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Biomedical subjects

C D Connelly

Publications and source records attributed to C D Connelly.

At least 19 recordsLinked to original sources
PubMed2001

Alpha(2) adrenoceptor agonists as potential analgesic agents. 3. Imidazolylmethylthiophenes.

A series of imidazolylmethylthiophenes has been prepared and evaluated as ligands for the alpha(2) adrenoceptor. These compounds were tested in two animal models that are predictive of analgesic activity in humans. The 3-thienyl compounds were generally the most potent, particularly those with substitution in the 4-position. A subset of the most active compounds was further evaluated for adverse cardiovascular effects in the anesthetized rat model. In addition to excellent binding at the alpha(2D) adrenoceptor, the 4-bromo analogues 20e and 21e were very active in the rat abdominal irritant test (RAIT) with ED(50) doses of 0.38 and 0.31 mg/kg, respectively. We constructed a pharmacophore model based on the biological activity of the present series, dexmedetomidine (1), and conformationally restrained analogues 3 and 4.

Adrenergic alpha-Agonists↗
PubMed2000

Roles, lifestyles, and well-being as predictors of alcohol consumption among young and midlife women.

Much remains to be learned about drinking patterns and their contexts among population-based women, that is, nontreatment seeking. This report involved secondary analysis of data obtained from 405 young women aged 18 to 35 years and 508 midlife women aged 36 to 55 years who were recruited for participation in two separate studies of women's health. Data were obtained from measures of women's roles: gender role attitudes; role strain; lifestyle behaviors, including alcohol use; well-being and distress; and demographic data; and were measured by descriptive and inferential statistics. Three important findings emerged. First, levels of weekly drinking patterns in both samples studied were consistent with national data. Second, when women were classified by the number of drinks of alcoholic beverages consumed per week, that is, fewer than 12 drinks per year, up to 10 drinks per week, or more than 10 drinks per week, significant differences emerged in both samples. However, patterns of risk and protective factors were inconsistent, which made it impossible to develop specific profiles across both study samples. Finally, the desire to cut down on weekly alcohol consumption was the most significant predictor of drinks per week in both samples.

Adolescent↗
PubMed2000

Assessment of intimate partner violence among high-risk postpartum mothers: concordance of clinical measures.

Intimate partner violence (IPV) may be a more common problem than some conditions for which pregnant women are routinely screened and evaluated. Screening for IPV necessitates competence in assessment using reliable and valid instruments. The present study examines the concordance in the prevalence of abuse reported by 436 high-risk postpartum mothers using (1) a single item hospital screen, (2) trained paraprofessional interviewer-interview format, and (3) the Conflict Tactics Scale (CTS), a standardized research instrument. The hospital screen identified 4% of the sample as scared, threatened or hurt, the Family Stress Checklist (FSC) identified 16.9% of the fathers as having severe potential for violence, and the CTS identified 18.6% of the sample as victims of physical abuse at the hands of the baby's father. There was minimal overlap between the ratings of severe potential for violence and the occurrence of violence as assessed by the CTS. Study findings illustrate the inadequacy of current procedures for detecting IPV with high-risk populations and highlight the need to develop reliable and valid assessments that can be easily utilized in the hospital setting.

Adolescent↗
PubMed1999

Alpha(2) adrenoceptor agonists as potential analgesic agents. 1. (Imidazolylmethyl)oxazoles and -thiazoles.

A series of (imidazolylmethyl)oxazoles and -thiazoles were prepared and evaluated as alpha(2) adrenoceptor agonists. These compounds were also tested in in vivo paradigms that are predictive of analgesic activity. Variations in both the imidazole and thiazole portions of the molecule were investigated. Some of the more potent compounds such as 22, 26, 45, and 53 displayed alpha(2) receptor binding in the 10-20 nM range and also had significant antinociceptive activity in the mouse abdominal irritant test (MAIT).

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1999

Method for comparison of the hemodynamic effects of equi-antinociceptive oral doses of drugs in anesthetized rats.

In a typical flowchart for discovery of novel analgesic (or other) agents, a critical path often involves maximization of the separation of the therapeutic endpoint from known adverse-effect (AE) endpoint(s). Although strategies can easily be designed for in vitro paradigms such as high-throughput screening, extension to in vivo testing can represent a major obstacle to the rapid progression to the next step in development. The problem can be particularly acute when the assessment is required for oral dosing, and when it is not known if the therapeutic and AE mechanism(s) of action are the same. As a case in point, alpha(2)-adrenoceptor (alpha(2)-AR) agonists have potential therapeutic use as analgesics, but they also produce cardiovascular (CV) effects. However, whether the two effects are inexorably linked has not been resolved, particularly for oral administration. The present study used a novel method for comparing the CV effects produced by alpha(2)-AR agonists given by intraduodenal administration to anesthetized rats at fixed ratios of the oral antinociceptive ED(50) dose of each agonist. The technique provided a useful screen of compounds. In addition,there was no correlation between CV endpoints and alpha(2A)-AR affinity, suggesting that oral alpha(2)-AR-mediated analgesia and CV effects might be separable or that other mechanisms might be involved.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1998

Hopefulness, self-esteem, and perceived social support among pregnant and nonpregnant adolescents.

