.7 ml) were tested. A DC mechanical lesion at the C2 level or a sham operation (SH, same spinal cord segment exposed but no DC lesion) was performed. The writhing-like responses to duodenal distension were tested again and the rats were compared with other rats with no lesions and with SH rats. For electrophysiologic testing, the extracellular activity of single neurons was recorded in the ventrobasal nucleus of the thalamus in anesthetized rats. The ventrobasal cells that responded to duodenal distension were tested further with this visceral stimulus before and after a lesion of the DC. RESULTS: The mechanical DC lesion significantly reduced the intensity of the writhing-like responses and increased the threshold volume that would elicit writhing-like responses compared with rats with no lesions and SH rats without any observable neurologic deficit. A lesion of the DC also significantly reduced the responses of ventrobasal cells to duodenal distension. CONCLUSIONS: The DC plays an important role in signaling epigastric nociception in this experimental model. A mechanical DC lesion can produce significant visceral antinociception in rats.

Abdominal Muscles↗
PubMed1998

A role for the dorsal column in nociceptive visceral input into the thalamus of primates.

A possible role of the dorsal column (DC) in the processing of visceral pain has gained attention after studies in the rat have revealed that the DC transmits a major part of the pelvic visceral nociceptive input from the colon into the thalamus. Furthermore, clinical interventions aimed at interrupting ascending DC axons near the midline were successful in relieving the pain suffered by patients with cancer of the pelvic organs. The purpose of this study was to check whether a DC lesion in monkeys would reduce the responses of thalamic neurons to graded colorectal distension (CRD) as in rats. Experiments were done on anesthetized male monkeys (Macaca fascicularis). Extracellular single cell recordings were made in the ventrolateral complex of the thalamus, mainly the ventral posterolateral (VPL) nucleus, in response to visceral and cutaneous stimulation. Of 80 VPL cells isolated, CRD activated 25, inhibited 25, and had no effect on 30 neurons. The responses of six viscerosensitive VPL neurons were recorded before and after a lesion of the DC at or above the T10 spinal segment. Lesions of other spinal tracts were made after the DC lesion. The results show that the DC lesion significantly reduced the responses of the thalamic neurons tested with CRD by >50%. Lesions of other tracts did not have a consistent effect. These results corroborate findings in the rat and support the proposal that the DC plays an important role in transmitting nociceptive visceral input into the thalamus and subsequently in visceral pain.

Animals↗
PubMed1997

Capsaicin-induced sensitization of primate spinothalamic tract cells is prevented by a protein kinase C inhibitor.

Protein kinase C (PKC) has been shown to be involved in nociceptive transmission in the spinal cord. This study tested the hypothesis that induction of central sensitization in the dorsal horn by an intradermal capsaicin injection involves activation of PKC. A PKC inhibitor (NPC15437) was infused through a microdialysis fiber into the spinal cord prior to capsaicin injection. The responses of spinothalamic tract (STT) cells were recorded before and after infusion of NPC15437, and after injection of capsaicin. STT cells show an increased background activity and increased responses to innocuous stimuli following capsaicin injection while responses to heat are decreased. Spinal infusion of the PKC inhibitor, NPC15437, had no effect on background activity or responses to peripherally applied stimuli prior to capsaicin injection. However, NPC15437 prevented the sensitization of cells to weak mechanical stimuli (brush and pressure) that occurs following capsaicin injection. NPC15437 had no effect on the increased background activity or decreased responses to heat stimuli induced by capsaicin injection, suggesting alternative mechanisms for these responses. These data suggest that PKC is important for the development of central sensitization to peripheral mechanical stimuli.

Animals↗
PubMed1997

Sensitization of postsynaptic dorsal column neuronal responses by colon inflammation.

