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Biomedical subjects

M T Smith

Publications and source records attributed to M T Smith.

At least 91 records · Page 5Linked to original sources
PubMed1998

The excitatory behavioral and antianalgesic pharmacology of normorphine-3-glucuronide after intracerebroventricular administration to rats.

In the adult male Sprague-Dawley rat, a species commonly used to study tolerance to the antinociceptive effects of morphine, approximately 10% of the morphine dose is metabolized to normorphine-3-glucuronide (NM3G). In contrast, NM3G is a relatively minor metabolite of morphine in human urine reportedly accounting for approximately 1% of the morphine dose. To date, the pharmacology of NM3G has been poorly characterized. Therefore, our studies were designed to determine whether the intrinsic pharmacology of NM3G is similar to that of morphine-3-glucuronide (M3G), the major metabolite of morphine, which has been shown to be a potent central nervous system (CNS) excitant and to attenuate the intrinsic antinociceptive effects of morphine in rats. The CNS excitatory potency of NM3G was found to be approximately half that of M3G, inducing convulsions in rats at intracerebroventricular (i.c.v.) doses of >/=16.8 nmol. When administered before morphine (70 nmol i. c.v.), NM3G (8.9 nmol i.c.v.) attenuated antinociception for up to 2 hr, but when administered after morphine, no significant attenuation of morphine antinociception was observed. Thus, after i.c.v. administration, NM3G like M3G, is a potent CNS excitant and antianalgesic in the rat. NM3G may therefore play a role in the development of tolerance to the antinociceptive effects of morphine in the rat as has been proposed previously for M3G.

Analgesics, Opioid↗
PubMed1998

Apparent insensitivity of the hotplate latency test for detection of antinociception following intraperitoneal, intravenous or intracerebroventricular M6G administration to rats.

Although morphine-6-glucuronide (M6G) has been shown to be analgesically active, the relative involvement of spinal and supraspinal structures in mediating M6G's pain-relieving effects following central and systemic administration to rats is unclear. As the tail flick and hotplate latency tests are reported to quantify antinociception mediated primarily by spinal and supraspinal mechanisms respectively, these methods were used to determine the comparative "apparent" levels of antinociception (expressed as percentage maximum possible effect, % MPE) achieved after M6G or morphine administration. Following i.v. or i.p. M6G (1.9-5.4 micromol) dosing or i.p. morphine (10 micromol) dosing, high levels of antinociception (>50% MPE) were achieved using the tail flick test whereas base-line levels of antinociception were observed 30 sec later in the same rats using the hotplate test. By contrast, antinociception evoked by i.v. morphine (10 micromol) exceeded 50% MPE using both the hotplate and tail flick tests although the "apparent" potency was approximately 2.5 times greater using the tail flick test. After i.c.v. dosing, M6G (0.22-3.3 nmol) was significantly (P < .05) more potent when assessed using the tail flick compared with the hotplate test. Taken together, these data strongly indicate that following central and systemic administration, M6G's antinociceptive effects are mediated primarily by spinal structures whereas both spinal and supraspinal mechanisms contribute to systemic morphine's antinociceptive effects.

Analgesics, Opioid↗
PubMed1997

Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C-->T mutation and rapid fractional excretion of chlorzoxazone.

Benzene is a ubiquitous occupational hematotoxin and leukemogen, but people vary in their response to this toxic agent. To evaluate the impact of interindividual variation in enzymes that activate (i.e., CYP2E1) and detoxify (i.e., NQO1) benzene and its metabolites, we carried out a case-control study in Shanghai, China, of occupational benzene poisoning (BP; i.e., hematotoxicity), which we show is itself strongly associated with subsequent development of acute nonlymphocytic leukemia and the related myelodysplastic syndromes (relative risk, 70.6; 95% confidence interval, 11.4-439.3). CYP2E1 and NQO1 genotypes were determined by PCR-RFLP, and CYP2E1 enzymatic activity was estimated by the fractional excretion of chlorzoxazone (fe(6-OH)) for 50 cases of BP and 50 controls. Subjects with both a rapid fe(6-OH). and two copies of the NQO1 609C-->T mutation had a 7.6-fold (95% confidence interval, 1.8-31.2) increased risk of BP compared to subjects with a slow fe(6-OH) who carried one or two wild-type NQO1 alleles. In contrast, the CYP2E1 PstI/RsaI polymorphism did not influence BP risk. This is the first report that provides evidence of human susceptibility to benzene-related disease. Further evaluation of susceptibility for hematotoxicity and hematological malignancy among workers with a history of occupational exposure to benzene is warranted.

