Biomedical subjects

K B Franklin

Publications and source records attributed to K B Franklin.

At least 37 records · Page 2Linked to original sources

PubMed1996

N-methyl-D-aspartate lesions of the pedunculopontine nucleus block acquisition and impair maintenance of responding reinforced with brain stimulation.

Excitotoxin lesions of the pedunculopontine tegmental nucleus have been found to block the acquisition of a conditioned place preference induced by morphine or amphetamine, and it has been suggested that such lesions may attenuate the primary reinforcing effects of these drugs and, possibly, other reinforcers. The present study examined the effects of pedunculopontine lesions on the reinforcing effects of brain stimulation. N-methyl-D-aspartate-induced lesions of the pedunculopontine nucleus prevented spontaneous acquisition of lever pressing for brain stimulation reinforcement during five daily 1 h sessions of training. The effective lesions damaged the retrorubral fields in addition to the pedunculopontine tegmental nucleus. N-methyl-D-aspartate (25 or 50 nmol) lesions of the retrorubral fields did not block acquisition of self-stimulation, however, controls reached their maximum rate of responding in the first session, responding of rats with retrorubral field lesions gradually increased over five days. When excitotoxin-induced lesions of the pedunculopontine nucleus were made after acquisition of self-stimulation, lesioned rats continued to respond to brain stimulation, but at a lower rate than controls. The results show that pedunculopontine lesions interfere with the learning and expression of a response reinforced by brain stimulation just as they block learning motivated by drugs and natural rewards. They also suggest that collateral damage to the retrorubral fields may contribute to the effects of pedunculopontine lesions on reinforced behaviour. These data support the view that the pedunculopontine tegmental nucleus is involved in the process by which reinforcers control purposive behaviour.

Animals↗

PubMed1996

Differential effects of ventral striatal lesions on the conditioned place preference induced by morphine or amphetamine.

The present experiment examined the role of the ventral striatum in the rewarding effect of morphine and amphetamine by testing whether lesions of cell bodies within this region disrupt the development of a conditioned place preference to either drug. Bilateral, N-methyl-D-aspartate- or kainic acid-induced lesions of the ventral striatum block a conditioned place preference to amphetamine (1.5 mg/kg x 3 pairings) but not to morphine (2 mg/kg x 3 pairings). Because both lesions spared anterior portions of the ventral striatum, we examined the effect of larger or more selective ventral striatal lesions on a conditioned place preference induced by morphine. Destruction of the entire ventral striatum reduced, but did not eliminate, a conditioned place preference to morphine, whereas selective lesions of the anterior ventral striatum were ineffective. These results indicate that the ventral striatum is not critically involved in morphine's rewarding effect and support the suggestion that the rewarding effects of opiates and stimulants do not involve identical neural substrates.

Amphetamine↗

PubMed1995

Effects of partial decortication on opioid analgesia in the formalin test.

Partially decorticated rats were tested for their response to nociceptive stimulation in the formalin and tail flick tests, and for the effect of morphine on these responses and on motor activity. Undrugged rats showed vigorous responses to nociceptive stimulation in both tests, and exhibited the typical biphasic time course of pain in the formalin test. Morphine 4 and 8 mg/kg produced dose-dependent analgesia in both tests in sham operated rats, and in rats with lesions that removed all or part of the cortex from the midline to the rhinal fissure (excluding the occipital cortex). In rats with lesions that extended deep into the piriform cortex and damaged the amygdala morphine analgesia was eliminated or attenuated. These and other recent findings suggest that analgesia in the formalin test depends on ascending connections to the forebrain, probably the amygdala.

Amygdala↗

PubMed1994

Lesions of the pedunculopontine tegmental nucleus abolish catalepsy and locomotor depression induced by morphine.

The cataleptic and locomotor depressant effects of morphine are mediated by a series of neural structures, all of which project to the pedunculopontine tegmental nucleus (PPTg). To test the idea that the PPTg is also involved in mediating morphine's effect on these behaviours, we examined catalepsy and spontaneous motor activity following bilateral lesions of the PPTg (0.5 microliters of 0.1 M N-methyl-D-aspartate infused over 10 min). We also examined the effect of PPTg lesions on motor functioning by observing sensorimotor responses, limb use, muscle tone and locomotion. PPTg lesions completely abolished the catalepsy and decreased activity that normally follows morphine administration. In addition lesioned animals exhibited increased muscle tone, and impairments in limb use and righting reflexes. Although the deficits were subtle, these results confirm that damage to the PPTg is associated with motor abnormalities.

Acoustic Stimulation↗

PubMed1994

Lesions of the pedunculopontine tegmental nucleus block drug-induced reinforcement but not amphetamine-induced locomotion.

