Effects of celecoxib and naproxen on renal function in the elderly.

OBJECTIVE: To compare the effects of celecoxib, a cyclooxygenase 2-specific inhibitor, with the nonspecific cyclooxygenase 1 and 2 inhibitor naproxen on renal function in 29 healthy elderly subjects in a single-blind, randomized, crossover study. METHODS: Subjects received either celecoxib, 200 mg twice daily, for 5 days followed by celecoxib, 400 mg twice daily, for the next 5 days, or they received naproxen, 500 mg twice daily, for 10 days. After a 7-day washout, subjects were crossed over to receive the other regimen. RESULTS: After the first dose, the trend was for a greater decrease in glomerular filtration rate with naproxen (-5.31 mL/min per 1.73 m2) compared with celecoxib (-0.86 mL/min per 1.73 m2). The treatment difference became statistically significant on day 6 (-7.53 vs -1.11 mL/min per 1.73 m2 for naproxen and celecoxib, respectively; P=.004). Urinary prostaglandin E2 and 6-keto-prostaglandin F1alpha excretion was significantly reduced from baseline across the treatment interval with both celecoxib and naproxen (P< or =.04). There were no significant differences in prostaglandin excretion between these 2 agents (P> or =.07). Small, transient decreases (P<.05) in urinary sodium excretion were observed after the initiation of both celecoxib and naproxen treatment. Sodium excretion values returned to baseline by the end of the study. CONCLUSIONS: The results indicate that cyclooxygenase 2-specific inhibition in healthy elderly subjects may spare renal hemodynamic function, although the effects on sodium excretion, as well as urinary prostaglandin E2 and 6-keto-prostaglandin F1alpha excretion, appear to be similar to those of nonspecific cyclooxygenase inhibitors such as naproxen.

Antinociception produced by oral, subcutaneous or intrathecal administration of SC-39566, an opioid dipeptide arylalkylamide, in the rodent.

This study characterized the prototypic "minimum structure" enkephalin SC-39566 [2,6-dimethyl-L-tyrosinyl-D-alanine-(3-phenyl-1-propyl)-amide hydrochloride]. SC-39566 bound with highest affinity to mu opioid receptors (Ki, 0.13 nM), as well as to delta (Ki, 4.0 nM) opioid receptors in the rat brain, and with much lower affinity to kappa opioid receptors (Ki, 83.8 nM) in the guinea pig brain. In the mouse, SC-39566 inhibited phenylbenzoquinone-induced writhing and increased tail-flick and hot-plate latencies in a dose-dependent manner after either s.c. or p.o. (i.g.; intragastrical) administration. This antinociception was antagonized by the opioid antagonist naloxone, but not by alpha adrenergic, serotonergic, histaminergic, muscarinic cholinergic or dopaminergic receptor antagonists. In the rat, SC-39566 dose-dependently inhibited acetic-acid-induced writhing after s.c. or i.g. administration and increased response latencies in the tail-flick and hot-plate test after s.c. or intrathecal (i.t.) administration. The increase in tail-flick latency produced by s.c. SC-39566 in the rat was antagonized by s.c. naloxone with an apparent pA2 value of 7.9. Pretreatment with naltrindole, a delta opioid receptor antagonist, increased the ED50 of SC-39566 by only 1.7-fold. In addition, the increase in tail-flick latency produced by i.t. SC-39566 was not antagonized by i.t. administration of naltrindole or nor-binaltorphimine, a kappa receptor antagonist. These data suggest that the antinociceptive activity of SC-39566 is mediated predominantly by mu opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative light microscopic localization of [3H]naltrindole binding sites in the rat brain.

The binding of radiolabeled naltrindole ([3H]NTI), a selective delta-opioid antagonist, was characterized using receptor autoradiography. Receptor binding properties were established in brain paste slices which demonstrated one site receptor occupancy with an apparent Kd of 0.25 +/- 0.08 nM (Bmax of 597.5 fmol/mg protein). Autoradiographic localization of [3H]NTI binding sites in the rat brain revealed high densities of these sites in the cortex (layers 1-3 and 6), caudate putamen, accumbens, claustrum, and internal plexiform layer of the olfactory bulb. Moderate to low levels of specific binding were observed in the hippocampus, thalamus, and substantia gelatinosa of the spinal cord.

Selective antagonism by naltrindole of the antinociceptive effects of the delta opioid agonist cyclic[D-penicillamine2-D-penicillamine5]enkephalin in the rat.

