DoD-NCCAM/NIH workshop on acupuncture for treatment of acute pain.

The Department of Defense (DoD) and the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health (NIH) cosponsored a workshop that explored the possible benefits of acupuncture treatment for acute pain. One goal of the workshop was to establish a roadmap to building an evidence base on that would indicate whether acupuncture is helpful for treating active-duty military personnel experiencing acute pain. The workshop highlighted brief presentations on the most current research on acupuncture and acute pain mechanisms. The impact of various modifiers (stress, genetics, population, phenotypes, etc.) on acute pain pathways and response to acupuncture treatment was discussed. Additional presentations focused on common neural mechanisms, an overview of real-world experience with using acupuncture to treat traumatic acute pain, and best tools and methods specific for acupuncture studies. Three breakout groups addressed the gaps, opportunities, and barriers to acupuncture use for acute pain in military and trauma settings. Different models of effectiveness research and optimal research designs for conducting trials in acute traumatic pain were also discussed.

Differential effects of morphine and LiCl on schedule-induced polydipsia.

Lithium chloride (LiCl) and morphine both produce a conditioned taste avoidance response, while only LiCl is able to elicit a conditioned rejection response (taste reactivity), indicating that the effects of conditioning are drug and preparation dependent. The present experiments extend this assessment to another behavioral preparation, schedule-induced polydipsia (SIP), by examining the ability of LiCl and morphine to produce conditioned suppression of nonregulatory drinking. In Experiment 1, schedule-induced saccharin consumption was followed by LiCl or morphine (at doses comparably effective in conditioning taste avoidance under water deprivation) or by the distilled water vehicle. Although both LiCl and morphine suppressed SIP, morphine produced a significantly weaker suppression than did LiCl. Using a massed feeding design in which animals received all their food pellets in a single meal, Experiment 2 determined that LiCl and morphine were equally effective in suppressing consumption, indicating that the differential effects seen under SIP were due to the schedule of spaced food pellet deliveries. The basis for the differential effects of LiCl and morphine on SIP may be a function of an increase in the reinforcing properties of drugs of abuse (such as morphine) within this procedure that mask the acquisition and/or display of the conditioned suppression. If so, then this procedure may be useful in assessing the reinforcing properties of such drugs.

Strain differences in the acquisition of nicotine-induced conditioned taste aversion.

Lewis (LEW) and Fischer (F344) rat strains differ on a variety of physiological and behavioral endpoints, including reactivity to drugs of abuse. Although they differ in drug reactivity, such assessments are generally limited to morphine and cocaine. To determine if these differences generalize to other drugs, the present study examined these strains for their reactivity to the affective properties of nicotine, specifically their sensitivity to nicotine in the conditioned taste aversion preparation. For four or five conditioning cycles given every other day, rats from both strains were allowed access to saccharin and injected with nicotine (0.1, 0.4, 0.8 mg/kg) or vehicle. On intervening days, all rats were given access to water and injected with vehicle. Under this one-bottle training and testing procedure, neither strain displayed aversions at the lowest dose of nicotine (0.1 mg/kg). Aversions were evident for both strains at 0.4 and 0.8 mg/kg, although the F344 rats acquired the aversions at 0.4 mg/kg faster and displayed a significantly greater aversion at 0.8 mg/kg than subjects from the LEW strain. For both strains, aversions were evident at all doses (and in a dose-dependent manner) when subjects were given access to saccharin and water in a two-bottle test. There were, however, no strain differences on this test. Differences between the two strains in their acquisition of nicotine-induced taste aversions were discussed in the context of aversion assessments with other compounds as well as in relation to differences in the self-administration of nicotine in the two strains.

Morphine- and cocaine-induced c-Fos levels in Lewis and Fischer rat strains.

