Evaluation of the abuse potential of methocarbamol.

The subjective and behavioral effects of p.o. administered methocarbamol, lorazepam and placebo were studied in a nonresidential group of adult male volunteers with histories of recreational substance abuse including sedative/hypnotics. In the first phase of the investigation, a dose run-up of methocarbamol (up to 12 g) was conducted in six subjects to determine appropriate doses. In the second phase, a randomized block cross-over study using 14 subjects was conducted. The following drug conditions were tested in the cross-over phase: placebo, lorazepam 1, 2 and 4 mg, and methocarbamol 2.25, 4.5 and 9 g. Drug conditions were tested under double-blind conditions. Psychomotor and cognitive performance measures and subject- and observer-rated behavioral responses were measured daily before dosing and for 5.5 hr after drug administration. The results showed that both lorazepam and methocarbamol produced statistically significant dose-related increases in subjects' ratings of drug effect and liking, although only lorazepam increased morphine-benzedrine group (MGB) scale scores. Methocarbamol also increased ratings on measures indicating the emergence of dysphoric and other side effects at high doses. Both drugs impaired psychomotor and cognitive performance, with lorazepam generally producing greater effects than methocarbamol. The results indicate that methocarbamol, at doses well above those used therapeutically, has some potential to be abused by persons with histories of sedative/hypnotic abuse; however, this potential for abuse is probably decreased by the accompanying side effects at high doses and is probably less than that of lorazepam.

Vasopressin-induced antinociception: an investigation into its physiological and hormonal basis.

Systemically administered lysine-8-vasopressin (LVP; 16-128 micrograms/kg) was found to induce a potent and dose-dependent antinociceptive effect, as measured by the tail-flick test in the rat. This effect could be seen in the absence of any significant change in general activity, indicating that it was not due to sedation or general motor debilitation. The antinociceptive effect of LVP does not appear to be mediated by endogenous opiates or other pituitary hormones, as evidenced by: 1) the lack of antagonism by the opiate receptor blocker naloxone, 2) the lack of cross-tolerance with morphine, and 3) its persistence after hypophysectomy. Des-glycinamide-LVP, a vasopressin analog with no appreciable pressor or antidiuretic action, showed no antinociceptive activity (128 micrograms/kg), and des-amino-arginine-vasopressin, a vasopressin analog with minimal pressor activity but greatly enhanced antidiuretic activity, was also relatively ineffective (128 micrograms/kg). These results suggest that the antinociceptive activity of vasopressin may be related to receptor types similar to those mediating its pressor effects. Nevertheless, the antinociceptive action of vasopressin does not appear to be secondary to its pressor activity, since phenylephrine failed to induce an antinociceptive effect at a dosage that mimicked the pressor response to vasopressin. These results are in concert with a growing body of evidence suggesting that vasopressin may be one of several nonopiate peptides that play a role in the modulation of pain sensitivity.

Effects of paleocerebellar lesions on DRL performance in the albino rat.

Normal rats and rats with paleocerebellar lesions were trained to bar press for food on continuous reinforcement (CRF) and differential reinforcement of low response rates (DRL) schedules. The animals with lesions showed normal acquisition of the CRF schedule, but they exhibited a marked deficit on the DRL task. This deficit was related to overresponding which appeared to result from an inability to inhibit the response, rather than from a dysfunction in timing ability or motor capacity. The DRL deficit, however, was overcome by the introduction of a salient stimulus object (wood block) into the operant situation. Although no explicit reinforcement contingencies were placed on interaction with the stimulus object, it appeared that the wood block facilitated the development of "collateral" behaviors that served to mediate the DRL interval. These results are consistent with the suggestion that the cerebellum may contribute to the sequential organization of complex behaviors.