Social inequities impact infant mortality due to congenital heart disease.

OBJECTIVES: To evaluate how educational, economic, and racial residential segregation may impact congenital heart disease infant mortality (CHD-IM). STUDY DESIGN: This is a population-based US ecological study. METHODS: This study evaluated linked live birth-infant death files from the National Center for Health Statistics for live births from 2006 to 2018 with cause of death attributed to CHD. Maternal race and education data were obtained from the live birth-infant death files, and income data were obtained from the American Community Survey. A spatial social polarization measure termed the Index of Concentration at the Extremes (ICE) was calculated and split by quintiles for maternal education, household income, and race for all US counties (n = 3142). The lowest quintile represents counties with highest concentration of disadvantaged groups (income < $25K, non-Hispanic Black, no high school degree). Proximity to a pediatric cardiac center (PCC) was also analyzed in a categorical manner based on whether each county was in a metropolitan area with a US News and World Report top 50 ranked PCC, a lower ranked PCC, or not proximal to any PCC. RESULTS: Between 2006 and 2018, 17,489 infant deaths were due to CHD, an unadjusted CHD-IM of 0.33 deaths per 1000 live births. The risk of CHD-IM was 1.5 times greater among those in the lowest ICE-education quintile (0.41 [0.39-0.44] vs 0.28 deaths/1000 live births [0.27-0.29], P < 0.0001) and the lowest ICE-income quintile (0.44 [0.41-0.47] vs 0.29 [0.28-0.30], P < 0.0001) in comparison to those in the highest quintiles. CHD-IM increases with higher ICE-race value (counties with a higher concentration of non-Hispanic White mothers). However, after adjusting for proximity to a US News and World Report top 50 ranked PCC in the multivariable models, CHD-IM decreases with higher ICE-race value. CONCLUSIONS: Counties with the highest concentration of lower-educated mothers and the highest concentration of low-income households were associated with higher rates of CHD-IM. Mortality as a function of race is more complicated and requires further investigation.

Adductor muscle activity abnormalities in abductor spasmodic dysphonia.

OBJECTIVE: To determine laryngeal muscle activation abnormalities associated with speech symptoms in abductor spasmodic dysphonia (ABSD). STUDY DESIGN: Bilateral laryngeal muscle recordings from the posterior cricoarytenoid, thyroarytenoid, and cricothyroid muscles were conducted in 12 ABSD patients. Patients' measures were compared during speech breaks and during speech without breaks and with 10 normal controls. RESULTS: Significant group differences were found in the thyroarytenoid muscle; the patients had significantly greater activity on the right side both during speech breaks and nonbreaks in comparison with the controls. Cricothyroid muscle levels were also increased on the right in the patients. CONCLUSION: An asymmetry in adductor muscle tone between the 2 sides in ABSD may account for difficulties with maintaining phonation and voice onset after voiceless consonants. SIGNIFICANCE: These abnormalities may indicate why PCA BOTOX injections have not been as effective in ABSD as thyroarytenoid injections have been in adductor spasmodic dysphonia.

Calcium activation of heart mitochondrial oxidative phosphorylation: rapid kinetics of mVO2, NADH, AND light scattering.

Parallel activation of heart mitochondria NADH and ATP production by Ca(2+) has been shown to involve the Ca(2+)-sensitive dehydrogenases and the F(0)F(1)-ATPase. In the current study we hypothesize that the response time of Ca(2+)-activated ATP production is rapid enough to support step changes in myocardial workload ( approximately 100 ms). To test this hypothesis, the rapid kinetics of Ca(2+) activation of mV(O(2)), [NADH], and light scattering were evaluated in isolated porcine heart mitochondria at 37 degrees C using a variety of optical techniques. The addition of Ca(2+) was associated with an initial response time (IRT) of mV(O(2)) that was dose-dependent with a minimum IRT of 0.27 +/- 0.02 s (n = 41) at 535 nm Ca(2+). The IRTs for NADH fluorescence and light scattering in response to Ca(2+) additions were similar to mV(O(2)). The Ca(2+) IRT for mV(O(2)) was significantly shorter than 1.6 mm ADP (2.36 +/- 0.47 s; p < or = 0.001, n = 13), 2.2 mm P(i) (2.32 +/- 0.29, p < or = 0.001, n = 13), or 10 mm creatine (15.6.+/-1.18 s, p < or = 0.001, n = 18) under similar experimental conditions. Calcium effects were inhibited with 8 microm ruthenium red (2.4 +/- 0.31 s; p < or = 0.001, n = 16) and reversed with EGTA (1.6 +/- 0.44; p < or = 0.01, n = 6). Estimates of Ca(2+) uptake into mitochondria using optical Ca(2+) indicators trapped in the matrix revealed a sufficiently rapid uptake to cause the metabolic effects observed. These data are consistent with the notion that extramitochondrial Ca(2+) can modify ATP production, via an increase in matrix Ca(2+) content, rapidly enough to support cardiac work transitions in vivo.

