PubMed Health⌕ Search

Biomedical subjects

D L Hammond

Publications and source records attributed to D L Hammond.

17 recordsLinked to original sources
PubMed1992

Actions of 4-amino-3-(5-methoxybenzo(b)furan-2-yl) butanoic acid and 4-amino-3-benzo(b)furan-2-yl butanoic acid in the rat spinal cord.

This study examined whether two putative GABAB receptor antagonists, 4-amino-3-(5-methoxybenzo (b)furan-2-yl) butanoic acid (MBFG) and 4-amino-3-benzo(b)furan-2-yl butanoic acid (BFG), antagonized the antinociception produced by intrathecal (i.t) administration of the GABAB receptor agonist baclofen in the rat. In rats pretreated with 30 micrograms i.t. MBFG, the dose-effect relationship of D,L-baclofen was shifted approximately 2-fold and 4-fold to the right in the tail flick and hot plate tests, respectively. No further shift was obtained in the presence of 60 micrograms i.t. MBFG. I.t. injection of MBFG by itself did not alter either tail flick or hot plate latency. These data suggest that MBFG is a GABAB receptor antagonist in the spinal cord in vivo, although of marginal utility. Contrary to expectations, i.t. administration of 30-60 micrograms BFG alone increased tail flick and hot plate latencies; this increase was partially attenuated by coadministration of the GABAB receptor antagonist phaclofen. Pretreatment with 10 micrograms i.t. BFG, which was itself without effect on nociceptive threshold, antagonized the antinociceptive effects of 0.3 microgram i.t. L-baclofen, but interacted with higher and lower doses of baclofen in a complex manner. These results suggest that BFG acts as weak, partial agonist at GABAB receptors and that it may have additional, non-specific effects in the spinal cord of the rat. The pharmacological properties of BFG, therefore, resemble those of the GABAB receptor partial agonist/antagonist beta-phenyl-GABA, to which it bears a strong structural resemblance.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1992

Antinociception after intracerebroventricular administration of naltrindole in the mouse.

Intracerebroventricular (i.c.v.) injection of the delta-opioid receptor antagonist naltrindole hydrochloride (2.2-22.2 nmol) in mice produced a dose-dependent increase in tail flick and hot plate latencies with respective ED50 and 95% confidence limits of 10.6 (8.3-13.9) and 16.4 (9.2-62.3) nmol. This increase in response latencies was antagonized by 1 mg/kg s.c. naloxone or by i.c.v. coadministration of 1.4 nmol ICI-174,864, a selective peptidergic delta-receptor antagonist. Pretreatment 24 h earlier with the irreversible mu-receptor antagonist beta-funaltrexamine (6 nmol i.c.v.) or 1 h earlier with the selective kappa-receptor antagonist nor-binaltorphimine (100 nmol i.c.v.) did not attenuate the antinociceptive effects of naltrindole. These data indicate that high doses of naltrindole may have agonist activity at supraspinal delta-opioid receptors in the mouse.

Animals↗
PubMed1992

Systemic analgesic activity and delta-opioid selectivity in [2,6-dimethyl-Tyr1,D-Pen2,D-Pen5]enkephalin.

The cyclic peptide [2,6-dimethyl-Tyr1,D-Pen2,D-Pen5]enkephalin (2) was synthesized by solid-phase techniques and contains the optically pure unnatural amino acid 2,6-dimethyltyrosine (DMT) as a replacement for the Tyr1 residue of [D-Pen2,D-Pen5]enkephalin (DPDPE, 1). This structural modification resulted in a 10-fold increase in the potency of 2 at the delta opioid receptor and a 35-fold increase in potency at the mu receptor while substantial delta receptor selectivity was maintained. In addition, 2 was 86-fold more effective than 1 at inhibiting electrically stimulated contractions of the mouse vas deferens. In the hot plate test, 2 was 7-fold more potent than 1 after intracerebroventricular administration in the mouse. While 1 was inactive following systemic administration of doses as high as 30 mg/kg, subcutaneous administration of 2 significantly inhibited writhing with an ED50 of 2.6 mg/kg. These results demonstrate that the potency and systemic activity of DPDPE are significantly increased by replacement of Tyr1 with DMT.

