Bruce G. Minor

Noradrenergic-serotonergic interactions and nociception in the rat

Spinal noradrenaline (NA) depletion in rats, via either systemic N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4) or intrathecal 6-hydroxydopamine (6-OHDA), reversed and/or abolished the analgesic effects of the 5-hydroxytryptamine (5-HT) agonists, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and p-chloroamphetamine (PCA), in shock titration, hot-plate and tail-flick measures of pain sensitivity. Spinal NA depletion also abolished the analgesic effects of 5-HT itself, administered intrathecally, in all three nociception tests and potentiated the analgesic effects of intrathecal NA, a demonstration of receptor supersensitivity. Spinal 5-HT depletion, via intrathecal 5,7-dihydroxytryptamine (5,7-DHT), only attenuated 5-MeODMT-induced analgesia in the tail-flick test but potentiated the 5-MeODMT effect in the hot-plate test. Intrathecal 5,7-DHT treatment caused a drastic potentiation of NA-induced analgesia in the shock titration and tail-flick tests but not in the hot-plate test. Biochemical analyses confirmed the NA and 5-HT depletion. The spinal noradrenergic system appears to be an important tonic factor modulating the function of the descending 5-hydroxytryptaminergic pathway.

EMLA cream in the treatment of post-herpetic neuralgia. Efficacy and pharmacokinetic profile.

The analgesic efficacy of 5% of EMLA cream (5 or 10 g) when applied for 24 h periods was evaluated in 5 female and 7 male patients (mean age 69 years, range 50-85 years) with refractory post-herpetic neuralgia (PHN). Mean visual analogue pain intensity scores for all patients were significantly improved 6 h after application (P less than 0.05). In a subgroup of patients with facial PHN receiving EMLA cream, 5 g (n = 4), there were significant improvements in pain intensity scores at 6 h (P less than 0.05). 8 h (P less than 0.01) and 10 h (P less than 0.01) after application. Plasma lignocaine and plasma prilocaine concentrations were well below potentially toxic levels in all patients after application.

Behavior of mother rats in conflict tests sensitive to antianxiety agents.

Previous studies of freezing and open-field activity have demonstrated that lactating rats are less fearful or less anxious than nonpregnant ones. The purpose of this investigation was to observe the behavior of mother rats in conflict tests, which are frequently used in studies on the neurobiology of anxiety. In the punished drinking test, in which licking from a water spout is punished by electric shocks, mothers (observed on Day 1 postpartum following 24 hr of water deprivation) were found to drink more than virgins. Mothers (Day 1 postpartum) also consumed more food than controls in an unfamiliar open field. In contrast, no difference between mothers (Day 5 postpartum) and virgins was present in the exploration of an electrified shock probe. The largest maternal anticonflict effects in the drinking and feeding tests were recorded when the females were tested with their pups. Increased punished drinking was also observed in virgin rats treated with the anxiolytic benzodiazepine midazolam. Water-deprived virgins and mothers did not differ in the shock titration test, a result suggesting that diminished pain reactivity was unlikely to account for the increased punished drinking in mothers. Moreover, females in late pregnancy, which are hypoalgesic (Gintzler, 1980), did not lick more than virgins in the punished drinking test. Following 24 hr of water deprivation, unpunished drinking was higher in lactating females than in virgins, so the increased acceptance of punishment by mothers might have been due to their being more thirsty than virgins.(ABSTRACT TRUNCATED AT 250 WORDS)

Antinociceptive Effects and Spinal Cord Tissue Concentrations after Intrathecal Injection of Guanfacine or Clonidine into Rats

In the present study, the antinociceptive effects of intrathecal injections of the α2-adrenoceptor agonists clonidine and guanfacine in rats was determined to establish their dose-response curves. Spinal cord tissue concentrations were also determined in a separate group of animals. Guanfacine was found to be more potent than clonidine and had a considerably longer duration of action. Thus, whereas the analgesic effect of clonidine declined to baseline by 4 hr after injecting doses of up to 50 μg, guanfacine still showed a considerable effect 18 hr after injecting both 25 and 50 μg. With both compounds, concentration gradients existed within the spinal cord. In the experiments with guanfacine, the region in the spinal cord tissue with the highest concentrations 10 min after injection contained around 30 pmollmg wet weight. At 3 hr, this figure was around 20 pmollmg. With clonidine, on the other hand, the concentration decreased from the maximal level of 200 pmollmg at 10 min to 10 pmollmg at 3 hr. On all occasions, except 10 min after injecting clonidine, it was found that the maximal tissue concentrations for both drugs remained below the cervical spinal cord, i.e., the rostral spread was less than expected, especially with drugs with such a long duration of action. The present investigation demonstrates analgesic effects of both clonidine and guanfacine after intrathecal administration, with guanfacine proving more potent and longer acting; the difference in duration of action is probably attributable to differences in rates of elimination of the drugs from spinal cord tissue.

Selective attention and place navigation in rats treated prenatally with methylazoxymethanol

Prenatal treatment of rats on gestation day 15 with methylazoxymethanol (MAM) caused forebrain microencephaly. The behavioral analyses included measures of spontaneous motor activity and tests for cognitive deficits, and were performed when the rats had reached adult age. Female MAM-treated rats failed to demonstrate contextual control of latent inhibition, which confirms earlier findings with male rats. Male MAM-treated rats demonstrated a notable impairment of place navigation in a swim-maze, but showed as strong sensory preconditioning as the control animals. Biochemical analyses indicated considerable increases in catecholamine levels in the cerebral cortex, hippocampus and striatum. The cognitive deficits, characterised by the various conditioning (taste-aversion) and instrumental learning (swim-maze) tasks, suggested that the MAM rats are deficient in their capacity to attend selectively to the relevant stimulus in complex arrangements of the stimulus situation.