The domain of hypnosis: a multifactorial model.

A conceptual framework is presented to help the reader understand some controversies in the hypnosis literature and a means of understanding some important differences and disagreements in the field. It is this author's view that hypnotic behavior can be understood as a complex mix of four conceptual (and empirical) independent dimensions: expectations, akin to the placebo response in clinical technique; suggestion; a cognitive component including relaxation, imagery in all modalities, and trance logic; dissociation, which is seen as the key component of deep hypnosis, and which may involve individual differences in the flexible control of experience.

Cannabinoids in clinical practice.

Cannabis has a potential for clinical use often obscured by unreliable and purely anecdotal reports. The most important natural cannabinoid is the psychoactive tetrahydrocannabinol (delta9-THC); others include cannabidiol (CBD) and cannabigerol (CBG). Not all the observed effects can be ascribed to THC, and the other constituents may also modulate its action; for example CBD reduces anxiety induced by THC. A standardised extract of the herb may be therefore be more beneficial in practice and clinical trial protocols have been drawn up to assess this. The mechanism of action is still not fully understood, although cannabinoid receptors have been cloned and natural ligands identified. Cannabis is frequently used by patients with multiple sclerosis (MS) for muscle spasm and pain, and in an experimental model of MS low doses of cannabinoids alleviated tremor. Most of the controlled studies have been carried out with THC rather than cannabis herb and so do not mimic the usual clincal situation. Small clinical studies have confirmed the usefulness of THC as an analgesic; CBD and CBG also have analgesic and antiinflammatory effects, indicating that there is scope for developing drugs which do not have the psychoactive properties of THC. Patients taking the synthetic derivative nabilone for neurogenic pain actually preferred cannabis herb and reported that it relieved not only pain but the associated depression and anxiety. Cannabinoids are effective in chemotherapy-induced emesis and nabilone has been licensed for this use for several years. Currently, the synthetic cannabinoid HU211 is undergoing trials as a protective agent after brain trauma. Anecdotal reports of cannabis use include case studies in migraine and Tourette's syndrome, and as a treatment for asthma and glaucoma. Apart from the smoking aspect, the safety profile of cannabis is fairly good. However, adverse reactions include panic or anxiety attacks, which are worse in the elderly and in women, and less likely in children. Although psychosis has been cited as a consequence of cannabis use, an examination of psychiatric hospital admissions found no evidence of this, however, it may exacerbate existing symptoms. The relatively slow elimination from the body of the cannabinoids has safety implications for cognitive tasks, especially driving and operating machinery; although driving impairment with cannabis is only moderate, there is a significant interaction with alcohol. Natural materials are highly variable and multiple components need to be standardised to ensure reproducible effects. Pure natural and synthetic compounds do not have these disadvantages but may not have the overall therapeutic effect of the herb.

Analysis and purification of phorbol esters using normal phase HPLC and photodiode-array detection.

For the first time a normal-phase HPLC method using photodiode-array detection is described for the analysis and purification of phorbol esters. The use of the method is demonstrated with examples of 10 different tigliane and daphnane esters (TPA, DOPP, DOPPA, Sap A, Sap B, Sap C, Sap D, Thy A, Ro and Rx). Both analytical and semipreparative techniques were developed. The method has been used in the final purification of DOPP and Rx from plant extracts. The method can be employed in the areas of phytochemistry, biochemistry and pharmacology/toxicology, where small samples of the toxic materials are required for research.

Characterization of phorbol ester binding to protein kinase C isotypes.