The role of a newly identified component of the postsynaptic dorsal column (PSDC) system in viscerosensory processing has been recently described. The purpose of this study was to examine the effect of colon inflammation on the responses of single PSDC cells, located in the vicinity of the central canal at L6-S1 spinal segments, to graded colorectal distension (CRD) and to cutaneous stimulation. Experiments were conducted on seven male Sprague-Dawley rats anesthetized with pentobarbital. Recordings were made from seven PSDC cells located around the central canal at L6-S1 in response to CRD and cutaneous stimulation before and after colon inflammation. Inflammation of the colon with mustard oil (MO) induced an increase in the background activity of these cells. Colon inflammation also potentiated the responses of the PSDC cells to graded CRD but not to cutaneous stimulation. This is consistent with previously observed effects of colon inflammation on the responses of viscerosensitive cells in the ventral posterolateral (VPL) nucleus of the thalamus and in the nucleus gracilis (NG). These observations support a role of the PSDC system in viscerosensory processing and primary visceral hyperalgesia.

Animals↗
PubMed1997

The subnucleus reticularis dorsalis is involved in antinociception produced by a low dose of naloxone during carrageenan-induced inflammation.

The present study was designed to investigate a role of the subnucleus reticularis dorsalis (SRD) in the analgesia produced by a low dose of naloxone during carrageenan-induced inflammation. Male Sprague-Dawley rats were divided into the following two groups: (1) rats with bilateral lesions of the SRD (n = 13) and 2) sham-operated rats (n = 24). In each group, effects of a low dose of naloxone (5 microg/kg, i.p.) on thermal nociception were examined 4 h, 7 and 28 days after the induction of unilateral inflammation. Carrageenan (6 mg in 0.15 ml saline) was injected subcutaneously into the plantar surface of the left hindpaw. The analgesic effect was assessed by prolongation of the paw withdrawal latency (PWL) to heating. Prior to carrageenan injection, a low dose of naloxone did not prolong PWLs in either group. Four hours after carrageenan, a low dose of naloxone produced a prolongation of PWLs in both sham-operated and SRD-lesioned rats. Seven days after carrageenan, naloxone failed to produce analgesia in the SRD-lesioned rats but did produce analgesia in the sham-operated rats. At 28 days, a low dose of naloxone induced hyperalgesia in the inflamed paw of both groups, whereas naloxone was ineffective in the contralateral non-inflamed paw. These results suggest that the SRD plays a role in naloxone-induced analgesia during the subacute phase of inflammation (e.g. 7 days after induction of inflammation).

Analgesia↗
PubMed1997

Dextrorphan attenuates responses of spinothalamic tract cells in normal and nerve-injured monkeys.

Spinal cord N-methyl-D-aspartate (NMDA) receptors play an important role in the transmission of acute and chronic pain. The present study investigated the ability of dextrorphan (DEX), a metabolite of dextromethorphan and a clinically safe NMDA antagonist, to attenuate the responses of nociceptive spinothalamic tract (STT) neurons in anesthetized monkeys. The STT cells were recorded extracellularly in the lumbosacral enlargement and were identified by antidromic activation from the ventral posterior lateral thalamic nucleus. DEX administered through a microdialysis fiber inserted into the dorsal horn inhibited the responses of STT cells in normal animals to noxious pinch and heat stimuli. In monkeys made neuropathic by tight ligation of the L7 or S1 spinal nerve, DEX significantly attenuated the responses of STT cells to noxious pinch and heat, as well as to innocuous brushing, pressure and von Frey filament stimuli. These findings strongly suggest that DEX should be considered a potentially useful therapeutic agent for the treatment of neuropathic pain in humans.

Animals↗
PubMed1997

Involvement of cGMP in nociceptive processing by and sensitization of spinothalamic neurons in primates.

