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G L Wilcox

Publications and source records attributed to G L Wilcox.

At least 55 records · Page 3Linked to original sources
PubMed1992

Nitric oxide mediates Fos expression in the spinal cord induced by mechanical noxious stimulation.

Immunocytochemical localization of Fos protein was used to analyze the involvement of nitric oxide (NO) in the expression of Fos in the spinal cord, induced by mechanical noxious stimulation (NS). Mechanical NS was applied to the left hindpaw 30 minutes after intrathecal administration of the NO synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME) and the resulting Fos expression in the spinal cord dorsal horn was compared with that obtained in rats exposed only to the mechanical NS. Pretreatment with L-NAME but not its stereoisomer N omega-nitro-D-arginine methyl ester (D-NAME), produced a dose-dependent suppression of Fos expression induced by mechanical noxious stimulation. These results indicate that NO modulates the expression of Fos in the dorsal horn induced by mechanical noxious stimulation and further support the hypothesis that NO is involved in nociceptive events occurring in the spinal cord in response to a peripheral noxious stimulus.

Animals↗
PubMed1992

Spinal interactions between opioid and noradrenergic agonists in mice: multiplicativity involves delta and alpha-2 receptors.

The nature of the interaction between spinally administered opioid and alpha-2 agonists was investigated using the substance P behavioral test in mice. Morphine and agonists which more selectively activate mu or delta opioid receptors were co-administered intrathecally with direct and indirect acting adrenergic agonists norepinephrine, cocaine or clonidine and the behavioral responses to intrathecally coadministered substance P were evaluated. The ED50 values for agonists administered separately and concurrently were computed and drug interactions were evaluated using isobolographic analyses. After separate administration, all the opioid and adrenergic agonists inhibited the substance P-induced behavioral responses. Upon coadministration of opioid and adrenergic agonists, a multiplicative interaction was observed between morphine or the delta agonist D-Pen2-D-Pen-5-enkephalin and the adrenergic agonists. Additive or antagonistic interactions were found between the mu agonist Tyr-D-Ala-NMe-Phe-Gly(ol) and the same adrenergic agonists. The opioid antagonist naloxone and the alpha-2 adrenergic antagonist idazoxan were given as intrathecal pretreatments at doses chosen to shift the dose-response curves of their corresponding agonist (given alone) 4- to 10-fold to the right; this always resulted in a smaller, but significant (2- to 4-fold) shift in the dose-response curve of the other agonist given alone. Intrathecal pretreatment with naloxone or idazoxan altered some interactions between the opioids and clonidine. Although naloxone blocked completely the multiplicative interaction between morphine and clonidine, idazoxan did not. Both naloxone and idazoxan changed the antagonistic interaction between Tyr-D-Ala-NMe-Phe-Gly(ol) and clonidine to a multiplicative interaction. Neither antagonist blocked the multiplicative interaction between D-Pen2-D-Pen5-enkephalin and clonidine. These results suggest that: 1) interactions between opioid and adrenergic agonists in mouse spinal cord are mediated by delta and alpha-2 receptor subtypes; 2) the synergistic interaction between morphine and alpha-2 adrenergic agonists may involve action at delta opioid receptors; and 3) antagonist action on these drug interactions is complex.

Adrenergic alpha-Antagonists↗
PubMed1991

Opioid and neurokinin activities of substance P fragments and their analogs.

Newly developed substance P (SP) analogs with altered N-terminal sequences which equalize the lipophilicity of the N-terminal and C-terminal elements and of their fusion product were examined using i.t. injection in mice. I.t. injection of either the full length analog or the C-terminal hexapeptide (CP) produced biting and scratching behavior similar to that elicited by SP. SPF was approximately 5-fold and CP 14-fold less potent than native SP. The N-terminal peptide (NP) was inactive by itself but inhibited CP-elicited behavior. Naloxone antagonized this action of NP and shifted the SPF dose-response curve 4-fold to the left. However, naloxone had no effect on the action of CP or on the action of any of the native neurokinins. The results are consistent with the hypothesis that N- and C-terminal analogs of SP can have opioid and SP-like actions, respectively, in the CNS of rodents. Furthermore, analogs of SP which include at least the terminal tetrapeptide retain neurokinin activity.