The concepts of hope, self-esteem, and social support have been identified as important factors in understanding a wide range of adolescent behaviors. The purpose of this exploratory study was to examine the relationship of perceived hopefulness, self-esteem, and social support with pregnancy status. Employing a cross-sectional design, a sample of pregnant (n = 58) and nonpregnant (n = 91) adolescents between the ages of 14 and 18 completed the Hopefulness Scale for Adolescents (HSA), the Rosenberg Self-Esteem Scale (RSES), and the Norbeck Social Support Questionnaire (NSSQ). Multiple regression analyses were used to assess the association of pregnancy status with hopefulness, self-esteem, and social support while controlling for age and socioeconomic status (SES). The effects of pregnancy status on each psychosocial variable were examined independently. Findings revealed pregnancy status was not associated with hopefulness, self-esteem, or perceived social support when age and SES were controlled.

Adolescent↗
PubMed1996

Alpha-subunit G-protein antisense oligodeoxynucleotide effects on supraspinal (i.c.v.) alpha2-adrenoceptor antinociception in mice.

An in vivo antisense strategy was used to examine the involvement of G-protein subunits in supraspinal (intracerebroventricular; i.c.v.) alpha2-adrenoceptor-mediated antinociception. Mice that were injected with 33-mer antisense oligodeoxyribonucleotides (6 nmol) or vehicle were tested (tail-flick) with an agonist (clonidine, guanfacine or BH-T 920) administered i.c.v. 18 - 24 h later. Gi3alpha antisense treatment attenuated BH-T 920 and clonidine-induced antinociception. Gi2alpha antisense produced differential effects on the three agonists. Gi1alpha and G(s)alpha antisense treatment had no significant effect. Together with the previous demonstration that i.c.v. mu-opioid antinociception is mediated via Gi2alpha, the present results suggest that different receptors may mediate antinociception via different G-protein subunits and, hence, that specific subunits might offer novel targets for drug discovery.

Adrenergic alpha-Agonists↗
PubMed1996

Unexpected antinociceptive effect of the N-oxide (RWJ 38705) of tramadol hydrochloride.

N-Oxides of centrally acting analgesics generally have minimal analgesic activity. However, the N-oxide of tramadol produced dose-related, long-lasting antinociception in the mouse abdominal irritant, 48 degrees C hot-plate, 55 degrees C hot-plate, and tail-flick tests (ED50 = 15.5, 84.7, 316.4 and 138.2 mg/kg, p.o., respectively). Tramadol N-oxide (T-N-O) (RWJ 38705) was also antinociceptive in the 51 degrees C hot-plate test in male (ED50 = 63.2 mg/kg, i.p.) and female (ED50 = 39.9 mg/kg, i.p.) rats. A characteristic feature of T-N-O was an extended duration of action in these tests (4-5 h). T-N-O had negligible affinity for opioid mu (Ki = 38.5 microM) delta. or kappa receptors (Ki > 100 microM) and, in contrast to tramadol, was essentially devoid of norepinephrine or serotonin neuronal reuptake inhibitory activity (Ki > 100 microM). However, T-N-O displayed tramadol-like characteristics in vivo. There were also significant amounts of tramadol in plasma after T-N-O administration, and the levels resulting from equal oral doses of T-N-O and tramadol were the same, suggesting that the conversion of T-N-O to tramadol was rapid and essentially quantitative. T-N-O was not readily metabolized to tramadol in rat hepatic S9 fraction (< 2%), implying that the conversion might occur in the gastrointestinal tract. Taken together, the results suggest that T-N-O acts as a prodrug for tramadol. T-N-O could offer the clinical benefits of an extended duration of action and a "blunted" plasma concentration spike, possibly leading to an enhanced side-effect profile.

Analgesics↗
PubMed1994

G-protein antisense oligodeoxyribonucleotides and mu-opioid supraspinal antinociception.