A mixed micellar assay was used to study the in vitro binding of [3H]phorbol-12, 13-dibutyrate ([3H]PDBu) to pure recombinant protein kinase C (PKC)-alpha, -beta 1, -beta 2, -gamma, -delta, -epsilon, and -zeta isotypes expressed in the baculovirus/insect cell system. Scatchard analysis revealed that all isotypes except PKC-zeta were able to specifically bind PDBu, with Kd values ranging from 1.6 to 18 nM in the presence of calcium. In the absence of calcium PKC-alpha, -beta 1, -beta 2, and -delta were observed to have a 2-3-fold drop in affinity, although Bmax values remained unchanged, at a stoichiometry of 1.4-2.8 mol of PDBu/mol of enzyme. Competition with specific [3H]PDBu binding was assessed for the phorbol esters PDBu, 12-tetradecanoylphorbol-13-O-acetate, 12-deoxyphorbol-13-O-phenylacetate, 12-deoxyphorbol-13-O-phenylacetate-20-acetate, thymeleatoxin, resiniferatoxin, and sapintoxin A. Resiniferatoxin and 12-deoxyphorbol-13-O-phenylacetate-20-acetate were found to compete effectively only with PDBu bound to the PKC-beta 1 and -beta 2 isotypes and were the least potent of the phorbol esters tested (IC50, > 5 microM). The phorbol esters sapintoxin A, 12-deoxyphorbol-13-O-phenylacetate, 12-tetradecanoylphorbol-13-O-acetate, and PDBu (in order of potency) competed for binding to all isotypes (IC50 values ranging from 2 to 70 nM), with unchanged or slightly decreased potency when calcium was replaced by ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. Thymeleatoxin, which was similar in other respects to these potent phorbol esters, was found to be less able to compete with binding to PKC-alpha and -epsilon isotypes (IC50, 3-5 microM). It appears that, whereas the binding of phorbol esters to PKC depends primarily on the C20 substituent, other areas of the molecule have an influence on this interaction and the PKC isotypes themselves display heterogeneity in their phorbol ester-binding characteristics.

Properties of a resiniferatoxin-stimulated, calcium inhibited but phosphatidylserine-dependent kinase, which is distinct from protein kinase C isotypes alpha, beta 1, gamma, delta, epsilon and eta.

We have separated a resiniferatoxin-stimulated histone-kinase activity from human neutrophils, elicited mouse macrophages and murine alveolar macrophages by hydroxyapatite chromatography. The assay conditions for resiniferatoxin kinase were optimized as part of this study and in the presence of phosphatidylserine but absence of Ca2+ the Ka for histone IIIs phosphorylation by resiniferatoxin was calculated as 16 nM. Using a phosphate gradient of 20-500 mM, peaks of protein kinase C activity could be washed from the hydroxyapatite column in 300 nM phosphate and resiniferatoxin kinase recovered in 500 mM phosphate. At the optimum concentration of 160 nM, the ability of resiniferatoxin to induce enzyme activity was compared with a range of phorbol esters all at the same concentration. These related compounds failed to activate resiniferatoxin kinase although they have previously been shown to activate protein kinase C isotypes. Similarly sn-1,2,-dioleoylglycerol and the potent irritant capsaicin at 30 microM failed to activate the kinase. A Scatchard analysis of [3H] phorbol dibutyrate binding produced a linear plot (Kd 41.6 nM; Bmax 11.6 fmol unit-1) and binding was inhibited by resiniferatoxin and 12-O-tetradecanoylphorbol-13-acetate (TPA), with resiniferatoxin 700 times more potent than TPA in this respect. A radiolabelled resiniferatoxin binding assay was also used to demonstrate specific binding of [3H]resiniferatoxin which could be inhibited by unlabelled compound. Resiniferatoxin kinase activity was shown to be distinct from the protein kinase C isotypes alpha, beta 1, gamma, delta and epsilon by means of immunological analysis and from the eta isotype, because that isotype was not stimulated by resiniferatoxin but was stimulated by TPA when a pseudosubstrate was used. In addition the resiniferatoxin-stimulated activity was inhibited in-vitro by the addition of Ca2+ (Ki 0.1-0.5 nM free Ca2+). Further purification of resiniferatoxin kinase by Superose chromatography indicated a major activity fraction of about 70-90 kDa. Thus resiniferatoxin kinase, isolated from human and mouse inflammatory cells is distinct from the known isotypes of protein kinase C and is a major resiniferatoxin receptor.

HL-60 cell differentiation induced by phorbol- and 12-deoxyphorbol-esters.