Animals↗
PubMed1991

Isobolographic analysis of analgesic interactions between intrathecally and intracerebroventricularly administered fentanyl, morphine and D-Ala2-D-Leu5-enkephalin in morphine-tolerant and nontolerant mice.

Concurrent administration of morphine sulfate i.c.v. and i.t. produces a multiplicative interaction for analgesia in the tail flick response in mice. This interaction decreases to an additive interaction in mice which are tolerant to s.c. morphine. To test the responses of opioids selective for mu or delta receptors, the present study examined the interactions between fentanyl citrate (mu agonist) and D-Ala2-D-Leu5 enkephalin (DADLE, a relatively selective delta agonist) administered i.c.v. and i.t. using the tail flick test in control and morphine pellet-implanted mice. A method was developed for assigning statistical significance to the resulting ED50 values when analyzed isobolographically. When fentanyl or DADLE was administered i.c.v. plus i.t., an additive interaction between sites occurred in control animals, which changed to an antagonistic interaction for fentanyl and a multiplicative interaction for DADLE after morphine pellet treatment. When morphine was given i.c.v. along with i.t. fentanyl or DADLE in control animals, multiplicative interactions occurred when equipotent doses were given. Thus, opioids which were more receptor-selective than morphine did not produce multiplicative interactions, but were multiplicative when given with morphine. These results suggest that activation of combinations of receptors (by morphine) was required for the multiplicative interaction. The supraspinal site involved mu receptors (which are not self-sufficient and require an additional component) and the spinal site involved mu or delta receptors. The use of isobolographic analysis required that the drugs, when administered concurrently at two sites, be given in a constant dose ratio.

Animals↗
PubMed1991

Spinal 5-HT3 receptor-mediated antinociception: possible release of GABA.

Although 5-HT is clearly involved in spinal analgesia, its mode of action remains obscure, perhaps because it has multiple and often opposing effects mediated by its multiple receptor subtypes. This investigation uses selective agonists and antagonists directed at the most recently defined class of 5-HT receptors (5-HT3 receptors) in behavioral and electrophysiological studies of nociception in the spinal cord of rodents. The results demonstrate uniformly inhibitory effects of a selective 5-HT3 agonist on responses to noxious stimuli. Intrathecally administered 2-methyl 5-HT produced dose-dependent antinociception in the tail-flick test and inhibited behaviors elicited by intrathecally administered agonists for excitatory amino acid and neurokinin receptors, namely NMDA and substance P (SP). All 20 dorsal horn neurons we examined, which projected to the brain and responded to both noxious stimuli and NMDA, were inhibited in a current-related manner by this 5-HT3 agonist applied iontophoretically. Both the behavioral and electrophysiological effects were blocked not only by the 5-HT3 antagonists zacopride and ICS 205-930, but also by antagonists to the inhibitory amino acid GABA. Therefore, 5-HT via an action at 5-HT3 receptors may evoked release of GABA, which may in turn inhibit nociceptive transmission at a site postsynaptic to terminals of primary afferent fibers. If the descending serotonergic analgesic system in humans operates similarly, understanding it may enable the development of new nonopioid, nonaddictive analgesics.

Analgesia↗
PubMed1989

Baclofen, gamma-aminobutyric acidB receptors and substance P in the mouse spinal cord.

