PubMed Health⌕ Search

Biomedical subjects

F V Abbott

Publications and source records attributed to F V Abbott.

At least 19 recordsLinked to original sources
PubMed2004

Elevated levels of some neuroactive progesterone metabolites, particularly isopregnanolone, in women with chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a controversial entity whose cause is unknown. In this study we have explored the possibility that progesterone metabolites may be involved. Plasma levels of the progesterone precursor pregnenolone, progesterone itself, and five ring A-reduced metabolites of progesterone were measured in 20 women with CFS and in 13 age-matched controls. To minimize the contribution of the ovary, women were either post-menopausal or in the follicular phase of the menstrual cycle (day 4-8), and progesterone levels were all well within the expected range (< or = 3.5 nmol/l). Mean values for progesterone and all of its metabolites were higher in CFS patients, the most marked being a 2.3-fold elevation in isopregnanolone (3beta,5alpha-tetrahydroprogesterone; p < or = 0.001). Progesterone levels were correlated with those of its metabolites, but even after controlling for progesterone by ANCOVA, isopregnanolone levels were still elevated (p < or = 0.001). These elevated levels of isopregnanolone could not be attributed to medications (antidepressants and anxiolytics). When the CFS patients were divided into two groups according to their Hamilton depression scale ratings, mean (+/-SD) isopregnanolone levels were higher (274+/-160 vs 197+/-119 pmol/l) in the less depressed group (ratings 2-14) than in the more depressed group (ratings 17-28), although this difference did not reach significance. Progesterone levels were negatively correlated with Hamilton depression rating scores (r=-0.56; p<0.01). These results suggest that increases in ring A-reduced progesterone metabolites, particularly isopregnanolone, are associated with CFS, and that the pathophysiology of CFS is unlikely to be due to depression.

Adult↗
PubMed2001

Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain.

An enhancement of neurotransmission of serotonin (5-HT), noradrenaline, or both, underlies the antidepressant response associated with most agents presently available to treat major depression. With respect to the 5-HT system, antidepressant drugs exert immediate effects on some neuronal elements controlling overall transmission, but it is the gradual changes in neuronal responses to such treatments that are ultimately responsible for producing their therapeutic benefits. In major depression, an increase in 5-HT1A transmission is thought to be a crucial determinant of the antidepressant response, whereas an enhancement of 5-HT2 transmission in the orbitofrontal cortex may mediate the therapeutic effect of 5-HT reuptake inhibitors in obsessive-compulsive disorder (OCD). The doses of medication and the durations of treatment necessary to obtain these alterations in 5-HT transmission in various brain structures of laboratory animals are fully consistent with the conditions in the clinic necessary to attenuate symptoms in depression and OCD. It is also possible that the relief of chronic pain produced by some antidepressants may be mediated, in part, by the blockade of peripheral 5-HT2A receptors. These observations emphasize the notion that the 5-HT system is endowed with different adaptive properties in various parts of the body, which, in addition to the multiplicity of 5-HT receptors, makes this chemospecific network important in many disorders.

Animals↗
PubMed2000

Phenacetin, acetaminophen and dipyrone: analgesic and rewarding effects.

The antinociceptive and rewarding effects of phenacetin, a mild analgesic with abuse liability, were compared with those of acetaminophen, dipyrone and indomethacin in the formalin and conditioned place preference tests. Phenacetin, acetaminophen and dipyrone attenuated the pain response, beginning at 50, 50 and 100 mg/kg, respectively. Systemically active drugs produced weaker antinociception when injected into the paw or intracerebroventricularly at doses approximately 10(3) lower than those required for systemic effects; dose effect relations were bell-shaped by the intracerebroventricular route. By all three routes, there was a clear ceiling to the effects of acetaminophen that is consistent with its clinical efficacy. Systemic phenacetin and acetaminophen produced a conditioned place preference at doses that produced antinociception. Dipyrone produced a place aversion by the systemic route and a place preference intracerebroventricularly. The latter had a bell-shaped dose effect relationship identical to that in the formalin test. Indomethacin was inactive in all tests, except for mild hyperalgesia by the intraventricular route. The results indicate that the antinociceptive effects of phenacetin, acetaminophen and dipyrone reflect a combination of peripheral and central actions, neither of which involves inhibition of cyclooxygenase. The central component of the antinociceptive effects may be related to activation of brain mechanisms that are involved in reinforcement.