The human promyelocytic leukaemia cell (HL-60) undergoes differentiation into a macrophage-like form when exposed to both tumour promoting- and non-promoting phorbol esters. We have investigated the effect of the two non-promoting phorbol esters, 12-deoxyphorbol-13-O-phenylacetate (Dopp) and 12-deoxyphorbol-13-O-phenylacetate-20-acetate (Doppa) on HL-60 cultures, and compared them with the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). All phorbol esters tested were found to be able to stop HL-60 proliferation and induce cell adherence and morphological changes characteristic of differentiation. TPA, fully differentiating at 1 nM, was more potent than Dopp and Doppa, which required 100 nM for full differentiation effects within the 4 day study. Doppa initially appeared weaker than Dopp at inhibiting incorporation of thymidine, the earliest effect studied, but we were able to detect rapid C-20 deacylation of Doppa, converting it to Dopp, using an HPLC protocol presented here. A detailed study of this thymidine incorporation inhibition showed that both TPA (10 nM or greater) and Dopp (500 nM or greater) have very similar time courses, with 50% inhibition occurring at approximately 12 h, in contrast to Doppa which had a significantly delayed time course at all doses tested. Exposure tests indicated that Dopp and Doppa could be washed from the cells much more easily than TPA. The data presented here strongly support the notion that the metabolic conversion of Doppa to Dopp by HL-60 cells was necessary to mediate its differentiating effects. Since protein kinase C (PKC)-beta 1, present in HL-60 cells, has been found to be the only PKC isotype activated so far in vitro by Doppa, our results suggest that activation of this isotype is not sufficient to drive HL-60 differentiation in vivo.

Phorbol esters showing selective activation of PKC isozymes in vitro regulate thyroid function and insulin-like growth factor binding protein secretion.

We have examined the effects of phorbol derivatives which show selective activation of protein kinase C (PKC) isozymes in vitro, on several parameters of thyroid function. Functions examined were iodide uptake and organification, iodocompound secretion and insulin-like growth factor binding protein (IGFBP) secretion, all of which have been shown previously to be modulated by 12-O-tetradecanoylphorbol 13-acetate (TPA), a pan activator of PKC isozymes. All of the agents examined, including DOPPA (12-deoxyphorbol-13-O-phenylacetate-20 acetate), which is specific for the beta 1 isozyme in vitro, were able to mimic the effects of TPA. These effects were evident by 2 h in the iodide uptake and organification assays, by 4 h in the secretion assays and by 8 h in the IGFBP secretion assays. The phorbol derivatives differed from TPA in their ability to down-regulate total PKC activity, DOPPA being weakly effective at 8 h (14.7% inhibition) when TPA had effected > 70% down-regulation of PKC. As the effects of DOPPA were detected by 8 h at the latest, these data indicate that the effects observed were due to PKC activation rather than down-regulation. Furthermore, the differences in down-regulation profiles between DOPPA and TPA suggest that in vivo, DOPPA may maintain its in vitro specificity. We conclude that inhibition of thyroid iodide uptake and its organification, stimulation of iodocompound secretion and stimulation of IGFBP-2 and IGFBP-3 secretion may be effected through the modulation of a limited number of PKC isozymes and possibly initially, only through PKC beta 1.

12-Deoxyphorbol-13-O-phenylacetate-20-acetate is not protein kinase C-beta isozyme-selective in vivo.

The phorbol ester, 12-deoxyphorbol-13-O-phenylacetate-20-acetate (DOPPA) has been shown to activate specifically the protein kinase C (PKC)-beta 1 isozyme in vitro (1). We have investigated the potential of DOPPA as a PKC-beta 1/2 isozyme-specific agonist in intact cells, employing U937 cells, which express beta 1/2, epsilon and zeta PKC and in Swiss 3T3 cells which lack PKC-beta 1/2 but express alpha, delta, epsilon and zeta PKC. Immunoblot analysis with isozyme-specific antibodies indicated that DOPPA can mediate the subcellular redistribution and down-modulation of all endogenous PKC isozymes (except PKC-zeta) in both U937 and Swiss 3T3 cells. Prolonged treatment (> 6 h) of cultures in down-modulation studies is complicated by the metabolism of DOPPA to 12-deoxyphorbol-13-phenylacetate (DOPP), a compound which activates all PKC isozymes tested in vitro (Ryves, W. J., et al. (1991) FEBS Lett., 288, 5-9). Nevertheless, because DOPPA induced rapid and dose-dependent phosphorylation of p80 in cells which do not express PCK-beta, p80 phosphorylation in Swiss 3T3 cells indicates that DOPPA can activate a non-beta PKC in vivo. The data suggest that DOPPA cannot be used as a PKC-beta-selective agonist in intact cell studies.