Benzene↗
PubMed1997

Genotoxicity of malathion in human lymphocytes assessed using the micronucleus assay in vitro and in vivo: a study of malathion-exposed workers.

The aerial application of malathion, a widely used organophosphate insecticide, has raised public concerns about potential adverse health effects. We therefore studied micronucleus formation in human lymphocytes as a biomarker of genotoxicity both in vitro and in vivo. Lymphocytes were cultured either as whole blood or after Ficoll isolation and treated with malathion in doses from 5 to 100 micrograms/ml for 48 h. A significant increase in micronucleated cells (47.5/1000 versus 16.0/1000 in DMSO control, p < 0.001) was found in isolated lymphocytes at high dose levels (75-100 micrograms/ml), concurrent with cytotoxicity and a strong inhibition of proliferation (p < 0.001). Many of the treated cells also possessed multiple micronuclei. Antikinetochore-antibody staining revealed that the majority of malathion-induced micronuclei were kinetochore-negative. A significant dose-response was also observed in whole blood cultures, although the increase in micronucleated cells was lower than in isolated lymphocyte cultures (p = 0.03). When the same technique was applied to lymphocytes of 38 intermittently malathion-exposed workers involved in the Mediterranean Fruit Fly Eradication Program in California, no change in either proliferation or micronucleus level was observed compared with an unexposed control group. We conclude that malathion has a relatively low potential to cause chromosome damage in vitro, and corresponding doses are much higher than ones that even professional applicators are likely to be exposed to in vivo. The potential risk of chromosome damage for malathion exposure in vivo is therefore relatively low. More studies are needed to assess the possibility of interaction of malathion with other pesticides through combined exposure.

Alcohol Drinking↗
PubMed1997

Morphine has a dual concentration-dependent effect on K(+)-evoked substance P release from rat peripheral airways.

Our previous investigations of possible lung mechanisms underlying the effectiveness of nebulized morphine for the relief of dyspnoea, have shown a high density of non-conventional opioid binding sites in rat airways with similar binding characteristics (opioid alkaloid-sensitive, opioid peptide-insensitive) to that of putative mu 3-opioid receptors on immune cells. To investigate whether these lung opioid binding sites are functional receptors, this study was designed to determine (using superfusion) whether morphine modulates the K(+)-evoked release of the pro-inflammatory neuropeptide, substance P (SP), from rat peripheral airways. Importantly, K(+)-evoked SP release was Ca(2+)-dependent, consistent with vesicular release. Submicromolar concentrations of morphine (1 and 200 nM) inhibited K(+)-evoked SP release from rat peripheral airways in a naloxone (1 microM) reversible manner. By contrast, 1 microM morphine enhanced K(+)-evoked SP release and this effect was not reversed by 1 microM naloxone. However, 100 microM naloxone not only antagonized the facilitatory effect of 1 microM morphine on K(+)-evoked SP release from rat peripheral airways but it inhibited release to a similar extent as 200 nM morphine. It is possible that these latter effects are mediated by non-conventional opioid receptors located on mast cells, activation of which causes naloxone-reversible histamine release that in turn augments the release of SP from sensory nerve terminals in the peripheral airways. Clearly, further studies are required to investigate this possibility.

Animals↗
PubMed1997

Biochemical synthesis, purification and preliminary pharmacological evaluation of normorphine-3-glucuronide.