It has been proposed that the positive reinforcing and motor stimulating effects of drugs involve the activation of a common neural substrate. Reinforcing effects of food, drugs and brain stimulation are blocked by lesions of the pedunculopontine tegmental nucleus (PPTg), which is a component of the mesencephalic locomotor region. This has suggested that the PPTg may be involved in both positive reinforcement and forward locomotion. In four separate experiments, rats were prepared with NMDA (0.5 microliters of 0.1 M solution) or sham lesions of the PPTg. Animals in the first two experiments were tested for the development of a conditioned place preference (CPP) to morphine (2 mg/kg x 3 pairings) or amphetamine (1.5 mg/kg x 3 pairings). Ten days later, spontaneous motor activity (SMA) was assessed in these animals following a subcutaneous injection of saline or amphetamine (1.5 mg/kg). In two further experiments, drug-naive lesioned and control animals were tested for SMA only (saline or 1.5 mg/kg amphetamine in Experiment 3, and saline, 0.5 mg/kg, or 3 mg/kg amphetamine in Experiment 4). Lesions of the PPTg blocked the development of a CPP to both morphine and amphetamine. In contrast, lesions had no effect on saline or amphetamine-stimulated SMA. The PPTg, therefore, appears to be involved in the reinforcing effects of amphetamine and morphine, but is not necessary for the expression of amphetamine-induced activity.

Amphetamine↗

PubMed1994

Morphine analgesia in the formalin test: evidence for forebrain and midbrain sites of action.

A mapping study was performed to determine where in the rat brain morphine acts to produce analgesia in the formalin test, which is an animal model of prolonged pain associated with tissue injury. A single dose (5 nmol) of morphine was bilaterally microinjected into a wide range of brain areas throughout the midbrain and forebrain. Strong analgesia was elicited from the posterior hypothalamic area, the periaqueductal gray and ventral tegmental area. Other sites from which analgesia was elicited were the nucleus accumbens and a few sites in the retrorubral field and caudate-putamen. Analgesia from the periaqueductal gray or nucleus accumbens was accompanied by decreased locomotor activity and catalepsy, whereas analgesia from the posterior hypothalamic area or ventral tegmentum was accompanied by a noticeable increase in locomotor activity and rearing. Morphine into various thalamic nuclei had no effect. These results indicate that the primary sites of action of morphine in the formalin test are probably the posterior hypothalamic area and periaqueductal gray, with an additional contribution from regions innervated by tegmental dopamine cells.

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↗

PubMed1993

Effects of pedunculopontine tegmental nucleus lesions on morphine-induced conditioned place preference and analgesia in the formalin test.

The development of a conditioned place preference to morphine (2 mg/kg; three pairings) and the analgesic effect of morphine (0, 4 or 8 mg/kg) in the formalin test were studied in rats with sham or neurotoxin lesions of the pedunculopontine tegmental nucleus. Lesions were induced by bilateral infusions of N-methyl-D-aspartate (0.5 microliter of 0.1 M solution) or vehicle over 10 min. No anti-seizure medication was administered in the first experiment, whereas animals in the second experiment were injected with diazepam (1 mg/kg) immediately after surgery. In Experiment 1, behaviour in the conditioned place preference and formalin tests was assessed in separate groups of lesioned and control rats. In Experiment 2, the same animals received both sets of tests. In both experiments lesions of the pedunculopontine tegmental nucleus blocked the development of a conditioned place preference to morphine, but had no effect on the behavioural response to formalin, or on its inhibition by morphine. Examination of cholinergic-stained cells found no correlation between the magnitude of behavioural effects and the number of acetylcholine cells destroyed by the lesions. These results confirm that the pedunculopontine tegmental nucleus mediates the development of a morphine-induced conditioned place preference, but not the analgesic effect of morphine.

Acetylcholine↗

PubMed1992

Infusions of 6-hydroxydopamine into the nucleus accumbens abolish the analgesic effect of amphetamine but not of morphine in the formalin test.

The effects of bilateral infusions of 6-hydroxydopamine into the nucleus accumbens on analgesia produced by D-amphetamine and morphine were examined, in separate experiments, in the formalin test in rats. The lesions in the two experiments were not significantly different and dopamine in the nucleus accumbens, olfactory tubercle and striatum was depleted to 21.1%, 40.3% and 65.0% of control values, respectively. D-Amphetamine (0.75 and 2.0 mg/kg) and morphine (3.0 and 6.0 mg/kg) attenuated the response to formalin in unlesioned control rats. The analgesic effect of amphetamine was severely reduced by 6-hydroxydopamine lesions, and the residual analgesia was correlated with the amount of dopamine in the nucleus accumbens, but not with dopamine levels in the olfactory tubercle or striatum. Lesions also attenuated the locomotor stimulant effect of amphetamine. The analgesic effect of morphine was not altered by 6-hydroxydopamine infusions, nor was there any correlation between the analgesic effect of morphine and dopamine concentration in the nucleus accumbens, olfactory tubercle or striatum. The results indicate that the dopamine innervation of the nucleus accumbens is not critical for the analgesic effect of morphine but plays a major role in the analgesic effect of amphetamine.

