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Biomedical subjects

B R Martin

Publications and source records attributed to B R Martin.

At least 109 records · Page 6Linked to original sources
PubMed1996

Agonist-antagonist characterization of 6'-cyanohex-2'-yne-delta 8-tetrahydrocannabinol in two isolated tissue preparations.

This investigation was directed at characterizing some of the pharmacological properties of 6'-cyanohex-2'-yne-delta 8-tetrahydrocannabinol (O-823), a compound with high affinity for cannabinoid binding sites (Ki = 0.77 nM). In mouse vasa deferentia, O-823 behaved as a potent partial cannabinoid CB1 receptor agonist (EC50 = 0.015 nM). In the guinea-pig myenteric plexus preparation, it antagonized WIN 55.212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholino)methyl]pyrrolo-[1,2,3-de ]-1, 4-benzoxazin-6-yl](1-naphthyl)methanone] and CP 55.940 [(-)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl ) cyclohexan-1-ol] with Kd values of 0.65 and 0.27 nM, respectively. After in vivo delta 9-tetrahydrocannabinol pretreatment. the sensitivity of vasa deferentia to O-823-induced inhibition of electrically evoked contractions was reduced by 127-fold. 3.162 nM O-823 was inhibitory in unpretreated vasa deferentia but antagonized CP 55,940 in pretreated tissues (Kd = 0.26 nM). O-823 is probably an antagonist in the myenteric plexus preparation and delta 9-tetrahydro-cannabinol pretreated vasa deferentia but a partial agonist in unpretreated vasa deferentia because the first two of these preparations contain fewer receptors than the third.

Analgesics↗
PubMed1996

Tolerance to the antinociceptive effect of epibatidine after acute and chronic administration in mice.

Epibatidine is a novel potent antinociceptive agent that acts through nicotinic receptors. In this study we investigated the development of tolerance to the antinociceptive effects of epibatidine enantiomers after acute and chronic administration in mice using the tail-flick test. Contrary to nicotine, mice treated with epibatidine enantiomers at different times and doses did not develop significant tolerance after s.c. acute nor after repeated injections. In mice that chronically received (+)-epibatidine, no significant tolerance was seen after acute challenge with (+)-epibatidine. However, a significant shift in (-)-epibatidine's dose-response curve was obtained in animals that received (-)-epibatidine. In nicotine-tolerant animals, no significant tolerance was seen after acute challenge with (+)-epibatidine. However, the animals were less sensitive to the acute (-)-epibatidine challenge. Our results show that development of tolerance to epibatidine antinociceptive effects has a different profile and characteristics than that found for nicotine.

Analgesics, Non-Narcotic↗
PubMed1996

Anandamide- and delta9-tetrahydrocannabinol-evoked arachidonic acid mobilization and blockade by SR141716A [N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4 -methyl-1H-pyrazole-3-carboximide hydrochloride].

The purpose of this study was to investigate whether anandamide induces cannabimimetic responses, mainly mobilization of arachidonic acid, in primary cultures of rat brain cortical astrocytes. Confluent monolayer cultures of astrocytes, prelabeled with [3H]arachidonic acid, were incubated with anandamide or delta9-tetrahydrocannabinol (delta9-THC) in the presence or absence of thimerosal, a fatty acid acyl CoA transferase inhibitor and phenylmethylsulfonyl fluoride, an amidohydrolase inhibitor. Anandamide and delta9-THC induced a time- and concentration-dependent release of arachidonic acid in the presence, but not in the absence, of thimerosal. Anandamide- and delta9-THC-stimulated arachidonic acid release was pertussis toxin-sensitive, indicating a receptor/G-protein involvement. A novel and selective cannabinoid receptor antagonist, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboximide hydrochloride], blocked the arachidonic acid release, suggesting a cannabinoid receptor-mediated pathway. In astrocytes, the magnitude of anandamide-induced arachidonic acid release was equal to that released by equimolar concentrations of delta9-THC. Furthermore, direct assay of amidohydrolase activity indicated that degradation of anandamide into arachidonic acid and ethanolamine was negligible in cortical astrocytes. Our results suggest that anandamide stimulates receptor-mediated release of arachidonic acid, and the receptor may be the cannabinoid receptor. Astrocytes, containing a cannabinoid receptor and lower or negligible amidohydrolase activity, may be an important brain cell model in which to study the cannabimimetic effects of anandamide at a cellular and molecular level.