Antinociceptive effects of baclofen, a gamma-aminobutyric acidB (GABAB) agonist, were studied in mice along with other GABAergic agents, all administered intrathecally (i.t.): i.e., muscimol (GABAA agonist), bicuculline (GABAA antagonist) and 5-aminovaleric acid (GABAB antagonist). After i.t. administration, none of the four compounds increased the withdrawal latency in the tail-flick test. With the intradermal hypertonic saline (6% saline) behavioral test, baclofen decreased the number of behaviors in a dose-dependent and 5-aminovaleric acid-reversible manner, whereas i.t. administered muscimol was ineffective. With the i.t. substance P (SP) behavioral test, muscimol was again ineffective, whereas the SP-induced behaviors were differentially modified by baclofen depending on the temporal order of their i.t. administration. Although baclofen, coadministered with SP, decreased the number of SP-induced behaviors, baclofen pretreatment (2-100 min before i.t. administration of SP) increased the number of behaviors in a dose-dependent and 5-aminovaleric acid-reversible manner. Two minutes after several fixed doses of baclofen were administered i.t., dose-response curves for induction of behaviors by SP (i.t.) were shifted progressively to the left by increasing doses of baclofen, suggesting that hypersensitivity to SP had developed during this time frame. Decreased responsiveness to a peripheral noxious stimulus (hypertonic saline-induced behavior) is therefore associated with hypersensitivity to i.t. applied SP (SP behavioral test). The selective action of a GABAB agonist on neurokinin-elicited behaviors shown in this study is in clear contrast to the selective action of a GABA agonist against excitatory amino acid spinal activity noted in the following paper.

Amino Acids↗
PubMed1989

Muscimol, gamma-aminobutyric acidA receptors and excitatory amino acids in the mouse spinal cord.

These experiments examined the effects of intrathecally administered gamma-aminobutyric acid (GABA) agonists on the effects of intrathecally administered excitatory amino acid (EAA) agonists: N-methyl-D-aspartic acid (NMDA), quisqualic acid and kainic acid. We have found that muscimol, a GABAA receptor agonist, but not baclofen, a GABAB receptor agonist, dose-dependently inhibited caudally directed biting and scratching behavior induced by all three EAA agonists. This nonselective blockade of the expression of effects mediated by all three types of EAA receptor is in marked contrast to the selective blockade of NMDA effects seen previously in the case of mu opioids and phencyclidine receptor agonists. Inhibition by muscimol was blocked with the GABAA receptor antagonist, bicuculline. Decreased latency or hyperalgesia in the tail-flick test, found previously to be induced selectively by NMDA and blocked by an NMDA receptor antagonist, was similarly affected by muscimol but not baclofen, each given intrathecally. However, muscimol prolonged the tail-flick latency only after presentation of NMDA suggesting a possible antinociceptive effect of GABAA agonists in the presence of agonists at NMDA receptors. This study together with the preceding paper resolves GABA-mediated spinal antinociception into two components: a GABAA agonist selectively blocks nociception involving EAA receptors whereas a GABAB agonist selectively blocks substance P spinal activity (the preceding paper).

Analgesia↗
PubMed1989

Intrathecal somatostatin in cat and mouse studies on pain, motor behavior, and histopathology.

Effects of intrathecal (i.t.) somatostatin (SST) on nociception, motor function, and spinal cord pathology were evaluated in cats and mice. Cats chronically implanted with i.t. lumbar catheters received either a single injection of 2 mg SST i.t. (group I, N = 4), four repetitive injections on consecutive days of 2 mg SST i.t. (group II, N = 4) or saline i.t. (group III, N = 2). No analgesic effects were observed following single or repeated SST injections as evaluated by the skin twitch response. However, significant impairment of hind leg motor function ranging from unbalanced gait to paralysis was observed following the first SST i.t. injection. Histological examination of spinal cords six days after the first SST injection in group II showed multiple pyknotic neurons in all cats. Some cats showed focal demyelination in the posterior column of the spinal cord white matter. Mice received a single percutaneous injection of 50 micrograms SST i.t. (group I, N = 7), 5 micrograms SST i.t. (group II, N = 3), or saline i.t., (group III, N = 5). No analgesic effects were observed in groups II and III as evaluated by the hot plate (HP) and tail flick (TF) tests. Injection of 50 micrograms SST i.t. (group I) caused reversible flaccid hind leg paralysis in all mice and concomitant increases in HP and TF latencies. Histologic examination revealed focal demyelination in the spinal cord in three out of seven mice in this group. Present data substantiate neurotoxic effects of i.t. SST and lack of behaviorally defined antinociception at innocuous dosages.