Normorphine was synthesised from morphine by thermal decomposition of an N-alpha-chloroethylchloroformate adduct, and purified (> 98% purity) using semi-preparative HPLC with ultraviolet detection. Normorphine-3-glucuronide (NM3G) was biochemically synthesised using the substrate normorphine, uridine diphosphoglucuronic acid and Sprague-Dawley rat liver microsomes in a 75% yield (relative to normorphine base). The synthesised NM3G was purified by precipitation and washing with acetonitrile. Determinations of purity using HPLC with electrochemical and ultraviolet detection confirmed that the NM3G produced was of high (> 99%) purity. Mass spectrometry, fourier transform infrared spectrophotometry and nuclear magnetic resonance spectrometry confirmed the structure, especially placement of the glucuronide moiety at the 3-phenolic position and not at the 17-nitrogen. Administration of NM3G by the intracerebroventricular (icv) route to rats in doses of 2.5 and 7.5 microg resulted in the development of central nervous system (CNS) excitatory behavioural effects including myoclonus, chewing, wet-dog shakes, ataxia and explosive motor behaviour. At an icv dose of 7.5 microg, NM3G also induced short periods of tonic-clonic convulsive activity. Thus, NM3G elicits CNS excitation following supraspinal administration in a manner analogous to morphine-3-glucuronide (M3G), the major metabolite of morphine (1). Further studies are required to determine whether NM3G attenuates morphine-induced antinociception in a similar manner to M3G.

Animals↗
PubMed1997

Gonadotropin antagonist modulates courtship behavior in male red-sided garter snakes, Thamnophis sirtalis parietalis.

Behavioral studies were used to investigate the central effects of chicken-I GnRH, chicken-II GnRH, and D-Phe2,6,Pro3-GnRH, a GnRH antagonist, on the courtship behavior of male red-sided garter snakes, Thamnophis sirtalis parietalis. Intracerebroventricular (i.c.v.) injections of chicken-I or chicken-II GnRH had no effect on time spent courting or latency to court when experimental males were exposed to unmated females, or when experimental males were exposed to the female sex attractiveness pheromone. I.c.v. injections of D-Phe2,6,Pro3-GnRH caused a significant decrease in latency to court when experimental males were exposed to unmated females. When males injected with D-Phe2,6,Pro3-GnRH were exposed to the female sex attractiveness pheromone, it caused a significant increase in time spent courting compared to that in saline-injected controls. D-Phe2,6,Pro3-GnRH was not able to initiate courtship behavior during the nonbreeding season, indicating that courtship behavior is dependent on the interaction of multiple components. This study does demonstrate that a hormone or neuropeptide can modulate sexual behavior in garter snakes.

Animal Communication↗
PubMed1997

Relationship of urinary arsenic to intake estimates and a biomarker of effect, bladder cell micronuclei.

The purpose of this study was to investigate methods for ascertaining arsenic exposure for use in biomarker studies. Urinary arsenic concentration is considered a good measure of recent arsenic exposure and is commonly used to monitor exposure in environmental and occupational settings. However, measurements reflect exposure only in the last few days. To cover longer time periods exposure can be estimated using arsenic intake data, calculated by combining measures of environmental arsenic and inhalation/ingestion rates. We compared these different exposure assessment approaches in a population chronically exposed to arsenic in drinking water in northern Chile. The study group consisted of 232 people, some drinking water low in arsenic (15 micrograms/l) and others drinking water with high arsenic concentrations (up to 670 micrograms/l). First morning urine samples and questionnaire data, including fluid intake information, were collected from all participants. Exfoliated bladder cells were collected from male participants for the bladder cell micronuclei assay. Eight different indices of exposure were generated, six based on urinary arsenic (microgram As/l urine; microgram As/g creatinine; microgram InAs/l urine; microgram MMA/l urine; microgram DMA/l urine; microgram As/h, excreted), and two on fluid intake data (microgram As/day, ingested; microgram As/l fluid ingested-day). The relationship between the different exposure indices was explored using correlation analysis. In men, exposure indices were also related to a biomarker of effect, bladder cell micronuclei. While creatinine-adjusted urinary arsenic concentrations had the strongest correlations with the two intake estimates (r = 0.76, r = 0.81), unadjusted urinary arsenic showed the strongest relationship with bladder cell micronuclei. These data suggest that, in the case of the bladder, unadjusted urinary arsenic concentrations better reflect the effective target organ dose compared to other exposure measures for biomarker studies.

Adolescent↗
PubMed1997

Lipomyces mesembrius sp. nov., a member of the L. starkeyi species-complex.

Lipomyces starkeyi is known to be associated with three strains-clusters showing high mutual nDNA reassociation within each cluster, but which reassociate ambiguously with the type of L. starkeyi. Representative strains of L. starkeyi and Cluster alpha were examined for possible genetic exchange by the prototrophic selection technique. Since no genetic recombination was detected, the strains are presumed to be genetically isolated. Cluster alpha is consequently assigned to the rank of species as Lipomyces mesembrius. A description of the new species is given. Lipomyces kononenkoae ssp. spencermartinsiae has been raised to the rank of species as L. spencermartinsiae.