Molecular modelling of tumour-promoting and non-promoting diterpene esters and molecular co-ordinates of the potent irritant resiniferatoxin.

The lowest energy conformer of seventeen diterpenes, representing five different phorbol and daphnane diterpene nuclei, has been generated. TPA possessed the highest minimum free energy of these compounds; all other compounds possessed a lower minimum free energy. Compounds based on the resiniferonol nucleus possessed the lowest minimum free energy (9.4-16.6% of that of TPA). The molecular co-ordinates of the non-promoting but potent irritant resiniferatoxin (Rx) are also reported. These studies may be important in elucidation of the biochemical mechanisms of action of diterpene esters, including an understanding of the interactions of diterpene esters with the phorbol ester binding domain of the protein kinase C isoform family.

Involvement of calcium in modulation of neutrophil function by phorbol esters that activate protein kinase C isotypes and related enzymes.

In this study, the effects of a series of phorbol esters with different spectra of biological activities and different patterns of activation of the isoenzymes of protein kinase C (PKC) have been studied in human neutrophils. The aim was to gain more information on which isoenzymes of PKC are involved in neutrophil activation, specifically inhibition of fMet-Leu-Phe (fMLP)-stimulated bivalent cation influx and stimulation of O2-. release (either alone or potentiation of the response to fMLP). Prior addition of both phorbol 12-myristate 13-acetate (PMA) and sapintoxin A (SAPA) inhibited fMLP-stimulated Mn2+ influx. Higher concentrations of resiniferatoxin (RX) were also inhibitory, inhibition being more apparent at longer preincubation times. However, 12-deoxyphorbol 13-O-phenylacetate (DOPPA) showed only a slight inhibitory effect and required a prolonged preincubation. PMA, SAPA and RX, but not DOPPA, stimulated O2-. release by themselves. Lower concentrations of PMA, SAPA and RX, which were ineffective alone, considerably potentiated O2-. release stimulated by fMLP, whereas DOPPA had little or no effect. These results rule out a major role for PKC-delta (not activated by SAPA) and PKC-beta 1 (activated by DOPPA), but suggest the involvement of RX kinase in addition to PKC in the inhibition of fMLP-stimulated Mn2+ influx and potentiation of fMLP-stimulated O2-. release. However, when the cytosolic free Ca2+ concentration ([Ca2+]i) was elevated with the Ca2+ ionophore ionomycin, DOPPA was able to stimulate O2-. release, which probably reflects the known Ca2+ requirement for activation of PKC-beta 1 by DOPPA in vitro. The effects of the other phorbols were also enhanced when [Ca2+]i was elevated; all of the phorbols synergize, to variable extents, with Ca2+ to activate PKC in vitro. Enhancement of RX-stimulated O2- release by elevation of [Ca2+]i was unexpected, since RX kinase has been reported to be inhibited by high concentrations of Ca2+ in vitro. Finally, use of fura-2 and SK&F 96365 to manipulate the fMLP-stimulated rise in [Ca2+]i showed that when fMLP was able to evoke its normal rise in [Ca2+]i (to a peak of 700-900 nM), O2-. release was potentiated by PMA, SAPA and RX. However, when fMLP was only able to evoke a small increase in [Ca2+]i (to a peak of 400 nM), potentiation by PMA was unaffected but potentiation by SAPA and RX was considerably reduced. This observation agrees with published data demonstrating that activation of PKC in vitro by SAPA is more Ca(2+)-dependent than activation by PMA.(ABSTRACT TRUNCATED AT 400 WORDS)

Role of protein kinase C in induction of gene expression and inhibition of cell proliferation by interferon alpha.