Blockade and reversal of 5-Methoxy-N, N-Dimethyltryptamine-induced analgesia following noradrenaline depletion

The acute effects of the 5-hydroxytryptamine agonist, 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), upon pain sensitivity, using shock titration, tail-flick and hot-plate methods, in noradrenaline- and 5-hydroxytryptamine-depleted rats were examined. Noradrenaline depletion, following the systemic administration of N-2-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 2 X 50 mg/kg, i.p.), caused a reversal of the analgesic effect of 5-MeO-DMT on shock-titration from hypo- to hypersensitivity, and a total blockade of the antinociceptive effect of 5-MeO-DMT upon pain responses in the hot-plate and tail-flick tests. Pretreatment with either p-chloroamphetamine (2 X 10 mg/kg) or p-chlorophenylalanine (200, 100, 100 mg/kg), that depletes central 5-hydroxytryptamine stores, failed to alter the analgesia caused by acute 5-MeO-DMT. Strong evidence is provided for the effect of central noradrenaline depletion upon the analgesic effect of the 5-HT agonist. These findings suggest an important tonic influence of the noradrenaline system upon the descending spinal 5-HT pathway in rats.

Analgesia induced by 5-hydroxytryptamine receptor agonists is blocked or reversed by noradrenaline-depletion in rats

The antinociceptive effect of acute administration of 5-HT receptor agonists and agents releasing 5-HT from neuronal terminals was studied in rats by using the hot-plate, tail-flick and shock-titration tests. Noradrenaline depletion by the noradrenaline-neurotoxin N-2-chloroethyl-N-ethyl-2-bromo-benzylamine hydrochloride (DSP4, 2 X 50 mg/kg) blocked the analgesia induced by the 5-hydroxytryptamine (5-HT) receptor agonists 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and quipazine, as well as that induced by acute release of 5-HT by p-chloroamphetamine (PCA) and increased 5-HT synthesis by 5-hydroxytryptophan (5-HTP). Analgesia in the tail-flick test was partly blocked by both methergoline and mianserin, whereas the analgesic effects of 5-MeODMT in the hot-plate and shock-titration tests were unaffected by the 5-HT antagonists. In the shock-titration test it was found that the DSP4-pretreated animals were made hyperalgesic by acute 5-MeODMT, and this hyperalgesia was blocked by both mianserin and methergoline, implying that this effect was 5-HT receptor mediated. It is therefore concluded that a functional central noradrenergic system is required for eliciting 5-HT receptor mediated analgesia, and that these interactions, at least in part, are probably spinally located.

Evidence for crosstolerance to the analgesic effects between morphine and selective α2-adrenoceptor agonists

Rats were injected subcutaneously (s.c.) with morphine (5mg/kg) until tolerance developed to its antinociceptive action, or with 0.9% saline which was used as vehicle for morphine. Subsequently, both groups of animals were given an intrathecal (i.th.) dose of either noradrenaline (2 μg), clonidine (12.5 μg) or guanfacine (12.5 μg), that had been found previously to be reliably antinociceptive. In the saline-treated animals, these doses of noradrenaline, clonidine or guanfacine induced clear antinociceptive effects, but not in the morphinegroup. It is therefore concluded that cross-tolerance to the antinociceptive effects of systemic morphine and the α-adrenoceptor agonists was obtained. The cross-tolerance between morphine on one hand, and noradrenaline, clonidine and guanfacine on the other, implies that a substantial opiate-adrenoceptor interaction exists in antinociceptive processes.

(+)-8-OH-DPAT and 5-MeODMT induced analgesia is antagonised by noradrenaline depletion

In experiments with both rats and mice the 5-HT agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-methoxy-N,N-dimethyl-tryptamine (5-MeODMT) were shown to produce reliable analgesic effects after acute administration (1 mg/kg SC) in the tail-flick, hot-plate and shock-titration tests of nociception. Prior treatment with the noradrenaline neurotoxin, N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4), systemically administered to both rats and mice abolished the analgesic effects of both the 5-HT agonist compounds in all the tests of nociception used. Intrathecal 6-hydroxydopamine (6-OHDA) treatment also abolished the analgesic effects of 8-OH-DPAT and 5-MeODMT; in the tail-flick test the analgesia induced by 8-OH-DPAT was reversed to an hyperalgesia. Biochemical analyses confirmed notable noradrenaline depletions in the spinal cord. It is concluded that an important interaction between presynaptic noradrenergic terminals and serotonergic receptor sites, possibly 5-HT1A, mediates spinal nociception processes.

Blockade of intrathecal 5-hydroxytryptamine-induced antinociception in rats by noradrenaline depletion

The analgesic effect of 5-hydroxytryptamine (5-HT, 200 and 250 micrograms/kg) administered into the lumbar intrathecal space of rats was blocked in the tail-flick, hot-plate and shock titration tests of nociception when the animals had previously been treated with N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4), which depletes noradrenaline in the spinal cord. These results suggest an important modulatory role of noradrenaline upon spinal 5-HT mechanisms.