Analgesics↗

PubMed1992

The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine.

Rats were trained to self-administer nicotine on a fixed-ratio schedule of reinforcement. Infusion of the nicotinic antagonist chlorisondamine into the cerebral ventricles produced a sustained reduction in nicotine self-administration compared to vehicle-treated controls. Lesions of the mesolimbic dopamine system were produced by microinfusion of 6-hydroxydopamine into the nucleus accumbens. Following production of the lesions, nicotine self-administration was markedly reduced for the 3-week test period; motor impairment did not appear to be responsible. Post mortem analysis of brain tissue showed that the lesion produced a pronounced decrease in dopamine content of the nucleus accumbens and the olfactory tubercle, and a small depletion in the striatum. These data demonstrate that the reinforcing effects of nicotine occur within the central nervous system, and that the mesolimbic dopamine projection plays an important role in these effects.

Animals↗

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

Modelling drug kinetics with brain stimulation: dopamine antagonists increase self-stimulation.

The rewarding effects of brain stimulation and drugs are believed to depend on a common neural system. However, the pattern of responding produced by drug reinforcers is different from the pattern produced by conventional brain stimulation. Furthermore, pharmacological antagonists of reinforcement increase the rate of drug self-administration but depress self-stimulation. To test the hypothesis that the differences in the characteristics of brain stimulation and drugs as reinforcers are due to differences in the kinetics of drugs and brain stimulation, we modelled drug kinetics with frequency-modulated trains of brain stimulation. We report that animals will self-administer such brain stimulation in a manner that resembles drug self-administration and that, under these conditions, dopamine antagonists can increase the rate of self-stimulation.

Animals↗

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

Dopamine receptor subtypes and formalin test analgesia.

The role played by dopamine D1 and D2 receptors in formalin test analgesia was explored by challenging D-amphetamine- and morphine-induced analgesia with mixed and selective D1 and D2 antagonists, and by examining the relative analgesic activity of mixed and selective D1 and D2 agonists. The mixed D1/D2 dopamine antagonist cis-flupenthixol (0.5 mg/kg), the D2 antagonist pimozide (0.5 mg/kg), and the D1 antagonist SCH 23390 (0.1 mg/kg) attenuated both D-amphetamine and morphine analgesia. The mixed D1/D2 agonist apomorphine and the selective D2 agonist quinpirole produced dose-dependent analgesia while the selective D1 agonist SKF 38393 was without effect. These data suggest that D1 receptors play an "enabling" role in D2 receptor-mediated analgesia in the formalin test.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1990

6-Hydroxydopamine lesions of the ventral tegmentum abolish D-amphetamine and morphine analgesia in the formalin test but not in the tail flick test.

The effect of bilateral 6-hydroxdopamine (with desipramine) lesions of the ventral tegmental area-substantia nigra region on analgesia produced by morphine and D-amphetamine was examined with the formalin and tail flick tests in rats. These lesions depleted dopamine, but not noradrenaline, in the ventral and anterior striatum. Morphine and D-amphetamine produced analgesia in the formalin test in sham lesioned rats but not in lesioned rats. In contrast, morphine produced the same degree of analgesia in the tail flick test in sham lesioned and lesioned rats while D-amphetamine did not produce analgesia in this test. These data suggest that morphine and D-amphetamine analgesia in the formalin test involves dopamine, whereas morphine analgesia in the tail flick test does not.

Analgesia↗

PubMed1990

6-Hydroxydopamine lesions of the olfactory tubercle do not alter (+)-amphetamine-conditioned place preference.

Rats received bilateral infusions of 6-hydroxydopamine into the olfactory tubercle, resulting in a substantial (89%) local depletion of dopamine. This treatment did not significantly alter conditioned place preference produced by (+)-amphetamine, suggesting that the mesolimbic dopaminergic projection to olfactory tubercle does not mediate the rewarding effects of (+)-amphetamine in rats.

Amphetamine↗

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↗

PubMed1987

Role of peripheral and central opioid activity in analgesia induced by restraint stress.

Rats subjected to prolonged restraint showed an increase in tail flick latency which outlasted the period of restraint by 15 min. This restraint could be blocked but not reversed by 1 mg/kg of naltrexone hydrochloride given subcutaneously. Naltrexone methobromide, administered subcutaneously in doses of 10 or 25 mg/kg, did not block the analgesia indicating that peripheral opioid receptors were probably not involved. Naltrexone hydrochloride was shown to have no effect on brain tryptophan uptake in restrained rats, a neurochemical event which had previously been shown to be critical to restraint-induced analgesia.

Analgesia↗