Animals↗
PubMed1988

Pharmacological studies of grooming and scratching behavior elicited by spinal substance P and excitatory amino acids.

Compounds that produce depolarization of nociceptive neurons in the dorsal horn of the spinal cord also elicit a rather specific kind of caudally directed biting, licking, and/or scratching behavior when they are injected intrathecally in mice. We sought to use this elicited grooming behavior as a test for compounds that might inhibit the neurons excited by the excitatory agents. All three neurokinins--substance P, neurokinin A (substance K), neurokinin B (neuromedin K)--and excitatory amino acids active at N-methyl-D-aspartate (NMDA) or quisqualate receptors produce similar behaviors, which last for 1 minute after i.t. injection. Our data indicate that mu opioid agonists or alpha adrenergic agonists block both neurokinin-elicited behavior and EAA-elicited behavior; delta opioid agonists block only neurokinin-elicited behavior; and PCP/sigma "opioid" agonists block only EAA-elicited behavior. Somatostatin and serotonin produce qualitatively different behaviors by themselves and, when administered with neurokinins, partially block neurokinin-elicited behavior.

Amino Acids↗
PubMed1988

New xenograft model for assessing experimental therapy of central nervous system tumors: human glioblastoma in the intrathecal compartment of the nude mouse.

Ten congenitally athymic "nude" mice and 10 immunocompetent mice underwent intrathecal inoculation with a human glioblastoma cell line (U87MG) via percutaneous lumbar puncture (5 x 10(5) cells/animal). All of the nude mice developed paraplegia with or without incontinence at 2 weeks and routinely died of inanition 3 weeks postimplantation. Histological examination confirmed extensive proliferation of neoplastic cells within the intrathecal space. A second group of animals was inoculated with 5 x 10(4) cells/animal: 20 nude mice, 10 cyclosporine A-immunosuppressed animals, and 10 immunocompetent control mice. The 20 mice were further divided into four subsets. Subset A did not receive chemotherapy, Subset B received 200 mg of carmustine (BCNU) per m2 by intraperitoneal injection, Subset C received a single dose of 4 mg of methotrexate (MTX) per m2 by intrathecal injection 4 hours after tumor inoculation, and Subset D received 12 mg of intrathecal MTX per m2. Decreasing the concentration of cells per animal by 1 log doubled the time interval required for the development of paralysis and incontinence to 4 weeks. Treatment with intrathecal MTX at a dose of 4 mg/m2 extended the symptom-free period by an additional week (to 5 weeks postinoculation), and a dose of 12 mg/m2 allowed an average of 6 weeks before the onset of neurological impairment. The xenografts did not grow in the immunocompetent control mice, the BCNU-treated group, or the cyclosporine A-immunosuppressed animals. An intrathecal xenograft model of central nervous system malignancies allows a novel approach to the evaluation of experimental chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Mutual potentiation of antinociceptive effects of morphine and clonidine on motor and sensory responses in rat spinal cord.

Clonidine and morphine depress nociceptive reflex responses when given alone; when given in combination, the effect of each is potentiated by the other. The present study was designed to test if activity in ascending axons evoked by electrical stimulation of afferent C-fibers in the sural nerve of the rat also exhibits potentiation of the depressant effects of clonidine and morphine when both drugs are administered in combination by intrathecal (i.t.) injection to the lumbar spinal cord. For comparison, experiments were also carried out on the tail-flick response in rats. The results show that clonidine produced a dose-dependent inhibition of the tail-flick response (Ed50 20 micrograms); a combination of ineffective doses of clonidine (0.3 microgram) and morphine (2 micrograms) significantly inhibited the tail-flick response; clonidine (35 micrograms) reduced spontaneous, C-fiber-evoked and, due to co-activation, A delta-fibre-evoked activity in ascending axons; and clonidine at a threshold (0.3 microgram) or higher (3 micrograms) dose administered together with morphine at a dose (2 micrograms) that caused only a moderate inhibition produced a supra-additive effect in significantly depressing spontaneous. A delta- and C-fiber-evoked ascending activity. The dose-response curve of depression by morphine alone of C-fiber-evoked activity (ED50 8 micrograms) is significantly shifted by clonidine to the left (ED50 0.9 microgram). Naloxone (0.2 mg/kg) injected intravenously did not affect the inhibition of ascending activity caused by clonidine at the highest dose (35 micrograms), but it reduced the depressant effect of combined i.t. administration of clonidine and morphine. The potentiation of the antinociceptive effects of clonidine and morphine given in combination are possibly due to actions of the two drugs at different sites between the nociceptive afferents and the neurons sending their axons to the brain.