The present study utilized an in vivo antisense strategy to examine the functional interaction of supraspinal mu-opioid receptors with the G protein subunits Gi1 alpha, Gi2 alpha, Gi3 alpha and Gs alpha. Mice were injected intracerebroventricularly (i.c.v.) with 33-base phosphorothioate oligodeoxyribonucleotides (12.5 micrograms) or with vehicle in equal volume (sterile water, 5 microliters) and the antinociceptive responses to i.c.v. morphine [D-Ala2,NMePhe4,Gly5-ol]enkephalin (DAMGO) or sufentanil were determined 18-24 h later using the tail-flick test. Treatment with antisense to Gi2 alpha, but not the other subunits, significantly attenuated morphine-induced antinociception. The degree of attenuation for the three mu-opioid agonists was in the order morphine > DAMGO > sufentanil, the inverse of their intrinsic efficacy.

Analgesics↗
PubMed1994

Etonitazene-induced antinociception in mu1 opioid receptor deficient CXBK mice: evidence for a role for mu2 receptors in supraspinal antinociception.

The prevailing view is that supraspinal mu opioid-mediated antinociception in mice is mediated via the mu 1 subtype. The purpose of the present study was to determine if the highly mu-selective compound etonitazene could produce supraspinal (intracerebroventricular; i.c.v.) antinociception in CXBK mice, which are deficient in brain mu1, but not mu2, opioid receptors. CXBK or normal Crl:CD-1 (ICR)BR mice were administered graded doses of etonitazene i.c.v. and 15 min later antinociception was assessed by a standard radiant-heat or 55 degrees C water tail-flick test. Etonitazene produced dose-related antinociception that was blocked by naloxone and by beta-FNA (demonstrating a mu opioid mechanism), but not by either ICI-174,864 or naltrindole (demonstrating the lack of involvement of delta opioid receptors). These findings suggest that mu2 opioid receptors are important contributors to opioid-induced supraspinal antinociception in mice.

Animals↗
PubMed1993

Scyliorhinin-I and -II induce reciprocal hindlimb scratching in mice: differentiation of spinal and supraspinal neurokinin receptors in vivo.

Scyliorhinin-I amide (SCY-I) (selective for NK-1 and NK-2 receptors) or scyliorhinin-II amide (SCY-II) (selective for NK-3 receptors) were injected either spinally (i.t.; intrathecally) or supraspinally (i.c.v.; intracerebroventricularly) to mice. Following i.c.v. administration, SCI-I and SCY-II produced potent, dose-related reciprocal hindlimb scratching about equipotently (ED50 = 0.05 and 0.08 nmol, respectively). However, following i.t. administration, only SCY-I elicited greater than 50% response (ED50 = 0.07 nmol). Reciprocal hindlimb scratching is a behavioral response that has not been associated previously with neurokinins. These results might provide the first functional in vivo correlate for the differential localization of neurokinin receptor types within the mammalian central nervous system.

Amino Acid Sequence↗
PubMed1992

Opioid efficacy is linked to the LiCl-sensitive, inositol-1,4,5-trisphosphate-restorable pathway.

Previous work demonstrated that a single subcutaneous injection of LiCl (10 mmol/kg; 18 h prior) significantly reduces the antinociceptive action of centrally administered (intracerebroventricular; i.c.v.) morphine in the tail-flick and that inositol-1,4,5-trisphosphate (IP3; 20 micrograms) restores the morphine response in LiCl-pretreated mice, implicating a phosphoinositide second messenger pathway in the mediation of morphine-induced analgesia. We now report that LiCl pretreatment shifted the antinociceptive dose-response curve produced by the opioid agonists morphine, [D-Ala2, MePhe4, Gly5-ol]enkephalin (DAMGO) and sufentanil in inverse order of their intrinsic efficacy. These results implicate the phosphoinositide pathway(s) as important determinant(s) of opioid efficacy and are interpreted as evidence for the existence of a second-messenger reserve for opioids of high efficacy and the possible role of the phosphoinositide pathway in the development of morphine tolerance.

Analgesics↗
PubMed1992

Supraspinal antinociception produced by [D-Met2]-FMRFamide in mice.