Acetaminophen↗
PubMed1998

Use and abuse of over-the-counter analgesic agents.

Pain and discomfort in everyday life are often treated with over-the-counter (OTC) analgesic medications. These drugs are remarkably safe, but serious side effects can occur. Up to 70% of the population in Western countries uses analgesics regularly, primarily for headaches, other specific pains and febrile illness. It is not known whether the patterns of use are consistent with good pain management practices. OTC analgesics are also widely used to treat dysphoric mood states and sleep disturbances, and high levels of OTC analgesic medication use are associated with psychiatric illness, particularly depressive symptoms, and the use of alcohol, nicotine and caffeine. More than 4 g per day of acetylsalicylic acid (ASA) or acetaminophen over long periods is considered abuse. People using excessive amounts of OTC analgesics may need more effective treatments for chronic pain, depression or dysthymia. The possibility that these drugs have subtle reinforcing properties needs to be investigated. Certainly phenacetin, which was taken off the market in the 1970s, had intoxicating effects. A better understanding of patterns of use is needed to determine the extent of problem use of OTC analgesics, and whether health could be improved by educating people about the appropriate use of these drugs.

Analgesics↗
PubMed1997

Options for management of acute pain in the rat.

Clinical recommendations for analgesics in laboratory rodents are usually derived from basic research. However, animal models of pain often involve withdrawal reflexes evoked by threshold-level stimuli, whereas pain associated with surgery or disease involves injury and inflammation. Moreover, the analgesics used in research tend to be chosen as exemplars of a drug class, without regard for whether the route of administration is practical, whether the drug has useful kinetics or whether the side effects are tolerable. This paper provides data on the efficacy of drugs from four classes, using the formalin test as a model of injury-induced pain. Formalin (50 microliters, 2.5 per cent) was injected subcutaneously into a rat's paw and the behavioural response (lifting or licking of the paw) was recorded. Buprenorphine at 0.1 mg/kg and dipyrone at 200 mg/kg completely suppressed the pain responses. When formalin was injected six hours after buprenorphine or dipyrone, pain scores were 30 per cent of control scores. In the absence of pain and handling, 0.6 mg/kg buprenorphine was lethal to 25 per cent of rats. Locomotor activity was slightly depressed by 300 mg/kg dipyrone. Xylazine at 2 mg/kg suppressed pain responses, but the analgesia had decreased to less than 50 per cent after two hours and the effects were variable thereafter; at 8 mg/kg rats were unresponsive to a strong pinch. Acepromazine at 2.5 mg/kg reduced pain to 20 per cent of control scores and this level of analgesia was maintained for six hours; neuroleptic effects were prominent at 5 mg/kg.

Acepromazine↗
PubMed1997

Persisting sensitization of the behavioural response to formalin-induced injury in the rat through activation of serotonin2A receptors.