Analgesia↗
PubMed1992

Morphine or U-50,488 suppresses Fos protein-like immunoreactivity in the spinal cord and nucleus tractus solitarii evoked by a noxious visceral stimulus in the rat.

Immunohistochemical visualization of Fos protein, the nuclear phosphoprotein product of the early-immediate gene c-fos, permits identification of populations of neurons that are activated in response to a variety of stimuli. This study examined the distribution of Fos-like immunoreactive (FLI) neurons in the spinal cord and the nucleus tractus solitarii (NTS) of the caudal medulla evoked by a noxious visceral stimulus in the unanesthetized rat. It also compared the inhibition of pain behavior and Fos expression by a mu-selective opioid agonist, morphine, and a kappa-selective opioid agonist, U-50,488. Intraperitoneal injection of 3.5% acetic acid in the unanesthetized rat evoked the expression of FLI in a discrete population of spinal cord neurons, the distribution of which closely mirrored the spinal terminations of visceral primary afferents. Specifically, FLI neurons were concentrated in laminae I, IIo, V, VII, and X. Large numbers of Fos-immunoreactive neurons were also present in the NTS of the caudal medulla, most likely as a result of spinosolitary tract and vaginal afferent input. The number of labeled neurons in both the spinal cord and the NTS was significantly correlated with the number of abdominal stretches, a pain behavior measure. Both morphine (1-10 mg/kg s.c.) and U-50,488 (3-30 mg/kg s.c.) produced a dose-dependent inhibition of the pain behavior in these animals and a dose-dependent suppression of the number of FLI neurons in both the spinal cord and in the NTS; complete suppression of FLI neurons was, however, not necessary for the production of antinociception. Furthermore, although equianalgesic doses of morphine and U-50,488 reduced the number of labelled neurons in the spinal cord to a comparable extent, morphine reduced the number of immunoreactive neurons in the NTS to a greater extent than did U-50,488. These results suggest that morphine and U-50,488 have comparable effects on the transmission of visceral nociceptive messages by spinal neurons, but differentially affect the autonomic response to noxious visceral stimuli.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

Developmental alterations in nociceptive threshold, immunoreactive calcitonin gene-related peptide and substance P, and fluoride-resistant acid phosphatase in neonatally capsaicin-treated rats.

This study examined the effect of neonatal administration of capsaicin on nociceptive threshold and the distribution of calcitonin gene-related peptide (CGRP), substance P (SP), and fluoride-resistant acid phosphatase (FRAP) in the dorsal horn of the spinal cord during the course of development (10 days to 12 weeks of age) in the rat. As early as 10 days of age, CGRP-like immunoreactivity was reduced in laminae I, II, and V, as well as in the bundles of fibers situated dorsal and ventral to the central canal. However, beginning on or about 6 weeks of age, the density of CGRP-like immunoreactivity in the superficial laminae and in the bundles dorsal and ventral to the central canal increased. Moreover, thick, nonvaricose CGRP-like immunoreactive fibers appeared in laminae III and IV. These recurring fibers were of primary afferent origin as demonstrated by their disappearance after multiple, unilateral rhizotomies. A similar age-dependent alteration in the density of FRAP activity was also observed. Although virtually absent at 10 days of age after neonatal administration of capsaicin, the density of FRAP activity increased in lamina II by 8 weeks of age. This activity disappeared after multiple, unilateral rhizotomies, indicating that the FRAP activity that reappeared was of primary afferent origin. Neonatal administration of capsaicin also reduced the density of SP-like immunoreactivity in the dorsal horn as early as 10 days of age, although the density of SP-like immunoreactivity showed some recovery after 6 weeks of age. However, unlike CGRP-like immunoreactivity or FRAP activity, the density of SP-like immunoreactivity in capsaicin-treated rats was not detectably altered by multiple, unilateral rhizotomies, indicating that it originated principally from intrinsic dorsal horn neurons. Age-dependent alterations in both thermal and mechanical, but not chemical, nociceptive thresholds were also observed in these same animals. Thus, tail flick latency, hot plate latency, and paw withdrawal threshold were maximally increased at 6 weeks of age, after which time thresholds declined to vehicle-treated values. In contrast, capsaicin-treated animals were uniformly insensitive to ophthalmic administration of capsaicin. The correspondence between developmental alterations in CGRP-like immunoreactivity or FRAP activity and in thermal and mechanical nociceptive thresholds is suggestive of a role of CGRP- or FRAP-containing primary afferents in thermal and mechanical nociception.

