Charles D. Cook

Sex and rat strain determine sensitivity to κ opioid-induced antinociception

Abstract.Rationale: Recent studies indicate that sex and rodent strain are determinants of sensitivity to opioid-induced antinociception. Objectives: The present study examined the influence of sex and rat strain on κ opioid-induced antinociception using a series of κ opioids that vary in their relative effectiveness. Methods: In a warm-water (50, 52 and 55°C) tail-withdrawal procedure, the antinociceptive effects of κ opioids were determined in male and female rats of the F344, Lewis and Sprague-Dawley (SD) strains. Results: In both males and females of each strain, spiradoline produced high levels of antinociception across all nociceptive stimulus intensities, whereas U50,488 produced high levels only at the low and moderate nociceptive stimulus intensities. Sex differences in the potency and effectiveness of these κ opioids were relatively small and not consistently obtained. Enadoline, bremazocine and nalorphine were less effective than spiradoline in producing antinociception, and at low and moderate nociceptive stimulus intensities these opioids were both more potent and effective in F344 and SD males than their female counterparts. In contrast, in Lewis rats, only bremazocine was more potent and effective in males. In combination tests, bremazocine shifted the spiradoline dose-effect curve leftward and/or upward in males and rightward in females (i.e., antagonized spiradoline). In contrast, in both males and females enadoline shifted the spiradoline dose-effect curve leftward and/or upward. Conclusions: These data indicate that κ opioids were generally more potent and effective as antinociceptive agents in males than females. Similar to data obtained with µ opioids, the magnitude of these sex differences was generally larger with the less effective κ opioids and determined, in part, by rat strain and nociceptive stimulus intensity.

Effects of the putative antagonist NCS382 on the behavioral pharmacological actions of gammahydroxybutyrate in mice.

Abstract.Rationale: Gammahydroxybutyrate (GHB) is an endogenous chemical found in the human brain that when administered systemically readily crosses the blood–brain barrier and produces behavioral effects. Some previously reported observations, including reports of specific antagonism by NCS382 (6,7,8,9-tetrahydro-5-[H]-benzocycloheptene-5-ol–4-ylidene acetic acid), support the hypothesis that GHB is a neurotransmitter with its own receptor system. In addition to its uncertain physiological role, the recent interest in GHB has been engendered by its illicit use and abuse. Objectives: To further characterize the behavioral effects of GHB and to evaluate NCS382 for its potential antagonistic effects. Methods: Following the administration of GHB alone and in combination with NCS382, mice were tested in a Functional Observational Battery (FOB) and for their effects on locomotor activity and on schedule-maintained behavior. Additionally, spontaneous and NCS382-precipitated withdrawal in rats chronically treated with GHB was examined. Results: In the FOB, GHB generally produced depressant-like effects that were generally not reversed by NCS382. GHB also dose dependently reduced locomotor activity and rates of operant behavior, which were generally not reversed by co-administrations with NCS382. Neither spontaneous nor NCS382-precipitated signs of physical dependence were observed following chronic GHB administration. Conclusion: GHB dose dependently produced depressant-like effects on learned and unlearned behavior. The putative GHB antagonist NCS382 failed to convincingly antagonize these effects. Physical dependence was not evident following spontaneous withdrawal or NCS382 challenge. Taken together, these results suggest that NCS382s ability to antagonize GHBs effects may be very limited.

Sex differences in (-)-pentazocine antinociception: Comparison to morphine and spiradoline in four rat strains using a thermal nociceptive assay

The present study examined the influence of sex on the antinociceptive effects of (−)-pentazocine, morphine and spiradoline in four rat strains, using a warm-water (50, 52 and 55°C) tail-withdrawal procedure.In F344, Lewis, Sprague–Dawley (SD) and Wistar rats, baseline latencies decreased with increases in water temperature, and at each water temperature latencies were longer in males than in their female counterparts. Morphine and spiradoline produced maximal or near maximal antinociceptive effects in males and females of each strain. Whereas morphine was generally more potent in males, sex differences were not consistently observed with spiradoline. In contrast, there were marked sex differences with (−)-pentazocine, and in each strain (−)-pentazocine was more potent and produced a greater maximal effect in males. The magnitude of the sex differences varied markedly across strains, with (−)-pentazocine being 2.5-fold more potent in males of the F344 strain, but 11-fold more potent in males of the Wistar strain. When collapsed across nociceptive stimulus intensities, sex differences were largest in the Wistar and Lewis strains and smallest in the SD and F344 strains.The present findings indicate that there are marked sex differences in (−)-pentazocine antinociception, and that the magnitude of this effect is genotype dependent.

The modulatory actions of dopamine D2/3 agonists and antagonists on the locomotor-activating effects of morphine and caffeine in mice

Morphine produces robust increases in locomotor activity in mice. Recent data indicate that dopamine (DA) D2/3 agonists attenuate the discriminative stimulus and antinociceptive effects of mu opioid agonists such as morphine. The present study was designed to determine the extent to which D2/3 receptor activation and blockade can modulate morphine-induced locomotion using a novel cumulative dosing procedure in Swiss-Webster mice. The results indicate that morphine-induced locomotion is nonsignificantly attenuated by the D2/3 agonists quinelorane and quinpirole, whereas the D2/3 antagonists eticlopride and nafadotride, as well as the partial D2/3 agonist BP897, significantly reduced morphine-induced locomotion. To determine the specificity of this modulation, these agonists and antagonists were examined in combination with caffeine, a drug that also indirectly alters DAergic activity. Unlike the effects on morphine, caffeine-induced locomotion was unaltered by eticlopride, nafadotride and BP897, but was attenuated by quinelorane and quinpirole. These results indicate that modulation of D2/3 receptors can, in turn, alter the locomotor-activating effects of morphine.

