Rodney J. Irvine

Mu receptor binding of some commonly used opioids and their metabolites

The binding affinity to the mu receptor of some opioids chemically related to morphine and some of their metabolites was examined in rat brain homogenates with 3H-DAMGO. The chemical group at position 6 of the molecule had little effect on binding (e.g. morphine-6-glucuronide Ki = 0.6 nM; morphine = 1.2 nM). Decreasing the length of the alkyl group at position 3 decreased the Ki values (morphine less than codeine less than ethylmorphine less than pholcodine). Analgesics with high clinical potency containing a methoxyl group at position 3 (e.g. hydrocodone, Ki = 19.8 nM) had relatively weak receptor binding, whilst their O-demethylated metabolites (e.g. hydromorphone, Ki = 0.6 nM) had much stronger binding. Many opioids may exert their pharmacological actions predominantly through metabolites.

The health effects of ecstasy: a literature review

Ecstasy (3,4-methylenedioxymethamphetamine, MDMA) is the third most used illicit drug, after cannabis and amphetamines. There has been considerable interest in the adverse effects of use, with particular attention given to a small number of deaths related to ecstasy use, and the neurotoxic effects of MDMA. This paper reviews case reports of adverse effects attributed to ecstasy use, and the findings of animal and human studies, so as to identify the health effects of ecstasy use, and factors contributing to their occurrence. The incidence of serious acute adverse events related to ecstasy is low. It is the unpredictability of those adverse events and the risk of mortality and substantial morbidity that makes the health consequences of ecstasy significant. Hyperthermia and hyponatraemia are the most significant acute adverse effects, and can occur even when MDMA is the only drug used. Ecstasy users should be aware of the importance of controlling body temperature and fluid intake, early signs of adverse effects, and the need to seek medical assistance promptly. Neurotoxicity is potentially the most significant long-term effect of ecstasy. The clinical implications of neurotoxicity are uncertain at this time, but short-term memory impairment may be significant.

The influence of restraint on blood pressure in the rat.

We examined the influence of procedures used in blood pressure measurement on blood pressure and the effects of antihypertensive agents. Subjects were spontaneously hypertensive rats (SHR) and their Wistar/Kyoto (WKY) controls. Blood pressure was recorded by telemetry. Twenty-four h baseline pressure were measured, and the effect of minor handling on blood pressure and heart rate was examined. The influence of restraint such as is used for tail-cuff blood pressures was examined. The effects of three different antihypertensive drugs was also examined in the SHR. In the home-cage environment, the SHRs showed higher systolic blood pressures, but had similar hypertensive responses to minor handling as the WKYs. Both strains had elevated heart rate and blood pressure when restrained in the manner used for tail-cuff readings. The antihypertensive effects of captopril and losartan in the SHR were unchanged when the animals were restrained but the hypotensive effect of hydralazine was greater. These results confirm that significant changes in heart rate and blood pressure can occur as a result of the minor procedures frequently used in blood pressure recording in both SHR and WKY rats. This suggests that telemetry may have significant advantages as a method for continuous blood pressure monitoring. The pharmacological profile of antihypertensive drugs may well be different in animals where telemetry is employed and are not subject to the stresses involved in previous methods of monitoring blood pressure.

Pharmacokinetic Profile of Single and Repeated Oral Doses of MDMA in Squirrel Monkeys: Relationship to Lasting Effects on Brain Serotonin Neurons