Amidohydrolases↗
PubMed1996

Structure-activity analysis of anandamide analogs: relationship to a cannabinoid pharmacophore.

Anandamides are endogenous fatty acid ethanolamides that have been shown to bind to the cannabinoid receptor and possess cannabimimetic activity yet are structurally dissimilar from the classical cannabinoids found in Cannabis sativa. We have employed molecular dynamics studies of a variety of anandamides to characterize their conformational mobility and determine whether there are pharmacophoric similarities with delta 9-THC. We have found that a looped conformation of these arachidonyl compounds is energetically favorable and that a structural correlation between this low-energy conformation and the classical cannabinoids can be obtained with the superposition of (1) the oxygen of the carboxyamide with the pyran oxygen in delta 9-THC, (2) the hydroxyl group of the ethanol with the phenolic hydroxyl group of delta 9-THC, (3) the five terminal carbons and the pentyl side chain of delta9-THC, and (4) the polyolefin loop overlaying with the cannabinoid tricyclic ring. The shape similarity is extended to show that other fatty acid ethanolamides that possess varying degrees of unsaturation also vary in their conformational mobility, which affects their ability to overlay with delta 9-THC as described above. Within this series of compounds, the most potent analog, the tetraene (arachidonyl) analog (i.e., anandamide itself), was determined to have restricted conformational mobility that favored an optimal pharmacophore overlay with delta9-THC. Eight pharmacologically active anandamide analogs are shown to have similar conformational mobility and pharmacophore alignments that are conformationally accessible. Furthermore, when these compounds are aligned to delta 9-THC according to the proposed pharmacophore overlay, their potencies are predicted by a quantitative model of cannabinoid structure--activity relationships based solely on classical and nonclassical cannabinoids with a reasonable degree of accuracy. The ability to incorporate the pharmacological potency of these anandamides into the cannabinoid pharmacophore model is also shown to support the relevance of the proposed pharmacophore model.

Animals↗
PubMed1996

Cannabinoid receptor down-regulation without alteration of the inhibitory effect of CP 55,940 on adenylyl cyclase in the cerebellum of CP 55,940-tolerant mice.

The objective of this study was to determine whether the development of tolerance to CP 55,940, a potent cannabinoid agonist, was due to changes in the receptor or second messenger system. ICR mice treated with CP 55,940 (2 mg/kg) twice a day for 6 and one-half days developed a high degree of tolerance to the pharmacological effects of CP 55,940. The ability of CP 55,940 to produce motor hypoactivity, hypothermia and immobility was reduced 163-, 97- and 19-fold, respectively. Evaluation of 3H-CP 55,940 binding to rat brain membranes indicated no difference in receptor affinity between the vehicle- and CP 55,940-treated animals. However, these binding studies revealed a 50% decrease in receptor number in the cerebellum of the CP 55,940-tolerant mice. Although cAMP is generally considered to be the second messenger for cannabinoid receptors, little difference was observed in the inhibitory effects of CP 55,940 on adenylyl cyclase activity in cerebellum between vehicle and drug-treated mice. However, there was an increase in receptor mRNA which suggests a compensation for receptor loss. There are several possible explanation for these results. There may be sufficient spare receptors such that CP 55,940-tolerant mice are capable of producing a maximal effect on the second messenger system. On the other hand, one could conclude that cannabinoid receptor down-regulation does not account for the development of tolerance to all of the effects of CP 55,940 in mice.

Adenylyl Cyclase Inhibitors↗
PubMed1996

Delta 9-tetrahydrocannabinol impairs spatial memory through a cannabinoid receptor mechanism.