Serotonin potentiates pain induced by intraplantar injection of other inflammatory mediators through the 5-hydroxytryptamine2A receptor, and 5-hydroxytryptamine2A antagonists dose-dependently block pain induced by formalin. The present study examined the temporal characteristics of 5-hydroxytryptamine-mediated potentiation of pain in the rat. Simultaneous injection of the 5-hydroxytryptamine2 receptor agonist alpha-methyl-5-hydroxytryptamine (10 micrograms) plus prostaglandin E2 (0.1 microgram) produced 10 min of lifting and licking of the injected paw. When alpha-methyl-5-hydroxytryptamine was injected before prostaglandin E2, the response decreased as the interval increased, and by 1 h, it was not different from injection of prostaglandin E2 alone. When prostaglandin E2 was injected prior to alpha-methyl-5-hydroxytryptamine, sensitization to the latter persisted for more than 3 h. It was blocked by the 5-hydroxytryptamine2 antagonist ketanserin (5 micrograms), injected locally 5 min before alpha-methyl-5-hydroxytryptamine. Ketanserin (5 micrograms) or the 5-hydroxytryptamine1A/2A antagonist spiperone (0.3 microgram), injected locally 5 min before alpha-methyl-5-hydroxytryptamine and prostaglandin E2, reduced pain by 80-90%, but only by 40-50% when injected 2 min after. Formalin produced a biphasic pain response. The 5-hydroxytryptamine2 antagonists, ketanserin (50 micrograms), spiperone (3 micrograms) and ritanserin (50 micrograms) injected 5 min before formalin reduced the pain response by 70, 90 and 74%, respectively, but only by 40, 30 and 24% when injected at the beginning of the second phase. Pretreatment of the paw with 2 micrograms indomethacin did not alter the response to alpha-methyl-5-hydroxytryptamine plus prostagladin E2, indicating that the sensitization was not due to prostaglandin synthesis. These data show that 5-hydroxytryptamine sensitizes tissue to the pain-producing actions of other inflammatory mediators, and that the sensitization produces a persisting change in tissue that can be blocked by pretreatment with an antagonist, but not reversed after it has occurred. The data imply that 5-hydroxytryptamine2A antagonists may act prophylactically to prevent the evolution of pain in injured tissue, but do not reduce already-present pain.

Animals↗
PubMed1996

Contribution of peripheral alpha 1A-adrenoceptors to pain induced by formalin or by alpha-methyl-5-hydroxytryptamine plus noradrenaline.

We examined the peripheral adrenergic mechanisms involved in pain induced by alpha-methyl-5-hydroxytryptamine (alpha-methyl-5-HT) plus (+/-)-noradrenaline or prostaglandin E2 and by intraplantar formalin. Agents were injected s.c. into the plantar surface of rats' paws, and the paw lifting and licking response scored. Pain produced by alpha-methyl-5-HT (10 micrograms) plus noradrenaline (10 micrograms) was blocked by pretreatment with the alpha-adrenoceptor antagonists, phentolamine (10 micrograms) and prazocin HCl (alpha 1; 40 micrograms), but not by timolol (beta; 10 micrograms) or idazoxan (alpha 2; 40 micrograms). Phenylepherine, but not clonidine, substituted for noradrenaline to induce pain when combined with alpha-methyl-5-HT. The alpha 1A-adrenoceptor antagonist, WB-4101 (2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane HCl), but not the alpha 1B- adrenoceptor antagonist, chloroethylclonidine, also blocked the pain response produced by alpha-methyl-5-HT plus noradrenaline. Neither of these agents altered pain produced by alpha-methyl-5-HT plus prostaglandin E2 (0.1 microgram). Formalin-induced pain (1%, 50 microliters) was biphasic, and timolol increased the first phase response. The second phase was attenuated by 40% by phentolamine (10 micrograms) injected 10 min before formalin or at the beginning of the second phase; 30 micrograms did not produce a larger effect. Prazosin and WP-4101, but not idazoxan or chloroethylclonidine, also attenuated the second phase. Thus, activation of alpha 1A-adrenoceptors can contribute to pain, but pain induced by alpha-methyl-5-HT plus prostaglandin E2 is independent of adrenergic function, indicating that adrenergic function is not necessary for induction of pain by inflammatory mediators. alpha 1A-Adrenoceptor blockade attenuates pain when administered after development of pain, implying that peripheral adrenergic mechanisms contribute to ongoing maintenance of pain.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1996

Activation of 5-HT2A receptors potentiates pain produced by inflammatory mediators.