Acid Phosphatase↗
PubMed1991

Selective antagonism by naltrindole of the antinociceptive effects of the delta opioid agonist cyclic[D-penicillamine2-D-penicillamine5]enkephalin in the rat.

Spinal delta opioid receptors have been proposed to mediate antinociception in the rat on the basis of 1) the efficacy of a small number of agonists; 2) the lack of effect of mu-selective antagonists; and 3) the lack of cross-tolerance with mu-selective agonists. However, direct evidence to support or refute this postulate has not been obtained in the rat due to a lack of suitable delta-selective antagonists. The present study characterized the ability of Naltrindole (NTI, 17-cyclopropylmethyl-6,7-dehydro-4,5 alpha-epoxy-3,14-dihydroxy-6,7-2',3'-indolomorphinan), a recently discovered delta-selective antagonist, to antagonize the antinocieption produced by intrathecal (i.t.) administration of the prototypic delta-selective agonist cyclic[D-penicillamine2-D-penicillamine5]enkephalin (DPDPE) or the mu-selective agonists morphine and [D-Ala2,MePhe4,Gly-ol5] enkephalin (DAMGO) in the rat. Intrathecal coadministration of NTI with DPDPE significantly antagonized the increase in tail-flick latency (TFL) and hot-plate latency (HPL) produced by DPDPE. In the absence of NTI, the ED50 values and 95% CL of DPDPE in the tail-flick and hot-plate tests were 2.8 (1.1-4.7) and 19.5 (13.3-33.7) micrograms, respectively. In the presence of 10 micrograms of NTI, the ED50 value of DPDPE in the tail-flick test was unchanged and was increased by 2-fold in the hot-plate test to 35.9 (26.2-60.1) micrograms. In the presence of 30 micrograms of NTI, the ED50 value of DPDPE in the tail-flick test was increased by 5-fold to 14.5 (8.5-24.9) micrograms and its antinociceptive effect in the hot-plate test was antagonized completely.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Antagonism of baclofen-induced antinociception by intrathecal administration of phaclofen or 2-hydroxy-saclofen, but not delta-aminovaleric acid in the rat.