The purpose of the present study was to investigate whether the cannabinoid and cholinergic systems impair working memory through a common mechanism. This hypothesis was tested by examining whether the cannabinoid antagonist SR141716A would ameliorate radial-arm performance deficits caused by either the naturally occurring cannabinoid, delta 9-THC, or scopolamine, a muscarinic antagonist. In addition, we evaluated whether the cholinesterase inhibitor, physostigmine, would prevent delta 9-THC-induced impairment of spatial memory. Finally, because the locomotor suppressive effects of cannabinoids may decrease radial arm choice accuracy independent of a direct effect on memory, we examined the impact of increasing the intertrial error on radial arm choice accuracy. As previously reported, delta 9-THC impaired maze performance (ED50 = 3.0 mg/kg). Increasing the intertrial interval from 5 s to 30 s resulted in a three-fold increase in the amount of time required to complete the maze without affecting choice accuracy. Importantly, SR141716A prevented delta 9-THC-induced deficits in radial-arm choice accuracy in a dose-dependent manner (AD50 = 2.4 mg/kg); however, the cannabinoid antagonist failed to improve the disruptive effects of scopolamine. Conversely, physostigmine failed to improve performance deficits produced by delta 9-THC. These data provide strong evidence that delta 9-THC impairs working memory through direct action at cannabinoid receptors. Moreover, these results suggest that scopolamine and delta 9-THC do not impair spatial memory in a common serial pathway, though they may converge on a third neurochemical system.

Animals↗
PubMed1996

Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of delta 8-tetrahydrocannabinol.

delta 8-Tetrahydrocannabinol (delta 8-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the structure of delta 8-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the micro-opioid receptor. Two novel analogs of delta 8-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-delta 8-THC) and a cyano analog with a dimethylpentyl side chain (CY-delta 8-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic delta 9-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-delta 8-THC shared discriminative stimulus effects with CP 55,940; for NM-delta 8-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of delta 9-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-delta 8-THC, but not CY-delta 8-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects.

Animals↗
PubMed1996

Molecular neurobiology of the cannabinoid receptor.

Marijuana is currently the most widely abused street drug. However, the functional significance of the cannabinoid receptor system in health and disease includes the use of cannabinoids as analgesics, antiemetics in cancer patients, anticonvulsants for epilepsy, and as antiglaucoma agents as well as immunomodulatory agents. Our knowledge of the mechanisms of action of cannabinoids has increased greatly in the past several years. Two cannabinoid receptors have been identified to date: one is located predominantly in the central nervous system (CBI), whereas the other is expressed in peripheral tissues (CB2). Both are members of the G-protein-coupled receptor family and couple to inhibition of adenylyl cyclase (as well as additional second messenger systems), in transfected cells expressing these receptors, and in the nervous system. An endogenous ligand has been isolated for the CBI receptor; it is arachidonic acid ethanolamide, or anandamide. Candidate endogenous ligands for the CB2 receptor have also been described. Another development is the discovery of a selective antagonist for the CBI receptor. The distribution of the cannabinoid receptor subtypes has been mapped by receptor autoradiography, RT-PCR and in situ hybridization. These new research tools will aid in the elucidation of the physiological role of the endogenous cannabinoid system.

Amino Acid Sequence↗
PubMed1996

Calcium retention estimated from indicators of skeletal status in adolescent girls and young women.

To determine clinically useful predictors of calcium retention during postpubertal growth, calcium balance, bio-chemical markers of bone turnover, and anthropometric variables were determined in 14 girls aged 11-14 y and in 11 young women aged 19-30 y. Subjects participated in a 3-wk calcium-balance study with a calcium intake of 1332 mg/d. Biochemical markers of bone turnover (serum osteocalcin, total alkaline phosphatase, bone alkaline phosphatase, tartrate-resistant acid phosphatase, and urinary cross-linked N-teleopeptides of type I collagen and hydroxyproline as the creatinine ratios) were measured in fasting samples. Total-body bone mineral density and total-body calcium content were significantly higher in adults than in adolescents (1.17 compared with 1.05 g/cm2 and 1019 compared with 791 g, respectively). At the observed retention of 326 mg/d, adolescents would require 2 y to reach the total bone calcium of the young adults. All biomarkers of bone turnover were strikingly higher in adolescents than in adults and were strongly correlated with calcium retention. A multiple-regression model using a biochemical marker of bone turnover (serum osteocalcin) and postmenarcheal age (a measure of sexual maturation) described 75% of the variability in calcium retention.