The ability of Phe-Met-Arg-Phe-NH2 (FMRFamide) or [D-Met2]-FMRFamide to produce antinociception in mice, or to block morphine-induced antinociception, was examined using the tail-flick and tail-immersion (55 degrees C) tests. [D-Met2]-FMRFamide dose-dependently produced antinociception following intracerebroventricular (i.c.v.) administration with ED50 values (95% confidence limits) of 5.0 (2.2-7.2) and 12.8 (8.1-19.9) micrograms in the tail-flick and tail-immersion tests, respectively. FMRFamide did not produce a maximal effect in the tail-flick test. Naloxone (administered s.c. 20 min prior to the i.c.v. administration of [D-Met2]-FMRFamide) dose-dependently attenuated [D-Met2]-FMRFamide-induced antinociception. The shift in the [D-Met2]-FMRFamide dose-response curve was parallel and a pA2 value for naloxone of 6.3 +/- 0.3 was determined from a Schild plot analysis. Mice made tolerant to the antinociceptive effect of morphine were cross-tolerant to the antinociceptive effect of [D-Met2]-FMRFamide. FMRFamide and [D-Met2]-FMRFamide both produced rightward, parallel shifts of the morphine antinociceptive dose-response curve. The findings that [D-Met2]-FMRFamide both elicited naloxone-sensitive antinociception and attenuated morphine-induced antinociception are consistent with the view that FMRFamide-related peptides (FaRPs) are weak agonists at opioid receptors and, further, appear to reconcile the apparently chimeric agonist and antagonist properties of these peptides observed in vivo.

Amino Acid Sequence↗
PubMed1991

XAMI and DCDM, agonists at cAMP-associated octopamine receptors in cockroach nerve cord, produce centrally mediated antinociception in mice.

The ability of XAMI (2,3-xylylaminomethyl-2'-imidazoline), the most potent agonist of cAMP-associated octopamine-sensitive adenylate cyclase in cockroach (Periplaneta americana) nerve cord yet reported, and DCDM (N-demethylchlordimeform), a partial octopamine agonist in this preparation, to produce centrally mediated antinociception in mice was evaluated. The antinociception produced by these compounds was compared to that previously reported for p-octopamine, a phenylethylamine and endogenous mammalian hydroxyphenolic analog of norepinephrine. Consonant with the reported greater agonistic activity of XAMI on octopamine-sensitive adenylate cyclase, XAMI was more potent than p-octopamine by spinal or supraspinal administration in the abdominal constriction test (E50 = 0.013 micrograms i.t., 1.45 micrograms i.c.v.) and in the 48 degrees C hot-plate test (ED50 = 0.06 micrograms i.t., 0.4 micrograms i.c.v.), but was inactive in the tail-flick test (up to 4.0 micrograms i.c.v. or i.t.). Unlike p-octopamine, both XAMI and DCDM were active by peripheral routes of administration. DCDM was orally active in the mouse acetylcholine-induced abdominal constriction test (ED50 = 9.98 mg/kg p.o.) and was active via the s.c. route in this test (ED50 = 2.36 mg/kg), the 48 degrees C hot-plate test (ED50 = 5.40 mg/kg) and the tail-flick test (ED50 between 15 and 30 mg/kg). It appeared to be a full agonist against these endpoints. XAMI produced dose-related antinociception in the abdominal constriction test (ED50 = 0.10 mg/kg s.c.) and in the 48 degrees C hot-plate test (ED50 = 3.71 mg/kg p.o. and 0.46 mg/kg s.c.), where the antinociceptive response persisted for at least 60 min following subcutaneous or oral administration. Both compounds were less potent via peripheral routes than clonidine (as reference) in these tests. Mechanistically, XAMI-induced antinociception was antagonized by yohimbine and idazoxan, but not the opiate antagonist naloxone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclase Inhibitors↗
PubMed1990

[D-Met2]-FMRFamide (DMFa): production of naloxone-sensitive antinociception in mouse tail-flick test.

Considerable data support the hypothesis that mammalian FMRFamide (Phe-Met-Arg-Phe-NH2) or mammalian FMRFamide-related peptides (FaRPs) function as endogenous antiopiates (for review see Raffa, 1988). We report here that central administration (i.c.v.) of a FaRP with D-amino acid substitution in the second position, i.e. [D-Met2]-FMRFamide (DMFa), produces dose-related, naloxone-reversible antinociception in the mouse tail-flick test. Hence, this modification appears to confer agonist-like activity.

Analgesics↗
PubMedDate not supplied

Mother's age and risk for physical abuse.

It is widely believed that young mothers are at greater risk of engaging in physical abuse. However, this relationship is not clearly supported by previous empirical research. This study reexamines the issue using a nationally representative sample of 1,997 mothers. All analyses controlled for family income, race, number of minor children in the home, age of abused child, mother's education, and whether mother was a single parent. Physical abuse was measured with the Conflict Tactics Scales. Using mother's age at time of birth of the abused child, the younger the mother, the greater the rate of child abuse; however, there was not a significant relationship when mother's age was measured at age at time of abuse. Large families and minority group children were also found to be at greater risk of abuse. The paper discusses implications for further research and for prevention of child abuse.

Adolescent↗