A large body of data indicates that (±)3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) can damage brain serotonin neurons in animals. However, the relevance of these preclinical data to humans is uncertain, because doses and routes of administration used in animals have generally differed from those used by humans. Here, we examined the pharmacokinetic profile of MDMA in squirrel monkeys after different routes of administration, and explored the relationship between acute plasma MDMA concentrations after repeated oral dosing and subsequent brain serotonin deficits. Oral MDMA administration engendered a plasma profile of MDMA in squirrel monkeys resembling that seen in humans, although the half-life of MDMA in monkeys is shorter (3 vs 6–9 h). MDMA was biotransformed into MDA, and the plasma ratio of MDA to MDMA was 3–5 / 100, similar to that in humans. MDMA accumulation in squirrel monkeys was nonlinear, and plasma levels were highly correlated with regional brain serotonin deficits observed 2 weeks later. The present results indicate that plasma concentrations of MDMA shown here to produce lasting serotonergic deficits in squirrel monkeys overlap those reported by other laboratories in some recreational ‘ecstasy’ consumers, and are two to three times higher than those found in humans administered a single 100–150 mg dose of MDMA in a controlled setting. Additional studies are needed on the relative sensitivity of brain serotonin neurons to MDMA toxicity in humans and non-human primates, the pharmacokinetic parameter(s) of MDMA most closely linked to the neurotoxic process, and metabolites other than MDA that may play a role.

Plasma drug concentrations and physiological measures in 'dance party' participants

The increasing use of (±) 3,4-methylenedioxymethamphetamine (MDMA) in the setting of large dance parties (‘raves’) and clubs has been the source of some concern, because of potential acute adverse events, and because animal studies suggest that MDMA has the potential to damage brain serotonin (5-HT) neurons. However, it is not yet known whether MDMA, as used in the setting of dance parties, leads to plasma levels of MDMA that are associated with toxicity to 5-HT neurons in animals. The present study sought to address this question. Plasma MDMA concentrations, vital signs, and a variety of blood and urine measures were obtained prior to, and hours after, individuals attended a dance party. After the dance party, subjects were without clinical complaints, had measurable amounts of residual MDMA in plasma, and nearly half of the subjects also tested positive for methamphetamine, another amphetamine analog that has been shown to have 5-HT neurotoxic potential in animals. Plasma concentrations of MDMA did not correlate with self-reported use of ‘ecstasy’ and, in some subjects, overlapped with those that have been associated with 5-HT neurotoxicity in non-human primates. Additional subjects were likely to have had similar concentrations while at the dance party, when one considers the reported time of drug ingestion and the plasma half-life of MDMA in humans. Hematological and biochemical analyses were generally unremarkable. Moderate increases in blood pressure, heart rate and body temperature were observed in the subjects with the highest MDMA plasma concentrations. These findings are consistent with epidemiological findings that most people who use MDMA at dance parties do not develop serious clinical complications, and suggest that some of these individuals may be at risk for developing MDMA-induced toxicity to brain serotonin neurons.

Naloxone methiodide reverses opioid-induced respiratory depression and analgesia without withdrawal.

Illicit opioid overdoses are a significant problem throughout the world, with most deaths being attributed to opioid-induced respiratory depression which may involve peripheral mechanisms. The current treatment for overdoses is naloxone hydrochloride, which is effective but induces significant withdrawal. We propose that selectively peripherally acting opioid receptor antagonists, such as naloxone methiodide, could reverse respiratory depression without inducing predominantly centrally mediated withdrawal. Acute administration of morphine (300 mg/kg, i.p.) was found to significantly depress respiratory rate and induce analgesia (P<0.0001). Both naloxone hydrochloride and naloxone methiodide were able to reverse these effects but naloxone methiodide precipitated no significant withdrawal. Naloxone methiodide was also able to reverse opioid-induced respiratory depression (P<0.001) and antinociception (P<0.01) after chronic morphine administration (300 mg/kg/day for 5 days) without inducing significant withdrawal. Therefore, peripherally selective opioid receptor antagonists should be investigated as possible treatments for opioid-induced respiratory depression which do not induce adverse effects, such as withdrawal.

Morphine formation from codeine in rat brain: A possible mechanism of codeine analgesia

The O-demethylation of codeine to morphine was demonstrated in rat brain homogenate. Maximal formation occurred at 10 minutes, with a Vmax of 5.93 +/- 0.16 nmol/g brain/h and Km of 37.82 +/- 4.99 microM. The formation was significantly (P less than 0.05) greater in the microvessel-rich brain fraction. Intraperitoneal injection of codeine in the rat resulted in brain concentrations of morphine which could not be solely attributed to transfer of morphine from the blood stream across the blood-brain barrier. Morphine formed in the brain after codeine administration may be an important mechanism for codeine-induced analgesia.