Adolescent↗
PubMed1996

Calcium bioavailability from bovine milk and dairy products in premenopausal women using intrinsic and extrinsic labeling techniques.

Stable isotopes were used to compare calcium fractional absorption from intrinsically and extrinsically labeled bovine milk as well as intrinsically labeled dairy product and cheese analogue. Healthy Caucasian women were fed a controlled diet for 4 d during the follicular phase of their menstrual cycle. With breakfast on the third day, participants ingested milk containing 44Ca (intrinsic) and 42CaCl2 (extrinsic) or dairy products containing 44Ca. Total feces were collected for 2 d prior to and 10 d after isotope ingestion. Polyethylene glycol was administered to monitor completeness of fecal collections. Total calcium was determined by atomic absorption spectrophotometry, and isotopic abundance was determined by high resolution fast atom bombardment mass spectrometry. Fractional absorption was determined as the difference between the administered isotopic dose and the quantity of 44Ca or 42Ca excreted in feces. The fractional absorption of calcium from milk was not affected by the method of labeling, lactose content, fermentation or the chemical form of calcium in dairy products or cheese analogue.

Absorption↗
PubMed1996

Differences in calcium kinetics between adolescent girls and young women.

Rapid bone accretion occurs throughout childhood but peaks during adolescence. The achievement of optimal peak bone mass, which can protect against osteoporosis later in life, is greatly dependent on rates of bone accretion. To identify differences in calcium metabolism during rapid vs. slower bone accretion, calcium kinetics were compared in 14 healthy girls aged 11-14 yr and 11 women aged 19-31 yr. Calcium kinetics were measured while subjects were undergoing a calcium balance study in a camp simulating a free-living environment. After 7 days on a diet containing 1,330 mg Ca/day, two stable isotopes were administered (44Ca orally and 42Ca intravenously), and blood samples and all urine and feces were collected for 14 days. Samples were analyzed for total calcium by atomic absorption spectrophotometry and for enrichment of 42Ca and 44Ca by fast atom bombardment mass spectrometry. Data from serum, urine, and feces were analyzed using the Simulation, Analysis and Modeling (SAAM) software. Data were fitted by a three-compartment model; the first pool was the same size in girls and women (1.6 g) but the second and third pools were larger in girls (2.85 vs. 1.66 g and 12 vs. 5 g). Compared with the women, girls absorbed more calcium from the diet (38 vs. 22% or 494 vs. 283 mg/day), excreted less calcium in urine (100 vs. 203 mg/day), deposited more calcium in bone (1,459 vs. 501 mg/day), and resorbed more calcium from the skeleton (1,177 vs. 542 mg/day), whereas endogenous calcium excretion did not differ between girls and women (112 vs. 121 mg/day). Girls retained more calcium than women (282 vs. -41 mg/day) through increased absorption, lower urine excretion, and higher bone turnover.

Absorption↗
PubMed1996

Characterization and modulation of acute tolerance to nicotine in mice.

Acute tolerance to the effects of nicotine is believed to play an important role in the development and maintenance of dependence to this drug. The objective of this study was to investigate and characterize the development of acute tolerance to nicotine after systemic and intrathecal administrations. Acute tolerance developed to several centrally mediated pharmacological effects of nicotine after systemic (motor coordination, body temperature, antinociception) and intrathecal (antinociception) injection of the drug. The appearance and the magnitude of acute tolerance varied depending on the response measured. Development of acute tolerance to nicotine-induced hypothermia and motor impairment was blocked after intraperitoneal pretreatment with nimodipine. Similarly, an intrathecal injection of nimodipine blocked the development of acute tolerance to nicotine-induced antinociception. On the other hand, intrathecal administration of calcium and thapsigargin enhanced the acute tolerance to nicotine-induced antinociception. Characterization of the acute tolerance to nicotine in several animal models revealed time and dose dependencies that are consistent with receptor-mediated events. More importantly, acute tolerance was modulated by agents that influence cellular calcium homeostasis.