Classification↗
PubMed1997

Comparison of industrial yeast strains for fermentation of spent sulphite pulping liquor fortified with wood hydrolysate.

Ethanol production from spent sulphite pulping liquor (SSL) was compared for four different yeasts. A second strain of S. cerevisiae as well as a 2-deoxyglucose-resistant strain formed through protoplast fusions between S. uvarum and S. diastaticus produced up to 27% more ethanol from SSL fortified with hydrolysis sugars than was produced by S. cerevisiae. The incremental improvement in ethanol yield appeared to vary with the degree of fortification, ranging from 5.8% for unfortified SSL, to 27% for the highest level of fortification tested. Decreasing fermentation rates were observed for SSL fortified with glucose, mannose and galactose, respectively. Sugar uptake rates in SSL fortified with glucose, galactose and mannose were 6.8, 2.8 and 2.0 g L-1 h-1, respectively. However, when these sugars were fermented along with a glucose cosubstrate, the rate at which the combined glucose/mannose medium was fermented was nearly identical to that of the glucose control.

Cellulose↗
PubMed1997

Induction of chromosome-specific aneuploidy and micronuclei in human lymphocytes by metabolites of 1,3-butadiene.

1,3-Butadiene is a carcinogen in rodents, but its potential carcinogenicity to humans remains controversial. Numerous studies have shown that butadiene and its metabolites cause sister chromatid exchanges in vitro and in vivo. To test for other types of genotoxicity, the micronucleus assay and fluorescence in situ hybridization (FISH) have been used to detect chromosome damage in human lymphocytes caused by two reactive metabolites of butadiene, diepoxybutane (DEB) and monoepoxybutene (MEB). DEB (0.5-5.0 microM) significantly increased micronucleus formation 4- to 6-fold (P <0.01) and MEB (1-500 microM) by 2- to 4-fold (P <0.01) over control levels. The ability of DEB and MEB to induce aneuploidy of chromosomes 7, 8, 12, and X was examined using dual-color FISH in both interphase and metaphase cells. These chromosomes were chosen because of their involvement in leukemogenesis. Both DEB and MEB caused dose-dependent increases in hyperdiploidy of chromosomes 12 and X, but had no discernible effect on chromosomes 7 and 8. These results suggest that DEB and MEB cause chromosome-specific aneuploidy in human cells. If formed in sufficient amounts, DEB and MEB may produce chromosome damage of the type found in leukemia following exposure to butadiene.

Aneuploidy↗
PubMed1997

Neuroanatomical distribution of chicken-I gonadotropin-releasing hormone (cGnRH-I) in the brain of the male red-sided garter snake.

Immunocytochemistry was used to investigate the neuroanatomical distribution of the chicken-I form of gonadotropin-releasing hormone (cGnRH-I) in reproductively active, male, red-sided garter snakes (Thamnophis sirtalis parietalis). Cell bodies with cGnRH-I immunoreactivity (ir) were found in the terminal nerve ganglion, nucleus of the diagonal band of Broca, medial preoptic area, and the hypothalamus. Fibers containing cGnRH-Iir were distributed in the following brain areas. Within the olfactory bulb, fibers were found in the internal plexiform, mitral and glomerular cell layers, as well as in the terminal nerve; within the forebrain, fibers were observed in the diagonal band of Broca, rostral and lateral septum, lateral pallium, retrobulbar region pars dorsomedialis, nucleus accumbens, medial preoptic area, hippocampal commissure, amygdala, posterior dorsal ventricular ridge, hypothalamus, median eminence, and the thalamus; within the midbrain, fibers were found in the interpeduncular nucleus and the stratum album periventricular of the optic tectum. This study shows that the distribution of cell bodies for cGnRH-Iir in this reptile is consistent with the distribution of immunoreactivity for cGnRH-I in birds and mammalian GnRH in amphibians and mammals. Using antiserum specific to cGnRH-I, the endogenous form of GnRH, this is the first study to show that the terminal nerve in a reptile contains GnRH immunoreactivity.

Animals↗
PubMed1997

Micronuclei in exfoliated bladder cells among individuals chronically exposed to arsenic in drinking water.