Recent studies have suggested that protein kinase C (PKC) may be involved in the mechanism of signal transduction by which members of the interferon (IFN) family regulate gene expression and cell phenotype. We have investigated the role of PKC in the control of cell growth and gene expression by IFN alpha in Daudi cells. Treatment of these cells with two analogues of staurosporine, which are potent inhibitors of PKC, completely blocked the induction by IFN alpha of the mRNA for 2',5'-oligoadenylate synthetase and the 6-16 gene. These compounds also inhibited cell proliferation and thymidine incorporation in this system. In contrast, the protein kinase inhibitor 1-(5-isoquinolinylsulphonyl)-2-methylpiperazine (H7) did not significantly inhibit the induction of these genes by IFN alpha and had no effect on Daudi cell growth or thymidine incorporation in the presence or absence of IFN alpha. No effect of IFN alpha on total PKC activity could be observed, and there were no significant changes in the overall levels of individual PKC isoforms or their mRNA following IFN alpha treatment. In contrast, treatment of Daudi cells with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate, which also inhibits cell proliferation, strongly down-regulated PKC. These data suggest that the activity of a PKC species, or a closely related enzyme, may be required both for continued cell proliferation and the response to IFN alpha in Daudi cells, but that IFN-induced growth inhibition does not involve overall down-regulation or change in activity of PKC.

The potent irritancy of the daphnane orthoester, resiniferatoxin, exhibits features of a mixed aetiology.

Resiniferatoxin-induced erythema of mouse ear was shown to possess characteristics of both a phorbol ester-mediated response and that induced by the neurogenic irritant, capsaicin. Whereas the response to the phorbol ester, sapintoxin D, was delayed and prolonged, and was augmented by capsaicin pretreatment, the response to resiniferatoxin was biphasic, with the early phase being antagonized by capsaicin desensitization. However, resiniferatoxin was most potent in inducing a delayed erythema which, unlike the capsaicin response, was sensitive to inhibition by low dose hydrocortisone treatment, but not to chronic capsaicin desensitization. It is concluded that the erythema response to resiniferatoxin has a mixed aetiology, which may explain the unique potency of this toxin.

Induction of Epstein-Barr virus lytic cycle by tumor-promoting and non-tumor-promoting phorbol esters requires active protein kinase C.

Exposure to the tiglian 12-O-tetradecanoylphorbol-13-acetate (TPA) represents one of the most efficient and widely used protocols for inducing Epstein-Barr virus (EBV)-infected cells from latent into lytic cycle. Since TPA is both a potent tumor promoter and a potent activator of the cellular protein kinase C (PKC), we sought to determine whether either of these activities was closely linked to EBV lytic cycle induction. A panel of TPA structural analogs, encompassing tiglians with different spectra of biological activities, was assayed on a number of EBV-positive B-lymphoid cell lines. Lytic cycle induction correlated with the capacity to activate PKC, not with tumor promoter status; some nonpromoting tiglians were as efficient as TPA in inducing lytic cycle antigen expression. We then sought more direct evidence for an involvement of PKC in the induction process. In initial experiments, 1-(5-isoquinolinyl sulphonyl)-2-methylpiperazine (H-7), the best available pharmacological inhibitor of PKC, completely blocked the induction of the lytic cycle by TPA and its active analogs. This is consistent with, but does not prove, a requirement for active PKC in the induction process, since H-7 targets PKC preferentially but also has some effects on other kinases. We therefore turned to the synthetic pseudosubstrate peptide PKC(19-36) as a means of specific PKC inhibition and to the closely related but inactive peptide PKC(19-Ser-25-36) as a control. Using the technique of scrape loading to deliver the peptides into cells of an adherent EBV-positive target line, we found that the pseudosubstrate peptide PKC(19-36) completely and specifically blocked tiglian-induced entry of the cells into the lytic cycle. The evidence both from TPA analogs and from enzyme inhibition studies therefore indicates that the pathway linking TPA treatment to lytic cycle induction involves active PKC. Interestingly, inhibition of PKC had no effect upon the spontaneous entry into lytic cycle which occurs in naturally productive cell lines, suggesting that spontaneous entry is signalled by another route.

Cannabinoids: the separation of central from peripheral effects on a structural basis.

A brief history of the therapeutic uses and legal problems of cannabis as well as the component cannabinoids is given. This is followed by a discussion of drug development from Delta (1)-tetrahydrocannabinol and its synthetic analogues. The controversy of whether the pharmacological effects are of central or peripheral origin is included. Then, the potentials for the development of new drugs based on the cannabinoid structure for the treatment of pain, inflammation, and related conditions are outlined. It is concluded that the central activity of cannabinoids is confirmed and that the presence of a C-5 hydroxy group confers potent peripheral activity.