Thomas F. Burks

Cholecystokinin-Induced Antinociception is Not Blocked by CCK-A or CCK-B Receptor Antagonists

To determine the relative importance of CCK-A, CCK-B, and opioid receptors in mediating the antinociceptive actions of cholecystokinin, we evaluated the actions of selective agonists and antagonists in the mouse hot plate assay. The agonists used were CCK (1-30 nmol i.c.v.), a CCK-A receptor agonist (SNF9019; 0.3-10 nmol i.c.v.), and a CCK-B receptor agonist (SNF9007; 0.3-10 nmol i.c.v.). The antagonists used were the CCK-A receptor antagonist, L364,718 (12.5 nmol i.c.v.), CCK-B receptor antagonist, L365,260 (2.5-25 nmol i.c.v.), and the nonselective opioid receptor antagonist naloxone (1 mg/kg s.c.). CCK and its receptor-selective analogues, SNF9019 and SNF9007, resulted in antinociception that was blocked by naloxone, but was not antagonized by L364,718 or L365,260. In contrast, in positive control experiments, the inhibitory effects of CCK, SNF9019, and SNF9007 on gastrointestinal propulsion in mice were antagonized by identical i.c.v. doses of L364,718 and L365,260. We conclude that centrally administered CCK produces antinociception in the mouse hot plate assay via opioid receptors, but independent of CCK-A or CCK-B receptors. It is necessary to speculate that other CCK receptors, not antagonized by currently available selective antagonists, may exist.

Interactions of oxytocin and vasopressin with CRF on the rat colon

Corticotropin-releasing factor (CRF), a primary mediator of stress responses, produces changes in the gastrointestinal tract identical to those induced by stress. CRF is tenfold more potent in females than in males, but gonadectomy reverses this difference. We postulated that positive modulators of CRF, such as oxytocin (OT) and vasopressin (AVP), may act in females to potentiate effects of CRF and thus could account for the gender-related differences in colonic sensitivity to CRF and stress. Given with CRF, neither OT, peripheral AVP, nor central AVP increased colonic transit any more than CRF alone, suggesting that OT and AVP do not potentiate CRFs actions in the colon. These data indicate that endogenous OT and AVP do not directly affect colonic transit, and that OT and AVP do not account for the gender-related differences in the effects of stress and CRF on colonic transit.

Inhibition of adenylyl cyclase activity by the cholecystokinin analog SNF 9007 in neuroblastoma × glioma NG108-15 hybrid cells

The effect of the cholecystokininB (CCKB) receptor-selective cholecystokinin octapeptide (CCK-8) analog SNF 9007 on forskolin-stimulated adenylyl cyclase activity in NG108-15 hybrid cells was measured. The activity of SNF 9007 was compared to the delta opioid agonists D-Pen2-D-Pen5-enkephalin (DPDPE, delta 1 receptor-selective) and Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2, (D-Ala2-deltorphin II, delta 2-receptor-selective) because SNF 9007 binds with moderate affinity to delta opioid receptors. SNF 9007 inhibited forskolin-stimulated adenylyl cyclase activity with efficacy similar to DPDPE. IC50 determinations showed that D-Ala2-deltorphin II was the most potent, followed by DPDPE, then SNF 9007 (IC50 values = 0.013, 0.21 and 4.8 microM, respectively). CCK-8 had no effect on adenylyl cyclase activity. The delta 1 receptor-selective antagonist 7-benzylidenenaltrexone hydrochloride (BNTX, 10 nM) had no effect on the activity of any of these agonists, but the delta 2 receptor-selective antagonist naltriben methanesulfonate (NTB, 10 nM) increased IC50 values of all the agonists. Combinations of BNTX and NTB (10 nM each) increased the D-Ala2-deltorphin II IC50 value 12-fold, the DPDPE IC50 value 18-fold and the SNF 9007 IC50 value 26-fold. The effect of the combined delta antagonists on SNF 9007 activity was different from the effect on DPDPE or D-Ala2-deltorphin II activity. These data suggest that the interaction of the CCK-8 analog SNF 9007 with opioid receptors in NG108-15 hybrid cells is different from the interaction of opioid peptides with these receptors.

Pharmacology in the new era of higher education: View from the USA

We are witnessing great changes in higher education in the USA, with profound implications for all of the biomedical sciences, including pharmacology. Higher education from 1950 to approximately 1980 witnessed expansion of scientific knowledge and expertise, increased numbers of health professional schools, more revenues for support of education and research, creation of new research institutes and growth of academic departments. We have now entered into a new era characterized by continuing expansion of knowledge, but with static or diminishing sizes and possibly numbers of schools and institutes, shrinkage of revenues, substitution of expertise and consolidation of departments. There have been many worthwhile scientific advances that should lead to new directions in education and research, but there are few resources available for supporting these new educational and research ventures. This article by Thomas Burks is adapted from the annual Croker Lecture, which was delivered at the 1994 meeting of the American Society for Pharmacology and Experimental Therapeutics.

Muscle receptors, neurotransmitters, and drugs

Motor activity in the antropyloroduodenal region ultimately determines the rate of emptying of the stomach. It was thought previously that the proximal stomach largely controlled emptying of liquids, whereas the distal stomach was responsible for emptying of digestible solids. It is now clear, however, that integrated motility functions of all parts of the stomach participate in efficient trituration and emptying of solids and liquids. While the proximal stomacl~ is importantly involved in receptive relaxation and accommodation of a meal and delivery of the meal to the distal stomach, the gastroduodenal junction serves as the final gatekeeper that regulates flow into the upper small intestine (1). The session on Mediation: muscle receptors, neurotransmitters and drugs explored the myogenic and neural bases of gastric motility and the actions of an exciting new class of gastrokinetic drugs of potential benefit in promotion of gastric emptying. Speakers in this session described regulatory and cellular mechanisms responsible for the functional control of aspects of gastric emptying. It is clear from the review of Daniel et al that the antropyloroduodenal region is linked by both descending and ascending neural pathways in the enteric nervous system that are subject to modulation by extrinsic neural influences of the vagal parasympathetic nerves and by sympathetic postganglionic fibers arising from paravertebral and prevertebral ganglia. Importantly, at least some of these neural pathways operate across the pylorus, providing the neural linkages necessary for integration of motor