Central sensitization of spinothalamic tract (STT) neurons in anesthetized monkeys after intradermal injection of capsaicin depends in part on disinhibition. Protein kinase C is suggested to participate in this process. The present study shows that the nitric oxide-cGMP (NO-cGMP) signal transduction system also contributes to sensitization of wide dynamic range (WDR) STT neurons located in the deep dorsal horn. The NO-cGMP system was activated by microdialysis administration into the dorsal horn of 8-bromo-cGMP, an analog of cGMP. Sensitization of STT cells by 8-bromo-cGMP increased the responses of deep WDR STT cells to both weak and strong mechanical stimulation of the skin and simultaneously attenuated the inhibition of the same neurons produced by stimulation in the periaqueductal gray (PAG). In contrast, WDR STT cells in the superficial dorsal horn and high-threshold (HT) STT cells in superficial or deep layers showed reduced responses to mechanical stimulation of the skin after infusion of 8-bromo-cGMP, and PAG inhibition of these neurons was unaffected. Sensitization of STT cells and the attenuation of PAG inhibition induced by intradermal injection of capsaicin were prevented by preteatment of the dorsal horn with a guanylate cyclase inhibitor, 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. The results support the hypothesis that activation of the NO-cGMP signal transduction system contributes to the sensitization of WDR STT neurons in the deep dorsal horn and helps explain why intradermal capsaicin injections often fail to sensitize superficial and HT STT cells. The results also support the idea that sensitization of STT cells is produced in part by disinhibition.

Animals↗
PubMed1997

Excitatory amino acid receptor involvement in peripheral nociceptive transmission in rats.

The involvement of excitatory amino acid receptors in peripheral nociceptive processing was assessed in two separate experiments. In the first, one knee joint cavity of rats was injected with 0.1 ml of L-glutamate (0.001 mM; 0.1 mM; 1.0 mM), L-aspartate (0.001 mM; 0.1 mM: 1.0 mM), L-arginine (0.1 mM) or different combinations of these amino acids. The animals tested for paw withdrawal latency to radiant heat and withdrawal threshold to von Frey filaments at different time points. Combinations of glutamate/aspartate, aspartate/arginine or glutamate/aspartate/arginine when injected into the joint, in the absence of any other treatment, reduced the paw withdrawal latency and withdrawal threshold immediately after the injection and persisting up to 5 h indicating the development of hyperalgesia and allodynia. Subsequent intra-articular injection of either an NMDA or a non-NMDA glutamate receptor antagonist ((+/-)-2-amino-7-phosphonoheptanoic acid (AP7), 0.2 mM) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 0.1 mM) attenuated the thermal hyperalgesia and the mechanical allodynia produced by glutamate/aspartate/arginine. On the other hand, in a second experiment intra-articular injection of AP7, ketamine or CNQX reversed the hyperalgesia and allodynia produced by injection of a mixture of kaolin and carrageenan into the joint. These receptor antagonists, however, did not have an effect on the joint edema. These findings provide evidence for a potential role of peripheral NMDA and non-NMDA receptors in nociceptive transmission.

2-Amino-5-phosphonovalerate↗
PubMed1997

Time course of degenerative and regenerative changes in the dorsal horn in a rat model of peripheral neuropathy.

The time course of histochemical changes in the dorsal horn of rats subjected to an experimental peripheral neuropathy has been examined. Qualitative and quantitative analyses of the changes in dorsal horn staining were made for soybean agglutinin (SBA)-binding glycoconjugates, the soluble lectins RL-14.5 and RL-29, the growth-associated protein (GAP)-43, and the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP). These analyses were made at various time points after chronic constriction of the sciatic nerve. Quantitative analysis indicated that staining density increased in the normal territories stained for SBA-binding glycoconjugates, RL-14.5, RL-29, and GAP-43 on the neuropathic side compared with the control side. In addition, there was an extension of the territories stained for SBA-binding glycoconjugates and RL-29 ipsilateral to the injury. The peak increases occurred at 14 or 28 days, followed by a decrease toward control levels by 70 days. In contrast, the staining density for SP in the ipsilateral dorsal horn decreased at 3 and 5 days and reached a peak decrease at 14 days. Then, the staining for SP returned toward control values. The staining for CGRP was unchanged at all time points examined. Dorsal rhizotomies ipsilateral to the nerve injury in neuropathic rats indicated that the increases in staining were attributable to changes in primary afferent neurons. These data suggest that peripheral neuropathy causes complex degenerative and regenerative changes in the central branches of primary afferent neurons. The associated synaptic reorganization may contribute to the sensory abnormalities that accompany peripheral neuropathy.

Animals↗