Afferent Pathways↗
PubMed1987

Nociceptive action of excitatory amino acids in the mouse: effects of spinally administered opioids, phencyclidine and sigma agonists.

Intrathecal administration of the excitatory amino acid (EAA) agonists, N-methyl-D-aspartate (NMDA), quisqualate (Quis) or kainic acid (KA), in the spinal subarachnoid space of mice produced a dose-related biting and scratching behavior. Higher doses appeared aversive, suggesting a nociceptive action for EAAs in the spinal cord. Intrathecally administered NMDA, but not Quis or KA, produced a hyperalgesic effect in the tail-flick and hot-plate tests. To test the hypothesis that EAA agonists are involved in transmission of nociceptive information in the spinal cord, we tested the effect of various opioid, sigma and phencyclidine compounds on the action of NMDA in the tail-flick, hot-plate and biting and scratching nociceptive tests. Our results indicated that the involvement of mu, sigma and phencyclidine receptors was predominant in blockade of the behavioral and hyperalgesic effects of intrathecally administered NMDA. Delta receptors appeared less involved, and involvement of kappa receptors was not detectable in blockade of the behavioral and hyperalgesic effects of intrathecally administered NMDA. Quis and KA effects were not altered by any of these agonists. Agonist doses required to inhibit NMDA-induced hyperalgesia in the tail-flick and hot-plate tests were significantly less than those needed to inhibit biting and scratching behavior. The adrenergic agonist norepinephrine inhibited NMDA- but not Quis- or KA-induced biting and scratching behavior. This action appeared to be alpha-1 mediated because it was reversed by phentolamine but not by yohimbine. These results suggest that the actions of EAAs in the spinal cord are differentially affected by various opioid phencyclidine, sigma and adrenergic receptor agonists and support the hypothesis that EAAs are involved in the transmission of nociceptive information in the spinal cord.

Animals↗
PubMed1987

Central and systemic morphine-induced antinociception in mice: contribution of descending serotonergic and noradrenergic pathways.

The relative importance of descending serotonergic and noradrenergic pathways to the antinociceptive action of supraspinally and systemically administered morphine sulfate, and to the antinociceptive synergism observed between spinally and supraspinally administered morphine was examined in mice. Morphine administered i.c.v., intrathecally (i.t.), s.c. or i.t. + i.c.v. produced a dose-dependent antinociceptive response, as measured by the tail-flick test. The dose-response curve for morphine (i.c.v.) was shifted significantly to the right by equal i.t. doses of methysergide or phentolamine. However, the most pronounced shift to the right was caused by i.t. administration of the selective alpha-2 antagonist yohimbine. Administration of a subantinociceptive dose of morphine (i.t.) along with morphine (i.c.v.) shifted the dose-response curve for morphine (i.c.v.) 6-fold to the left. The resulting dose-response curve for morphine (i.c.v.) was shifted to the right more by phentolamine (i.t.) than by methysergide (i.t.). Similarly, the dose-response curve for morphine (s.c.) was shifted more to the right by phentolamine (i.t.) than by methysergide (i.t.). These results suggest that the descending noradrenergic system, more than the serotonergic system, may be an important component in spinal/supraspinal interactive mechanisms that may mediate the antinociceptive action of systemically administered morphine.