Inorganic arsenic is an established cause of lung and skin cancer. Epidemiological evidence from Taiwan suggests that arsenic causes more fatal internal cancers, with the highest relative risks reported for bladder cancer. We conducted a cross-sectional biomarker study in a Chilean male population chronically exposed to high (70 subjects) and low (55 subjects) arsenic levels in their drinking water (average concentrations, 600 and 15 micrograms As/liter, respectively). A fluorescent version of the exfoliated bladder cell micronucleus (MN) assay was used employing fluorescence in situ hybridization with a centromeric probe to identify the presence (MN+) or absence (MN-) of whole chromosomes within micronuclei, thereby determining the mechanism of arsenic-induced genotoxicity in vivo. We divided the study population into quintiles by urinary arsenic levels and found an exposure-dependent increase in micronucleated cell prevalence in quintiles 2-4 (urinary arsenic, 54-729 micrograms/liter). The largest increase appeared when quintile 4 was compared to quintile 1 [prevalence ratio, 3.0; 95% confidence interval (CI), 1.9-4.6]. The prevalence of MN+ increased to 3.1-fold in quintile 4 (95% CI, 1.4-6.6), and the prevalence of MN-increased to 7.5-fold in quintile 3 (95% CI, 2.8-20.3), suggesting that chromosome breakage was the major cause of MN formation. Prevalences of total MN, MN+, and MN- returned to baseline levels in quintile 5 (urinary arsenic, 729-1894 micrograms/liter), perhaps due to cytostasis or cytotoxicity. These results add additional weight to the hypothesis that ingesting arsenic-contaminated water enhances bladder cancer risk and suggest that arsenic induces genetic damage to bladder cells at drinking water levels close to the current United States Maximum Contaminant Level of 50 micrograms/liter for arsenic.

Adult↗
PubMed1997

Decrease in bladder cell micronucleus prevalence after intervention to lower the concentration of arsenic in drinking water.

Epidemiological studies performed in Taiwan, Argentina, and Chile suggest that ingestion of arsenic (As) may cause bladder cancer. Because of these findings, we previously investigated the relationship between As ingestion and genetic damage to the urothelium in two cross-sectional biomarker studies, one in Nevada and one in Chile. In both studies, we found that increased levels of micronucleated cells (MNCs) in exfoliated bladder cells were associated with elevated concentrations of As in drinking water, suggesting that As induces genetic damage to bladder cells. To further investigate this relationship, we conducted an intervention study in a subset of highly exposed men (n = 34) from the cross-sectional study in Chile. Subjects whose usual source of water contained about 600 micrograms/liter As were supplied with water lower in As (45 micrograms/liter) for 8 weeks, allowing ample opportunity for renewal and exfoliation of bladder epithelial cells. Mean urinary As levels decreased during the intervention from 742 to 225 micrograms/liter. Bladder MNC prevalence also decreased from 2.63 MNCs/1000 cells preintervention to 1.79 MNCs/1000 cells postintervention (P < 0.05). When the analysis was limited to individuals previously having subcytotoxic urinary As levels (< 700 micrograms/liter), the change between pre- and postintervention MNC was more pronounced: the level decreased from 3.54 to 1.47 MNCs/1000 cells, respectively (P = 0.002). Among smokers, MNC prevalences decreased from 4.45 MNCs/1000 cells preintervention to 1.44 MNCs/1000 cells postintervention (P = 0.002). Among nonsmokers, the decrease was much smaller: 2.04 MNCs/1000 cells preintervention to 1.90 MNCs/1000 cells postintervention (P = 0.25), suggesting that smoker's bladder cells could be more susceptible to genotoxic damage caused by As. The reduction in bladder MNC prevalence with reduction in As intake provides further evidence that As is genotoxic to bladder cells.

Adult↗
PubMed1996

Quantification of epithelial cell micronuclei by fluorescence in situ hybridization (FISH) in mortuary science students exposed to formaldehyde.