Lewis (LEW) and Fischer 344 (F344) rat strains have been reported to differ in their sensitivity to the rewarding and aversive effects of both cocaine and morphine. Specifically, LEW rats self-administer morphine and cocaine to a greater extent than F344 rats, while LEW (compared to F344) rats are more sensitive to the aversive effects of cocaine but less sensitive to the aversive effects of morphine. Consistent with assessments of the rewarding effects of morphine and cocaine in these two strains, LEW rats have lower basal, and generally higher drug-induced, activity in brain regions associated with reward. Although the brain areas that mediate the aversive effects of drugs are becoming better defined, no studies have compared the activation of these areas by aversion-inducing drugs in the LEW and F344 strains. As such, the relationship between the ability of drugs to activate these aversion-associated brain areas and to induce a conditioned taste aversion (CTA) in these strains is unknown. To explore this relationship, LEW and F344 rats were injected with saline or doses of morphine or cocaine (32 mg/kg for both drugs) that have been shown to generate differential taste aversion learning in these strains. All animals were subsequently tested for c-Fos expression in areas of the brain associated with aversion learning (the lateral and medial parabrachial nucleus, intermediate and caudal nucleus tractus solitarius and area postrema), reward (the shell of the nucleus accumbens) and locomotion (the core of the nucleus accumbens and the caudate putamen). The present results indicated that patterns of morphine- and cocaine-induced c-Fos within CTA-associated, but not reward- or locomotor-associated, brain regions paralleled the differential behavioral sensitivities of LEW and F344 rats to these drugs within CTA learning. Analyses with other drugs that do and do not induce aversions differentially would further assess the role of these brain areas in aversion learning, in general, and in strain-dependent differences, in particular.

Effects of anorectic drugs on food intake under progressive-ratio and free-access conditions in rats.

The effects of two anorectic drugs, dexfenfluramine and phentermine, on food intake under different food-access conditions were examined. Experiment 1 compared the effects of these drugs on food intake under a progressive-ratio (PR) schedule and free-access conditions. Dexfenfluramine decreased food intake under both conditions, but the doses required to decrease intake under free-access conditions were higher than those required to reduce intake under the PR condition. Intermediate doses of phentermine sometimes increased breaking points, and higher doses decreased them. Phentermine decreased food intake at the same doses under both access conditions. Thus the potency of dexfenfluramine, but not phentermine, to decrease food-maintained behavior depended upon the food-access condition. Experiment 2 used a novel mixed progressive-ratio schedule of food delivery to study the duration of drug effects. Sessions consisted of five components separated by 3-hr timeouts. The ratio requirement reset at the beginning of each component and a new breaking point was obtained. Both dexfenfluramine and phentermine dose-dependently decreased breaking points early in the session. In some rats, compensatory increases in breaking point were observed. That is, breaking points later in the session increased over control levels, resulting in no change in the total number of food pellets earned for the session compared to control. The present findings suggest that the effects of some anorectic drugs depend upon the access conditions for food; increasing the effort to obtain food may enhance their ability to decrease food-maintained behavior.

A new progressive ratio schedule for support of morphine self-administration in opiate dependent rats.

RATIONALE AND OBJECTIVES: In preliminary studies, we observed that opiate dependent rats self-administered only a small number of morphine injections under a PR (progressive ratio) schedule developed to study psychostimulant self-administration. Therefore, a new schedule was developed to support morphine self-administration by incrementing response requirements in a relatively gradual manner. The present study compared morphine self-administration under a commonly used PR schedule to self-administration maintained by our modified PR schedule. METHODS: After pretreatment with non-contingent morphine, rats acquired self-administration under fixed-ratio (FR) schedules of intravenous morphine delivery. Morphine-maintained behavior was evaluated under a standard PR schedule (termed "PR3-4", because the third response requirement was four lever presses), and our modified PR schedule (termed "PR9-4", because the ninth response requirement was four lever presses). The PR9-4 schedule was also evaluated for self-administration of morphine doses of 0.001-3.2 mg/kg per injection. RESULTS: The number of ratios completed for morphine self-administration on the PR9-4 schedule, but not the PR3-4 schedule, exceeded values obtained during extinction. Dose-related increases in completed ratios occurred for morphine self-administration on the PR9-4 schedule, with stable patterns emerging after three sessions. A relatively flat dose-response relationship was observed, which did not increase monotonically with morphine dose. Morphine self-administration on the PR9-4 schedule decreased mean inter-injection interval and prolonged the duration of responding during 6-h sessions. CONCLUSIONS: In the present study, a schedule that incremented response requirement gradually (PR9-4) supported reliable self-administration across a range of morphine doses.

Strain-dependent differences in schedule-induced polydipsia: an assessment in Lewis and Fischer rats.