Previous results from our laboratory indicate that serotonin (5-HT) potentiates pain produced by other inflammatory mediators. To characterize the receptor subtype(s) mediating this synergistic effect of 5-HT, selective 5-HT agonists were injected, alone or with noradrenaline (NA) or prostaglandin E2 (PGE2), into the plantar surface of the paws of rats. The behavioural response (favouring, elevation and licking the paw) was recorded using the rating scale developed to quantify formalin-induced pain. The 5-HT1A and 5-HT3 agonists, 8-OH-DPAT and 2-methyl-5-HT, respectively, produced only transient responses by themselves and did not interact with PGE2 or NA. The 5-HT2 agonists, alpha-methyl-5-HT and DOI, also produced transient responses alone, but induced lifting and licking of the injected paw lasting more than 30 min when combined with PGE2 or NA. The lifting and licking response produced by 5-HT plus PGE2 was not altered by intraplantar pretreatment with the 5-HT1A and 5-HT3 antagonists, BMY 7378 and tropisetron, but was attenuated by the 5-HT2A/2C antagonist ketanserin. The pain response produced by alpha-methyl-5-HT plus PGE2 was blocked by pretreatment with the 5-HT2A/2C antagonists ketanserin and ritanserin, and the 5-HT2A antagonist spiperone (MPE50 values 1.4, 7.7 and 0.06 nmol, respectively). The second phase of the response to intraplantar formalin was also attenuated by ketanserin, ritanserin and spiperone (MPE50 values 11.3, 21.8 and 0.23 nmol, respectively). These data imply that 5-HT2A antagonists may be effective peripherally acting analgesics or analgesic adjuncts in pain associated with 5-HT release from platelets, such acute injury and, perhaps, some chronic pain states.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Peripheral opioid modulation of pain and inflammation in the formalin test.

The effects of local treatment with opioid receptor agonists on the early (0-10 min) and late (20-40 min) behavioural response and extravasation induced by intraplantar injection of 1% formalin in rats were examined. The mu-opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO) depressed pain behaviour in the late phase, and extravasation in both phases. The kappa-opioid receptor agonist trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] benzeneacetamide methanesulfonate (U50,488H) suppressed the behavioural response in both phases, but extravasation was enhanced in the early phase and not altered in the late phase. The delta-opioid receptor agonist [D-Pen2,5]enkephalin (DPDPE) enhanced the behavioural response in the late phase, but inhibited extravasation in the both early and late phases. Systemic injection of the agonists had no effects, and pretreatment with s.c. naloxone methiodide reversed the effects of locally administered agonists. These data (1) support the notion that different pathophysiological mechanisms underlie the two phases of the formalin test, and (2) indicate that depending on the receptor specificity, opioid receptor agonists have both pro- and antinociceptive effects, as well as pro- and antiinflammatory activity.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

Behavioural effects of intraplantar injection of inflammatory mediators in the rat.

The behavioural response to intraplantar injection of inflammatory mediators was examined using the rating scale developed to assess formalin-induced pain. Serotonin, bradykinin, prostaglandin E2, substance P and histamine induced dose-dependent favouring of the injected paw. Serotonin, bradykinin and prostaglandin E2 also induced transient dose-dependent paw elevation (lifting) and licking. Noradrenaline produced only a weak favouring response. Serotonin produced a synergistic increase in lifting and licking when combined with any of the other mediators, while all other combinations of agents taken two at a time showed additivity. There was apparent antagonism between some combinations in the favouring response; this may reflect overestimation of the baseline. The data indicate that (i) the overt spontaneous behaviour of rats can be used to evaluate spontaneous pain, (ii) the favouring response and the lifting and licking responses are qualitatively different, the former being similar to hyperalgesia and the latter possibility representing overt pain, (iii) hyperalgesia and overt pain are related, but the generation of overt pain involves specific mechanisms in addition to those required to induce hyperalgesia, and (iv) serotonin may function to enhance the pain-producing effects of inflammatory mediators, even when they lack intrinsic activity. The data show that some inflammatory mediators produce transient overt pain when high doses are injected into normal tissue in rats. Combination of inflammatory mediators with low doses of serotonin produced a synergistic increase in the pain response. The data suggest that serotonin released from platelets in injured tissue plays a central role in the pain associated with injury, and that serotonin antagonists may have promise as peripherally acting analgesics or analgesic adjuncts by blocking a synergistic process involved in algogenesis.