This study evaluated the ability of two new, selective antagonists of the gamma-aminobutyric acidB (GABAB) receptor, phaclofen (PHAC) and 2-hydroxy-saclofen (2-OH-S), to antagonize the increase in tail-flick latency (TFL) and hot-plate latency (HPL) produced by i.t. administered baclofen (BAC) in the rat. The putative GABAB receptor antagonist delta-aminovaleric acid (DAVA) was also examined for comparative purposes. Intrathecal (i.t.) pretreatment with increasing doses of PHAC (10-100 micrograms) shifted the dose-effect relationship of i.t. administered BAC progressively to the right in a parallel manner in both the tail-flick (TF) and hot-plate (HP) test. Schild analysis of the data yielded an apparent pA2 value of 7.3 +/- 0.1 and a slope of -0.98 +/- 0.14. By comparison, PHAC did not antagonize the increase in HPL produced by i.t. injection of the serotonin1A agonist, 8-hydroxy-N,N-dipropyl-2-aminotetralin. These observations indicate that PHAC competitively and selectively antagonizes BAC and further suggest that the antinociceptive effects of i.t. administered BAC are mediated by the PHAC-sensitive subtype of the GABAB receptor. Intrathecal injection of PHAC alone did not decrease TFL or HPL, suggesting that spinal GABAB receptors involved in nociception are not tonically activated. Although i.t. pretreatment with 2-OH-S (10-30 micrograms) also antagonized the antinociceptive effects of i.t. administered BAC, increasing doses of 2-OH-S did not produce progressive, rightward shifts in the dose-effect relationship of BAC. Indeed, i.t. administration of 2-OH-S alone modestly increased TFL, but not HPL in the rat. These observations suggest that 2-OH-S may be a partial agonist at spinal GABAB receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1989

Intermittent shock titration task in the rhesus monkey and its validity as an analgesiometric procedure.

This study addressed issues concerning the validity of the shock titration paradigm by using focal, pulsed electrocutaneous stimulation and including unavoidable suprathreshold intensity stimuli among titratable, threshold intensity trials. In saline-treated monkeys, the distribution of response latencies on suprathreshold intensity trials, and the relationships between stimulus intensity and response latency, percent response or trial duration were consistent with those expected of painful stimuli. Morphine (0.3-3 mg/kg i.m.), meperidine (0.3-3 mg/kg i.m.) and pentazocine (1-6 mg/kg i.m.) each dose-dependently increased escape thresholds, but did not increase response latency on titratable trials. In contrast, diazepam (0.12-0.5 mg/kg i.m.) produced a dose-dependent increase in escape threshold and a significant increase in response latency on titratable trials. Sedative anxiolytics with muscle relaxant properties could therefore be distinguished from opioid analgesics. Morphine, meperidine, pentazocine and diazepam also produced a dose-dependent rightward shift in the frequency distribution of responses to suprathreshold stimuli at doses below those that significantly increased escape threshold. Thus, the antinociceptive effect of an opioid analgesic was detectable in the monkey in the clinically effective dose range. This paradigm permits analysis of drug effects at both escape threshold and suprathreshold intensities of noxious stimuli. The concomitant measurement of escape threshold and response latency on titratable trials with analysis of the frequency distribution of responses on suprathreshold trials yields a sensitive and discriminating analgesiometric procedure with potential application to rodent, as well as primate, species.

Analgesia↗
PubMed1989

Developmental alterations in thermal nociceptive threshold and the distribution of immunoreactive calcitonin gene-related peptide and substance P after neonatal administration of capsaicin in the rat.

Age-dependent changes in thermal nociceptive threshold, as determined by the hot plate test, occurred in rats treated neonatally with capsaicin. From 4 weeks of age, hot plate latency increased to a maximum at 8 weeks of age and then declined to control values by 16 weeks of age. Although substantially diminished by 10 days of age, calcitonin gene-related peptide (CGRP)-like immunoreactivity increased in laminae I and II between 8 and 16 weeks of age. In addition, a dense plexus of CGRP-like immunoreactive fibers appeared in laminae III and IV. Similar changes in substance P-like immunoreactivity were not observed. The parallel timecourse of these alterations suggests that CGRP is involved in nociceptive processing in the spinal cord.

Aging↗
PubMed1988

GABAergic modulation of nociceptive threshold: effects of THIP and bicuculline microinjected in the ventral medulla of the rat.