Strain-dependent differences have been used to highlight unknown genetic contributions to important behavioral and physiological end points. In this regard, the Fischer (F344) and Lewis (LEW) rat strains have often been studied because they exhibit a myriad of behavioral and physiological differences. Recently, schedule-induced polydipsia (SIP), a potential model of stress and drug abuse, has been reported to differ between the two strains (see [Pharmacol. Biochem. Behav. 67 (2002) 809]) with F344 rats displaying greater levels of consumption than LEW rats. Given the importance of SIP as a behavioral model of stress and of drug abuse, the present study further explored SIP in F344 and LEW strains by assessing the acquisition and steady-state performance of SIP (under a fixed-time 30 schedule of food delivery; FT30), its characteristic postprandial temporal licking pattern and its modulation by variations in the food delivery schedule (FT15, FT30 and FT60). F344 rats acquired SIP at a faster rate and drank at a higher asymptotic level than LEW rats. Both strains displayed the typical inverted U-shaped post-pellet pattern of drinking and changes in levels of consumption (and displacement of the initiation of post-pellet drinking) with changes in the FT value, supporting the position that the increased drinking seen in both groups was schedule induced. These strain differences in SIP are consistent with the fact that the F344 and LEW strains differ on other behavioral and physiological indices of stress and raise the issue of the use of this model in the assessment of differential drug intake between the two strains.

Effects of interleukin-1beta on food-maintained behavior in the mouse.

The present studies compared the effect of parenteral administration of the proinflammatory cytokine interleukin-1beta (IL-1beta) on food-seeking behavior under various conditions. IL-1beta (100 ng/mouse) decreased home cage consumption of sweetened milk to a greater extent in ad libitum fed mice than in mice that were food-restricted to maintain 85-90% of their free-feeding body weight. When operant responding for milk was maintained under a fixed-ratio 10 response (FR10) schedule of milk delivery, IL-1beta (30-300 ng/mouse) significantly decreased milk-maintained responding in mice fed ad libitum, but not in food-restricted mice. When food-restricted mice were trained under either an FR4 or FR32 response schedule of milk delivery, IL-1beta (100-300 ng/mouse) produced significant decreases in FR32, but not in FR4 responding. When responding was maintained under a progressive-ratio 10 response (PR10) schedule of milk delivery, IL-1beta (30-300 ng/mouse) dose-dependently decreased breaking points. These results indicate that the effects of IL-1beta on food-maintained behavior depend on both the level of motivation (as assessed by food restriction) and on the response cost for the milk (as assessed by ratio requirement). These findings suggest that motivational factors may be capable of attenuating some of the behavioral effects of these agents.

Development of long-acting dopamine transporter ligands as potential cocaine-abuse therapeutic agents: chiral hydroxyl-containing derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine.

In our search for long-acting agents for the treatment of cocaine abuse, a series of optically pure hydroxylated derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (2) (GBR 12909 and GBR 12935, respectively) were synthesized and evaluated in vitro and in vivo. The enantiomers of the 2-hydroxylated analogues displayed substantial enantioselectivity. The S enantiomers displayed higher dopamine transporter (DAT) affinity and the R enantiomers were found to interact at the serotonin transporter (SERT) with higher affinity. The two-carbon spacer between the hydroxyl group and the piperazine ring was essential for enantioselectivity, and the length of the alkyl chain between the phenyl group and the piperazine ring influenced binding affinity and selectivity for the DAT and SERT. Phenylethyl analogues had a higher binding affinity for the SERT and a weaker affinity and selectivity for the DAT than the corresponding phenylpropyl analogues. Thus, (S)-(+)-1-[4-[2-[bis(4-fluorophenyl)methoxy]ethyl]piperazinyl]-3-phenylpropan-2-ol (6) displayed the highest affinity to the DAT, and (S)-(+)-1-[4-[2-(diphenylmethoxy)ethyl]piperazinyl]-3-phenylpropan-2-ol (8) had the highest selectivity. The latter (8) is one of the most DAT selective ligands known. In accord with the in vitro data, 6 showed greater potency than 7 in elevating extracellular dopamine levels in a microdialysis assay and in inhibiting cocaine-maintained responding in rhesus monkeys.