Analgesia↗
PubMed1986

Intradermal hypertonic saline-induced behavior as a nociceptive test in mice.

We report a nociceptive test involving peripheral irritation which produces behavior similar to that elicited by intrathecally injected substance P. Intradermal hypertonic saline injected to the lower abdominal area produced quantifiable behavior in mice. The behavior consisted of licking, biting and scratching directed to the location of i.d. injection, and was dose-dependent with respect to the concentration and volume of saline. Intrathecally administered (D-Pro2, D-Trp7,9)-SP, a substance P antagonist, dose-dependently blocked the behaviors induced by intrathecally administered substance P as well as those induced by intradermally injected hypertonic saline, indicating a possibly common final pathway at the spinal cord level for the manifestation of both behaviors. Hypertonic saline-induced behavior was blocked completely by morphine and a partial opiate agonist (pentazocine) in a dose-dependent manner, but was not blocked by another partial opiate agonist (nalorphine). The behavior was not blocked by non-steroidal anti-inflammatory agents. This nociceptive test, in conjunction with the substance P-induced behavior test, may allow discrimination between agents acting pre- or post-synaptically in the spinal cord. Baclofen, a GABAB agonist thought to act presynaptically, changed substance P-induced behavior and hypertonic saline-induced behavior in opposite directions.

Animals↗
PubMed1986

Phencyclidine selectively blocks a spinal action of N-methyl-D-aspartate in mice.

Excitatory amino acids (EAAs) administered intrathecally (i.t.) in the mouse elicit a caudally directed biting and scratching behavior. N-methyl-D-aspartate (NMDA) is a potent agonist that produces this behavior, and its action is inhibited by the NMDA receptor antagonist, D-2-aminophosphonovaleric acid (D-APV). The behavioral response to the agonists resembles the response to i.t. substance P (SP) except that the response to the EAAs is more intense and, at higher doses, is accompanied by vocalization. The behavioral response to i.t. EAAs is not enhanced by i.t. SP. Whereas [D-Ala2-D-Leu5]enkephalin (DADL) and norepinephrine (NE) inhibit SP-induced biting and scratching, these compounds only partially inhibit EAA-induced behavior. Phencyclidine (PCP), on the other hand, inhibits completely NMDA-induced behavior but not behavior induced by SP or other EAAs. We conclude that the behavior induced by i.t. EAAs is mediated by spinal EAA receptors and that this response is pharmacologically distinct from responses to SP.

2-Amino-5-phosphonovalerate↗
PubMed1986

Antinociceptive effect of morphine on rat spinothalamic tract and other dorsal horn neurons.

The importance of the spinothalamic tract in pain transmission makes it an attractive candidate for study with respect to the effects of antinociceptive compounds. We have been interested in the analgesic actions of opioids and noradrenergic agents at the spinal level and have investigated the effects of these agents on extracellularly recorded nociceptive dorsal horn neurons in the rat. Spinothalamic tract cells were identified by antidromic activation from the somatosensory thalamus. Morphine was administered by bathing the spinal cord in an artificial cerebrospinal fluid solution which contained a known concentration of drug. We observed a dose-related inhibition, naloxone-reversible in some cases, of activity produced by spinally administered morphine in identified rat spinothalamic tract cells and dorsal horn nociceptive neurons. Morphine had no effect on stimulus-evoked responses of low threshold dorsal horn neurons.

Administration, Topical↗
PubMed1984

Tolerance to morphine analgesia: decreased multiplicative interaction between spinal and supraspinal sites.

Mice injected with morphine at both a supraspinal (intracerebroventricular) and a spinal (intrathecal) site showed a multiplicative interaction between sites for the tail-flick analgesic response. In morphine pellet-implanted mice, the decrease in this interaction was the source of tolerance developed to subcutaneous morphine whereas the separate sites showed no tolerance. During morphine withdrawal (after removal of the morphine pellet) synergism between sites returned but the separate sites showed development of tolerance.

Analgesia↗