Animals↗
PubMed1996

In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A): inhibition of delta 9-tetrahydrocannabinol-induced responses and apparent agonist activity.

SR141716A has been described as a cannabinoid receptor antagonist. This study was conducted to determine whether SR141716A was capable of antagonizing the pharmacological effects of the prototypical cannabinoid agonist delta 9-THC. The AD50 (+/- 95% confidence limits) obtained after a 10 min i.v. pretreatment with SR141716A in measures of hypoactivity, hypothermia, and antinociception were: 0.12 (0.02-0.66), 0.087 (0.037-0.201), and 0.16 (0.03-1.01) mg/kg, respectively. The effect of SR141716A lasted up to 1 hr (antinociception, 10 mg/kg), 4 hr (locomotion, 1 and 3 mg/kg), or 24 hr (hypothermia, 3 mg/kg). Further evaluation revealed an AD50 value of 2.7 mg/kg (1.7-4.4) in the PPQ-stretch procedure. Additionally, the ED50 (+/- S.E.) of morphine in the tail-flick antinociception procedure was increased by SR141716A (30 mg/kg, i.v.) from 3.2 (+/- 0.3) to 5.3 (+/- 0.6) mg/kg. Finally, SR141716A produced direct effects on locomotor activity at doses greater than 3 mg/kg. Locomotion was stimulated to more than 200% of control (20 mg/kg), with an ED50 value of 4.7 (+/- 1.5) mg/kg. The ED50 value represents stimulation to levels approximately 150% of control. It is not clear whether this pharmacological activity represents an uncharacterized action of SR141716A, or an index of tonic activity of an endogenous cannabinergic system. SR141716A will be useful in establishing the biochemical events responsible for the in vivo effects of exogenous cannabinoids, as well as in establishing the existence of a putative endogenous cannabinergic system.

Analgesia↗
PubMed1996

Investigation of brain sites mediating cannabinoid-induced antinociception in rats: evidence supporting periaqueductal gray involvement.

The purpose of this study was to elucidate brain areas that mediate cannabinoid-induced antinociception as assessed in the tail-flick test. Intracerebroventricular administration of the prototypical cannabinoid, delta 9-tetrahydrocannabinol, and the potent bicyclic analog, CP-55,940, produced antinociception at ED50 values of 373 and 64 nmol/rat, respectively. Hypothermic and cataleptic effects also were observed after i.c.v. administration of CP-55,940, but not delta 9-tetrahydrocannabinol. In contrast, the endogenous cannabinoid, anandamide, failed to elicit any apparent pharmacological effects. Administration of CP-55,940 into the caudate putamen produced catalepsy, but failed to produce either antinociception or hypothermia. Micro-injection of CP-55,940 into the ventrolateral aspect of the periaqueductal gray (PAG), in the region of the dorsal raphe, produced antinociception (ED50 dose = 28 nmol/rat), catalepsy and hypothermia. CP-56,667, the inactive stereoisomer of CP-55,940, failed to produce any effects when injected into the same site. Additional studies demonstrated that pertussis toxin completely prevented the pharmacological effects of CP-55,940 when both agents were administered into the posterior ventrolateral PAG. In contrast, dibutyryl-cAMP failed to attenuate cannabinoid-induced antinociception. Finally, CP-55,940 administered into either the posterior dorsolateral or the anterior ventrolateral areas of the PAG was without effect. These results indicate that the antinociceptive and cataleptic effects of cannabinoids in the PAG are dose-related, exhibit regional specificity and are enantioselective. Moreover, the complete prevention of these pharmacological effects by pertussis toxin pretreatment in the PAG is consistent with the involvement of G proteins. These findings suggest that the posterior ventrolateral PAG may be an important brain area for the antinociceptive and cataleptic effects of the cannabinoids.

Analgesics↗
PubMed1996

Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands.