Effects of sex, hindpaw injection site and stimulus modality on nociceptive sensitivity in arthritic rats.

Injection of Complete Freunds adjuvant (CFA) into the hindpaw produces inflammation and alterations in nociceptive sensitivity. The present study was designed to compare the effects of CFA injection into the dorsal and plantar surfaces of the hindpaw on nociceptive sensitivity of the hindpaw to mechanical pressure, warm-water and a hotplate stimulus in male and female rats. CFA or vehicle (VEH) was injected into the dorsal or plantar surface of the right hindpaw on day 0 and tests were conducted on days 4, 6, 8, 10, 11 and 18. Up until day 11 the inflammation was confined to the injected hindpaw (monoarthritic state), whereas by day 18 both hindpaws were inflamed (polyarthritic state). The site of the CFA injection had minimal effects on thermal or mechanical sensitivity with the following exceptions. On days 11 and 18 males had higher hotplate latencies when injected in the dorsal as compared to the plantar surface. For both males and females, warm-water paw withdrawal latencies were longer in those rats injected in the dorsal versus the plantar surface on day 18. No sex differences in paw pressure thresholds were observed on days 11 and 18 in CFA-treated rats. In the warm-water paw withdrawal test CFA-treated males exhibited longer latencies than CFA-treated females on day 11, but similar latencies on day 18. In the hotplate test CFA-treated females exhibited shorter latencies than CFA-treated males on days 11 and 18. The present results demonstrate that nociceptive sensitivity is the result of the interplay among sex, CFA injection site (plantar vs. dorsal), arthritic state (mono- vs. polyarthritic) and stimulus modality (mechanical vs. thermal).

Modulation of the locomotor activating effects of the noncompetitive NMDA receptor antagonist MK801 by dopamine D2/3 receptor agonists in mice

The noncompetitive NMDA receptor antagonist MK801 (dizocilpine) produces behavioral stimulation mediated, in part, through indirect activation of the dopamine (DA) system. Previous reports indicate that D2/3 agonists inhibit MK801-induced stereotypies; however, it is unclear if these agonists also attenuate MK801-induced locomotion. As such, the ability of the D2/3 agonists, quinelorane and quinpirole, and the partial D3 agonist, BP897, to attenuate the locomotor activating effects of MK801 was examined in mice. MK801 (0.1-1.0 mg/kg) produced a biphasic effect on total distance traveled with the intermediate dose of 0.3 mg/kg producing the greatest stimulation. The increase in MK801-induced total distance traveled was attenuated by the coadministration of quinelorane and quinpirole at doses that alone had no effect on activity. Similarly, the partial D3 agonist, BP897, blocked the effects of MK801. The D3-preferring antagonist, nafadotride, reversed the attenuation of quinelorane and partially reversed the attenuation of quinpirole. The D2-preferring antagonist, eticlopride, reversed the attenuating effects of quinelorane, but was not effective against quinpirole. Nafadotride and eticlopride were ineffective against the attenuating effects of BP897 on MK801-induced locomotion. Because BP897 is a partial agonist it was tested against quinelorane/MK801 and quinpirole/MK801 combinations. BP897 reversed the attenuating effects of quinelorane, but not those of quinpirole on MK801s effects. These results demonstrate that the DA system, through D2/3 receptor activation, modulates the locomotor activating effects produced by noncompetitive NMDA receptor blockade.

RTI 113, a 3-phenyltropane analog, produces long-lasting cocaine-like discriminative stimulus effects in rats and squirrel monkeys

The 3-phenyltropane analog, 3beta-(4-chlorophenyl)tropane-2beta-carboxylic acid phenyl ester hydrochloride (RTI 113), has been shown to decrease cocaine self-administration in rats, squirrel monkeys and rhesus monkeys. Consequently, it has been proposed as a potential agonist pharmacotherapy for cocaine dependence. However, the time course of the discriminative stimulus effects of RTI 113 has not been determined. The present study was designed to compare the time course of the discriminative stimulus effects of RTI 113 with that of cocaine in rats and squirrel monkeys. Tests were conducted using a drug discrimination procedure in which rats and squirrel monkeys were trained to discriminate 10 and 0.3 mg/kg cocaine from saline, respectively. RTI 113 substituted for cocaine in both species. The time course of the discriminative stimulus effects of RTI 113 was approximately five times longer compared to that of cocaine. RTI 113 is a 3-phenyltropane analog that has long acting cocaine-like discriminative stimulus effects in both rats and squirrel monkeys. These results, combined with those indicating that RTI 113 decreases cocaine self-administration, suggest that RTI 113, or analogs of RTI 113, may be useful tools for developing potential agonist therapies for cocaine dependence.