Animals↗
PubMed1993

Pentobarbital, diazepam, and ethanol abolish the interphase diminution of pain in the formalin test: evidence for pain modulation by GABAA receptors.

There are two phases to the behavioral response to injection of formalin. After an initial vigorous response, a period of reduced pain occurs 10 to 15 min after formalin, followed by reemergence of pain-related behaviors. These phases are believed to represent acute chemical stimulation of afferent neurons followed by injury-related inflammatory pain. Pentobarbital (10, 15, or 25 mg/kg), diazepam (0.5, 1.5, or 5.0 mg/kg), or ethanol (0.5, 1.0, or 1.5 g/kg) attenuated the diminution of pain between the two phases, so that pain was continuous throughout 60 min of testing, but had no effect on pain scores during the peaks of either phase. The effects of pentobarbital and diazepam were blocked by picrotoxin (2.5 mg/kg), which itself had no effect. Ro 15-1788 also blocked the effect of diazepam. Picrotoxin did not effectively antagonize the effect of ethanol. A high dose of picrotoxin (5.0 mg/kg) caused seizures in some rats and also eliminated the interphase depression of pain. The results suggest that the biphasic time course of formalin pain is produced by a central antinociceptive mechanism that is inhibited by GABAA receptors.

Analgesics↗
PubMed1992

Acute tryptophan depletion blocks morphine analgesia in the cold-pressor test in humans.

The effects of depletion of the serotonin precursor, L-tryptophan, on the threshold and tolerance to cold pressor pain, and the analgesic effect of morphine (10 mg intramuscularly), were tested in a double blind trial on human volunteers. Effects on mood were also assessed using the Profile of Mood States and the Addiction Research Center Inventory (ARCI) Scales. To deplete tryptophan, subjects were fed a tryptophan-deficient amino acid mixture 4.5 h before morphine was administered. Controls received the mixture with tryptophan, which is equivalent to a nutritionally balanced protein. The tryptophan-deficient meal reduced plasma tryptophan more than 70% but had no effect on threshold or tolerance to cold pressor pain. After morphine, tolerance to cold pressor pain increased in controls. Tryptophan depletion abolished this analgesic effect. Pain threshold was not altered by morphine. In subjects with normal tryptophan, the analgesic effect of morphine was predicted by the level of plasma morphine-6-glucuronide, but not by the level of morphine. Morphine increased scores on the LSD scale of the ARCI, but had no effect on other measures of mood. Tryptophan depletion also failed to alter mood in these subjects, who had unusually low depression scores before tryptophan depletion.

Adolescent↗
PubMed1992

A survey of pain in hospitalized patients aged 4-14 years.

One hundred fifty randomly selected hospitalized children between the ages of 4-14 were interviewed to assess their pain experience in the hospital. Follow-up information was obtained through parent interviews 3 weeks, 3 months, and 6 months later. On enrollment, more than 87% of children reported having had pain within 24 h and, of those, 19% reported their usual pain intensity as in the severe range. Thirty-eight percent of children had received analgesic medication during the preceding 24 h. Children who had undergone surgery were three to four times more likely to have received narcotic analgesic than nonsurgical patients, although similar proportions in both groups reported moderate to severe pain intensity. In spite of these reports of significant pain by a substantial number of children during hospitalization, at the 3-week follow-up check, by parent report, 68% were pain free. The parents of those with pain were contacted at 3 and 6 months postenrollment, and 96% of children were no longer experiencing pain. Five children reported pain at all contact points; three of these were suffering chronic diseases and the other two had suffered major trauma from motor-vehicle accidents.