Differential behavioural and neurochemical effects of para-methoxyamphetamine and 3,4-methylenedioxymethamphetamine in the rat

1. This study was prompted by recent deaths that have occurred after recreational administration of the substituted amphetamine para-methoxyamphetamine (PMA). Because relatively little is known regarding its mechanism(s) of action, its effects on physiological, behavioural and neurochemical parameters were compared with the well known effects of 3,4-methylenedioxymethamphetamine (MDMA). 2. Equivalent doses of PMA (5-20 mg/kg) produced greater hypothermia than MDMA at an ambient temperature of 20 degrees C. At 30 degrees C, PMA continued to evoke hypothermia except the highest dose where hyperthermia ensued. MDMA altered body temperature only at the highest dose where hyperthermia also resulted. 3. At both 20 and 30 degrees C, MDMA stimulated locomotor activity whereas PMA had modest effects and then, only at high doses. 4. In vivo chronoamperometry was used to measure the effect of MDMA and PMA on release, and inhibition of uptake, of serotonin (5-HT) and dopamine (DA) in the dorsal striatum of anaesthetised rats. As expected, MDMA evoked release of DA and inhibited uptake of both DA and 5-HT. By contrast, PMA was a relatively weak releasing agent and did not inhibit DA uptake. However, PMA potently inhibited uptake of 5-HT. 5. Taken together these data suggest that the acute adverse effects of PMA are more likely to be associated with alterations in serotonergic rather than dopaminergic neurotransmission.

Naloxone and its quaternary derivative, naloxone methiodide, have differing affinities for μ, δ, and κ opioid receptors in mouse brain homogenates

Abstract Naloxone and naloxone methiodide both act on opioid receptors but naloxone methiodide has limited access to the brain. Naloxone methiodide has been shown to have a lower affinity for opioid receptors than naloxone in the rat and guinea pig but has not been tested in the mouse. We aimed to investigate this by using [ 3 H]DAMGO, [ 3 H]DPDPE and [ 3 H]U-69,593 to compare the ability of naloxone and naloxone methiodide to displace binding to μ, δ and κ opioid receptors in mouse brain homogenates. Significant binding was observed for each receptor type and the binding affinity for naloxone versus naloxone methiodide was found to be 15:1 for μ, 6:1 for κ and 330:1 for δ receptors. Therefore, naloxone methiodide does have a lower affinity for opioid receptors than naloxone in mouse brain tissue, which must be taken into consideration in experimental designs.

Increases in use of novel synthetic stimulant are not directly linked to decreased use of 3,4-methylenedioxy-N-methylamphetamine (MDMA)

A decline in 3,4-methylenedioxy-N-methylamphetamine (MDMA) use in Adelaide, Australia from 2009 to 2010 was confirmed by us previously. Reports suggested that the shortage in MDMA supply was associated with an increased prevalence of other synthetic stimulants, but quantitative measurements were unavailable. To obtain objective data on the community use of synthetic stimulants, we collected wastewater samples from multiple treatment plants in Adelaide, Australia from 2009 to 2011 and analysed them using solid-phase extraction/liquid chromatography/tandem mass spectrometry (SPE-LC-MS/MS), targeting MDMA and some of the most reported synthetic cathinones and piperazines. Data were temporally compared. MDMA and six other synthetic stimulants were detected and quantified in wastewater samples. While MDMA level decreased markedly from 2009 to 2010 and remained low in 2011, localized increased use of mephedrone, methylone, methylenedioxypyrovalerone (MDPV), benzylpiperazine (BZP), 3-trifluoromethylphenylpiperazine (TFMPP), but not methcathinone, was observed in 2010 and 2011. This suggested that the decline in MDMA use was associated with an increase in the use of a number of other synthetic stimulants. However, the lag time from the decrease in MDMA to the increase in use of a number of these stimulants, together with the highly regionalized use of all synthetic stimulants except methcathinone indicates that there was no direct population wide substitution in response to the reduction in MDMA.