Two cannabinoid receptors have been identified to date; one is located predominantly in the central nervous system (CB1), whereas the other is located exclusively in the periphery (CB2). The purposes of this study were to explore further the binding requirements of the CB2 receptor and to search for compounds displaying distinct affinities for either cannabinoid receptor. The binding affinities of a series of cannabinoids tested previously at the CB1 receptor were determined at cloned human CB1 and CB2 receptors using a filtration assay. In addition, possible allosteric regulation of the CB2 receptor was examined. Sodium and a GTP analog elicited a concentration-dependent decrease in specific binding to the CB2 receptor. The affinity of cannabinol for CB2 receptors (Ki = 96.3 +/- 14 nM) was confirmed to be in approximately the same range as that of delta 9-THC (Ki = 36.4 +/- 10 nM). Affinities at cloned CB1 and CB2 receptors were compared with affinities determined in the brain. Although most of the chosen compounds did not discriminate between CB1 and CB2, several ligands were identified that showed selectivity. Affinity ratios demonstrated that two 2'-fluoro analogs of anandamide were over 23-fold selective for the CB1 receptor and confirmed the CB1 selectivity of SR141716A {N- (piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamidehydrochloride}. In addition, WIN-55, 212-2 {(R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl) methyl] pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl) methanone} and a closely related propyl indole analog were shown to be 6.75- and 27.5- fold selective, respectively, for the CB2 receptor. These ligands can now serve as a basis for the design of compounds with even greater selectivity.

Animals↗
PubMed1996

Dependence on delta 9-tetrahydrocannabinol: studies on precipitated and abrupt withdrawal.

A cannabinoid antagonist, SR 141716A, dose dependently precipitated a behavioral withdrawal syndrome in rats continuously infused i.p. for only 4 days with relatively low-dose regimens of delta 9-tetrahydrocannabinol. The following dose regimens, expressed as mg/kg/24 hr, were used for days 1 through 4: high-12.5, 25, 50 and 100; medium-2.5, 5, 10 and 20; and low-0.5, 1, 2 and 4. The major withdrawal signs of the syndrome were scratching, rubbing face with paws, licking, wetdog shakes, arched back and ptosis (at least 50% closure of eyelids). At the highest dose regimen, other signs noted in fewer subjects were biting, tongue rolling, retropulsion, head shakes, extended limbs or high stepping, ataxia, myoclonic spasms and front paw treading. During abrupt withdrawal (delta 9 tetrahydrocannabinol was discontinued and vehicle substituted) abstinence signs were also noted; however, except during a 48-hr observation period, withdrawal was not sufficiently robust to achieve statistical significance. The results of this study provide evidence that a modest course of delta 9-tetrahydrocannabinol can produce physical dependence. Hence, the risk and incidence of marijuana dependence in humans may be greater than previously projected.

Animals↗
PubMed1996

Inhalation exposure to volatilized opioids produces antinociception in mice.

The goal of this study was to determine whether opioids of varying potencies are pharmacologically active via the inhalation route of administration in mice. The opioids evaluated included heroin, morphine, codeine, fentanyl and meperidine; each of these drugs has the potential for abuse in humans. Inhalation exposure to each of these compounds produced antinociception in a dose-dependent manner as assessed in the tall-flick test. No pyrolysis products were detected after heating either morphine or codeine at 250 degrees C for 5 min. Although 6-acetylmorphine was found after heating heroin, it accounted for less than 5% of the recovered sample. Heroin was somewhat less potent by inhalation administration than i.v. injection, with ED50 values of 1.6 and 0.69 mumol/kg, respectively. In contrast, the relative potency of morphine was substantially greater when inhaled than when injected, with respective ED50 values of 0.77 and 3.9 mumol/kg. Whereas the body to brain ratios of [3H]morphine were approximately 8 and 20 for inhalation exposure and i.v. injection, respectively, the ratio for heroin was approximately 5 regardless of administration route. This pattern of results suggests that the increase in morphine potency upon inhalation may have resulted from an increased accessibility to the brain compared with i.v. injection. Finally, naloxone reversed the antinociceptive effects of volatilized heroin, but neither the kappa selective antagonist nor-binaltorphimine nor the delta selective antagonist naltrindole blocked this antinociception, which suggests the involvement of mu opioid receptors. These findings taken together suggest the potential for the abuse of a variety of opioids, in addition to heroin, through the inhalation route of administration by humans.

Administration, Inhalation↗