Neurons of the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis pars alpha (NGCp alpha) have been implicated in the regulation of nociceptive threshold and production of antinociception. Previous studies have shown that the activity of these neurons is modulated by noradrenergic, cholinergic and serotonergic afferents. The present study examined whether these neurons are additionally subject to regulation by a GABAergic input. Microinjection of the GABAA receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; 0.3 or 1.0 microgram) in the NRM or NGCp alpha significantly decreased tail flick latency (TFL) and increased responsiveness to noxious pinch. Hot plate latency (HPL) was not affected by microinjection of 0.3 microgram THIP. Although HPL was increased after microinjection of 1.0 microgram THIP, this effect may reflect motoric disturbances. In contrast to the hyperalgesia produced by THIP, microinjection of the GABAA receptor antagonist bicuculline methiodide (0.04 or 0.1 microgram) produced a small, but significant increase in TFL. Responsiveness to noxious pinch and HPL were not affected by either dose. These findings indicate that neurons of the NRM or NGCp alpha involved in the regulation of nociceptive threshold are subject to an inhibitory GABAergic input mediated by a GABAA receptor. However, in contrast to previously described inhibitory inputs, the GABAergic influence does not appear to be tonically active to a substantial extent in the unanesthetized rat.

Animals↗
PubMed1987

The antinociceptive effects of prostaglandin antagonists in the rat.

This study examined the antinociceptive effects of two prostaglandin antagonists, SC-25469 and SC-19220 in the rat. SC-25469 and SC-19220 inhibited acetic acid-induced writhing with ED50 s of 6.9 and 6.8 mg/kg p.o., respectively. When compared to other analgesics, the rank order of potency in the writhing test was morphine greater than pentazocine = U-50,488 greater than SC-25469 = SC-19220 greater than ibuprofen greater than aspirin greater than acetaminophen. SC-25469 (150 and 300 mg/kg p.o.) and SC-19220 (50-300 mg/kg p.o.) also suppressed the behavioral response to s.c. injection of formalin, as did aspirin (50-150 mg/kg p.o.), ibuprofen (25-100 mg/kg p.o.) and acetaminophen (300 mg/kg p.o.). However, the suppression was not of the magnitude observed after administration of morphine (ED50: 0.9 mg/kg s.c.), pentazocine (ED50: 2.4 mg/kg s.c.) or U-50,488 (ED50: 0.8 mg/kg s.c.). This study demonstrates the antinociceptive properties of prostaglandin antagonists in two distinct tests of nociception.

Acetaminophen↗
PubMed1985

Effects of intrathecally administered methysergide and yohimbine on microstimulation-produced antinociception in the rat.

This study examined whether intrathecal (i.t.) administration of the serotonergic antagonist methysergide, of the alpha 2 noradrenergic antagonist yohimbine, or of both drugs antagonized stimulation-produced antinociception (SPA) evoked from the nucleus raphe magnus (NRM) and the nucleus reticularis paragigantocellularis (NRPG) of lightly anesthetized rats. The increase in tail flick latency (TFL), but not the increase in paw pinch withdrawal threshold (PWT), evoked from NRM sites was antagonized by i.t. administration of methysergide. Intrathecal administration of yohimbine antagonized both the increase in TFL and the increase in PWT produced by stimulation of NRM sites. Stimulation of sites in the NRPG also increased TFL and PWT; these increases were not antagonized by i.t. administration of methysergide. Although i.t. administration of yohimbine antagonized the increase in TFL evoked from the NRPG, the increase in PWT was not antagonized. When coadministered intrathecally, methysergide and yohimbine antagonized the increases in TFL and PWT produced by stimulation of NRM and of NRPG sites. In contrast, i.v. administration of the same doses of methysergide and yohimbine did not antagonize either the increase in TFL or the increase in PWT evoked from either set of sites. These results support the concept that activation of serotonergic and noradrenergic bulbospinal neurons mediates SPA and additionally suggest that the noradrenergic component involves an alpha 2 noradrenergic receptor.

Animals↗
PubMed1985

Efflux of 5-hydroxytryptamine and noradrenaline into spinal cord superfusates during stimulation of the rat medulla.