Adolescent↗
PubMed1991

Morphine-6-glucuronide contributes to rewarding effects of opiates.

It was recently confirmed that a metabolite of morphine, morphine-6-glucuronide (M6G), is a long lasting, powerful analgesic in humans and animals and may account for a major component of clinical opiate analgesia. It is reported here that M6G is also a powerful behavioral reinforcer in the conditioned place preference test in rats, indicating that it has rewarding properties, and is therefore likely to have abuse potential. The induction of a place preference by M6G is blocked by naltrexone, indicating that the rewarding effect of M6G is mediated by opioid receptors. Given systemically M6G is approximately equipotent with morphine. When given intracerebroventricularly to bypass the blood-brain barrier, M6G is 146 times more potent than morphine in the place preference test. Thus 6-substituted metabolites of opiates may play a more significant role in the effects of opiates than has been previously assumed.

Animals↗
PubMed1991

The effect of tryptophan supplementation on autotomy induced by nerve lesions in rats.

Rats were fed an artificial diet containing either their normal, or five times their normal, daily requirement of tryptophan for up to five weeks and were tested in an animal model of deafferentation pain, nerve lesion-induced autotomy. In this model one of the hind limbs of the animal was denervated, and the extent to which the animal attacked its denervated paw was assessed. Rats receiving the high-tryptophan diet showed significantly lower levels of autotomy, compared to rats fed the control diet. 5-Hydroxytryptamine and 5-hydroxyindoleacetic acid in the brain and spinal cord were significantly elevated in rats receiving the high-tryptophan diet, indicating that the supplemented diet produced a chronic increase in CNS indoleamine metabolism. Currently there is no accepted pharmacological treatment of deafferentiation pain. Our results suggest that tryptophan should be tested in phantom limb pain and other deafferentation pain syndromes.

Animals↗
PubMed1990

Reduction of postoperative morbidity following patient-controlled morphine.

The present study examined the impact of two methods of pain management on recovery in 38 women undergoing hysterectomy. One group received IV morphine in the recovery room and IM morphine on the ward on a PRN basis (PRN group). In the other group, a loading dose of morphine 8 mg IV was given when the patient first complained of pain and patient-controlled IV morphine (PCA) was initiated and continued for 48 h (PCA group). Both groups received similar amounts of morphine overall, differently distributed over time. The PCA patients received 8 mg.h-1 in the recovery room (approximately 2.5 hrs) and less thereafter. The PRN patients received approximately 2 mg.h-1 for the entire 48-hr period. Pain control was better throughout convalescence and less variable across time with PCA management. Minute ventilation also recovered faster and by day four was 25 per cent above the preoperative baseline in the PCA group. In addition, oral temperature became normal one day earlier, ambulation recovered more rapidly and patients were discharged from hospital earlier. The data suggest that early treatment with relatively high, self-titrated morphine doses may alter the course of the metabolic response to surgery.

Adult↗
PubMed1990

Tryptophan-morphine interactions and postoperative pain.

Patients undergoing abdominal surgery were infused with saline or the 5-hydroxytryptamine (5-HT) precursor tryptophan starting in the operating room and continuing for three hours in the recovery room. There was a nonsignificant trend for patients who received tryptophan to have higher pain scores. In the saline-treated patients, plasma tryptophan was below the range for normal healthy subjects, and there was a strong positive relationship between plasma tryptophan and morphine requirements. These data, taken together with animal data obtained using the formalin pain test, suggest that a 5-HT system in the brain can antagonize the dissociative state produced by morphine, which helps patients to tolerate pain. When plasma tryptophan falls below normal levels, brain 5-HT falls and morphine requirements are reduced. While tryptophan may potentiate spinal 5-HT function to decrease nociceptive afference in some circumstances, there may be clinical conditions in which the use of tryptophan is contraindicated.

Double-Blind Method↗