A micronucleus assay employing fluorescence in situ hybridization (FISH) with a centromeric probe was used on specimens of exfoliated buccal and nasal cells collected from mortuary science students exposed to embalming fluid containing formaldehyde. FISH labeling allowed micronuclei (MN) containing a whole chromosome (centromere-positive, MN+) to be differentiated from those containing only chromosomal fragments (centromere-negative, MN-). Each student was sampled before and after the 90 day embalming class. We determined if an increase in MN frequency could be attributed to formaldehyde exposure and was specific to either MN+ or MN-. In buccal cells, total MN frequency was significantly increased from 0.6/1000 to 2/1000 (p = 0.007) following the course, whereas in nasal cells it was not (2 and 2.5/1000, respectively, p = 0.2). Cells with multiple MN were present only in samples taken after exposure to embalming fluid. Although the baseline frequency was higher for MN+ in both buccal (0.4/1000 for MN+ and 0.1/1000 for MN-) and nasal cells (1.2/1000 for MN+ and 0.5/1000 for MN-), the increase in MN frequency was greater for MN-, (9-fold, p = 0.005 for buccal cells; 2-fold, p = 0.03 for nasal cells) than for MN+ (> 2-fold, p = 0.08 for buccal cells; no change, p = 0.31 for nasal cells) in both tissues. Thus, the primary mechanism of micronucleus formation appeared to be chromosome breakage. This finding is consistent with known clastogenic properties of formaldehyde, the component of embalming fluid most likely responsible for micronucleus induction.

Adult↗
PubMed1996

hprt mutation frequency among workers exposed to 1,3-butadiene in China.

Hypoxanthine-guanine phosphoribosyl transferase (hprt) mutation frequency (M(f)) was studied in workers at a polybutadiene rubber production facility in Yanshan, China. Exposed workers included for study were active either as process analysts, who sampled butadiene production process lines and analyzed product by gas chromatography, or as process operators, who did routine process control, minor maintenance and, as needed, major repair operations. For process analysts at the polymer and dimethyl formamide (DMF) facilities, the median air levels of BD were 1.0 and 3.5 ppm, respectively. Among process operators, air levels of 1.1 ppm were found during routine activities, while the median air level during pump repair and related operations was 45 ppm (6-h time-weighted average). Overall, M(f) was similar in unexposed (mean M(f) = 20.2 x 10(-6)) and butadiene-exposed (mean M(f) = 21.6 x 10(-6)) workers (P = 0.68). M(f) decreased with cloning efficiency, increased with age, and was moderately greater in women than in men. After adjustment by multiple regression analysis for mean age, sex, and cloning efficiency, the adjusted mean M(f)(Xadj) was 13.6 x 10(-6) in unexposed and 18.0 x 10(-6) in butadiene-exposed. This 32% difference was, however, not statistically significant (P = 0.13). Butadiene exposure was associated with a modest, if any, increase in hprt M(f) in this population of Chinese workers.

Adult↗
PubMed1996

Quantitative autoradiography of peripheral opioid binding sites in rat lung.

Previous studies in our laboratory have characterized non-conventional opioid binding sites in membrane preparations from both rat and human lung. The studies described in this paper utilized autoradiography to investigate the regional distribution of these [3H]morphine binding sites within rat lungs. Specific binding of [3H]morphine was saturable and Rosenthal analysis of tissue section wipes revealed the presence of both high-affinity and low-affinity opioid binding sites. The mean +/- S.E.M. binding affinity and the mean +/- S.E.M. density values for the low-affinity binding site (Kd = 217 +/- 160 nM, Bmax = 12 +/- 8 pmol/mg protein) were similar to the values obtained in our previous whole-rat lung membrane binding assays (Kd = 187 +/- 36 nM, Bmax = 13.5 +/- 2 pmol/mg protein) (Cabot, P.J., P.R. Dodd, T. Cramond and M.T. Smith, 1994, Eur. J. Pharmacol. 268, 247). Quantitative autoradiography showed that the highest density of opioid binding sites appeared to be present within the alveolar wall (13.2 +/- 0.8 pmol/mg protein). A significantly lower (P < 0.05) density of binding was also observed in the smooth muscle of the trachea and main bronchi (5.5 +/- 2.1 pmol/mg protein). However, no morphine binding sites were evident in the smooth muscle surrounding the smaller airways and pulmonary vasculature within the lobes of the rat lung. It remains to be investigated whether the opioid binding sites located within the trachea and main bronchi of the rat airways are the prejunctional opioid receptors on C-afferent nerve fibres which modulate the release of potent inflammatory neuropeptides.

Analgesics, Opioid↗