High pressure liquid chromatography with electrochemical detection was used to quantify the efflux, in the same sample, of endogenous 5-hydroxytryptamine (5-HT), noradrenaline (NA), and 5-hydroxyindoleacetic acid (5-HIAA) into superfusates of the rat spinal cord in vivo. The efflux of these three agents was measured prior to, and during, electrical stimulation of the nucleus raphe magnus (n.r.m.) and nucleus reticularis paragigantocellularis (n.r.p.g.), two medullary nuclei implicated in antinociception. In untreated rats, basal efflux of 5-HT and NA was 0.21 and 0.12 ng/ml of superfusate respectively; the basal efflux of 5-HIAA was 18.17 ng/ml. Stimulation of the n.r.m. and n.r.p.g. in these animals increased the efflux of 5-HT and 5-HIAA, but did not alter the efflux of NA. 60 min after administration of fluoxetine (10 mg/kg, I.P.), a 5-HT uptake inhibitor, basal efflux of 5-HT and NA was unaltered, but the basal efflux of 5-HIAA was decreased. In these rats, stimulation of the n.r.m. and n.r.p.g. increased the efflux of 5-HT and of NA. The efflux of 5-HIAA was not altered. In rats pre-treated with both fluoxetine and desipramine (10 mg/kg, I.P.), the basal efflux of NA was increased while that of 5-HIAA was decreased; the basal efflux of 5-HT was not affected. The efflux of NA, but not of 5-HT, was increased in these animals during stimulation of the n.r.m. and n.r.p.g. The efflux of 5-HIAA was not changed by stimulation. Addition of fluoxetine alone or with desipramine to the superfusate in high concentrations greatly increased basal efflux of 5-HT. Failure of stimulation of the ventromedial medulla to increase the efflux of 5-HT in these animals may be related to feed-back inhibition of release by the high concentration of 5-HT initially present in the superfusate. These results indicate that electrical stimulation of the n.r.m. and n.r.p.g. increases the efflux of endogenous 5-HT and NA from the spinal cord. These stimulation sites are coincident with brain-stem sites at which stimulation produces antinociception by activation of spinal serotonergic and noradrenergic receptors. Thus, the ability of stimulation at these sites to evoke the spinal release of the probable neurotransmitters further supports the hypothesis that the antinociceptive effect is mediated by activation of serotonergic and noradrenergic neurones projecting to the spinal cord.

Animals↗
PubMed1985

Shock titration in the rhesus monkey: effects of opiate and nonopiate analgesics.

This study evaluated the antinociceptive effects of several opiate and nonopiate analgesics in the rhesus monkey using a discrete trial shock titration paradigm. Morphine sulfate (1, 5 and 10 mg/kg i.m.) and codeine sulfate (3, 10 and 30 mg/kg i.m.) produced a significant and dose-dependent increase in mean shock threshold that was not accompanied by a significant increase in mean response latency. The mean number of shocks terminated was significantly decreased at the highest dose of each opiate. Aspirin (100 and 300 mg/kg p.o.) or ibuprofen (200 mg/kg p.o.) did not significantly increase mean shock threshold or mean response latency or decrease mean number of shocks terminated. However, 6 mg/kg i.m. of 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin-3-ol produced a significant increase in mean shock threshold and mean response latency with no significant effect on mean number of shocks terminated. The absence of any effects of a 2-mg/kg dose of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol and the severe side effects produced by 10 mg/kg prevented determination of its dose-response relationship. Diazepam (0.5, 2 and 8 mg/kg i.m.) produced a significant, dose-dependent increase in mean shock threshold and a significant increase in mean response latency with no consistent or significant effect on mean number of shocks terminated. Doses of 2 and 8 mg/kg of diazepam also produced signs of ataxia. These results suggest that the discrete trial shock titration paradigm is suitable for demonstration of the antinociceptive effects of opiate and certain nonopiate analgesics, but not nonsteroidal anti-inflammatory analgesics in the rhesus monkey.

Administration, Oral↗