Spinal delta opioid receptors have been proposed to mediate antinociception in the rat on the basis of 1) the efficacy of a small number of agonists; 2) the lack of effect of mu-selective antagonists; and 3) the lack of cross-tolerance with mu-selective agonists. However, direct evidence to support or refute this postulate has not been obtained in the rat due to a lack of suitable delta-selective antagonists. The present study characterized the ability of Naltrindole (NTI, 17-cyclopropylmethyl-6,7-dehydro-4,5 alpha-epoxy-3,14-dihydroxy-6,7-2',3'-indolomorphinan), a recently discovered delta-selective antagonist, to antagonize the antinocieption produced by intrathecal (i.t.) administration of the prototypic delta-selective agonist cyclic[D-penicillamine2-D-penicillamine5]enkephalin (DPDPE) or the mu-selective agonists morphine and [D-Ala2,MePhe4,Gly-ol5] enkephalin (DAMGO) in the rat. Intrathecal coadministration of NTI with DPDPE significantly antagonized the increase in tail-flick latency (TFL) and hot-plate latency (HPL) produced by DPDPE. In the absence of NTI, the ED50 values and 95% CL of DPDPE in the tail-flick and hot-plate tests were 2.8 (1.1-4.7) and 19.5 (13.3-33.7) micrograms, respectively. In the presence of 10 micrograms of NTI, the ED50 value of DPDPE in the tail-flick test was unchanged and was increased by 2-fold in the hot-plate test to 35.9 (26.2-60.1) micrograms. In the presence of 30 micrograms of NTI, the ED50 value of DPDPE in the tail-flick test was increased by 5-fold to 14.5 (8.5-24.9) micrograms and its antinociceptive effect in the hot-plate test was antagonized completely.(ABSTRACT TRUNCATED AT 250 WORDS)

GABAergic modulation of nociceptive threshold: effects of THIP and bicuculline microinjected in the ventral medulla of the rat.

Neurons of the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis pars alpha (NGCp alpha) have been implicated in the regulation of nociceptive threshold and production of antinociception. Previous studies have shown that the activity of these neurons is modulated by noradrenergic, cholinergic and serotonergic afferents. The present study examined whether these neurons are additionally subject to regulation by a GABAergic input. Microinjection of the GABAA receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; 0.3 or 1.0 microgram) in the NRM or NGCp alpha significantly decreased tail flick latency (TFL) and increased responsiveness to noxious pinch. Hot plate latency (HPL) was not affected by microinjection of 0.3 microgram THIP. Although HPL was increased after microinjection of 1.0 microgram THIP, this effect may reflect motoric disturbances. In contrast to the hyperalgesia produced by THIP, microinjection of the GABAA receptor antagonist bicuculline methiodide (0.04 or 0.1 microgram) produced a small, but significant increase in TFL. Responsiveness to noxious pinch and HPL were not affected by either dose. These findings indicate that neurons of the NRM or NGCp alpha involved in the regulation of nociceptive threshold are subject to an inhibitory GABAergic input mediated by a GABAA receptor. However, in contrast to previously described inhibitory inputs, the GABAergic influence does not appear to be tonically active to a substantial extent in the unanesthetized rat.

The antinociceptive effects of prostaglandin antagonists in the rat.

This study examined the antinociceptive effects of two prostaglandin antagonists, SC-25469 and SC-19220 in the rat. SC-25469 and SC-19220 inhibited acetic acid-induced writhing with ED50 s of 6.9 and 6.8 mg/kg p.o., respectively. When compared to other analgesics, the rank order of potency in the writhing test was morphine greater than pentazocine = U-50,488 greater than SC-25469 = SC-19220 greater than ibuprofen greater than aspirin greater than acetaminophen. SC-25469 (150 and 300 mg/kg p.o.) and SC-19220 (50-300 mg/kg p.o.) also suppressed the behavioral response to s.c. injection of formalin, as did aspirin (50-150 mg/kg p.o.), ibuprofen (25-100 mg/kg p.o.) and acetaminophen (300 mg/kg p.o.). However, the suppression was not of the magnitude observed after administration of morphine (ED50: 0.9 mg/kg s.c.), pentazocine (ED50: 2.4 mg/kg s.c.) or U-50,488 (ED50: 0.8 mg/kg s.c.). This study demonstrates the antinociceptive properties of prostaglandin antagonists in two distinct tests of nociception.

Effects of intrathecally administered THIP, baclofen and muscimol on nociceptive threshold.

This study examined whether the antinociceptive activity of THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), a GABA agonist, is mediated through an action exerted at the level of the spinal cord. Intrathecal injection of doses of THIP devoid of motor effects (1-2 micrograms) did not increase tail flick or hot plate latencies in the rat. Although hot plate latency was transiently increased by intrathecal injection of 5 micrograms THIP, slight motor impairment was observed at this dose. Higher doses of THIP (15-50 micrograms) produced flaccidity of the hindlimbs. Intrathecal injection of low doses of muscimol (0.25 microgram) that did not produce motor impairment increased tail flick, but not hot plate, latencies. Baclofen produced motor incoordination following intrathecal injection of 10 micrograms; however, intrathecal injection of 1 microgram significantly increased both tail flick and hot plate latencies without attendant motor effects. Thus, baclofen was the only compound in which the antinociceptive effect was clearly distinguished from the motor effect. These results additionally indicate that the spinal cord does not mediate the antinociceptive activity of THIP.