Faculty Bibliography

Electrical stimulation in lateral hypothalamic sites (ESLH) supporting appetitive behavior and reward also diminishes pain and aversion responses that are organized high in the neuraxis. A paired-pulse stimulation technique was used, in two different behavioral paradigms, to infer the absolute refractory periods of LH neurons that mediate this apparent supraspinal analgesia. In both paradigms, recovery from refractoriness--reflected by increased analgesic action--was evident at intrapair intervals of 0.8 msec and greater. This finding suggests that the overlap, if any, between first stage neurons mediating analgesia and appetitive/reward behavior may be restricted to the 'heterogeneous slow population' distinguished by Gratton and Wise. The dopamine antagonist pimozide, at doses known to diminish ESLH-induced feeding and reward (0.25 and 0.5 mg/kg), failed to affect analgesia. Thus, the dopaminergic second stage neurons deemed critical to feeding and reward may not play an important role in analgesia. Finally, ESLH-induced ameliorative action as a case of 'aversion-gating' or a dimension of classical somatosensory analgesia is discussed

A new fluorinated derivative of N-propylnormetazocine, N-(3-fluoropropyl)-N-normetazocine (1) was synthesized. 1 was similar to the unfluorinated analog 3 in its ability to compete with (3H)-naltrexone for binding sites in rat brain membranes and its potency in antagonizing morphine analgesia in rats. Competition of both compounds against (3H)-naltrexone was little affected by the presence of sodium chloride, a characteristic frequently exhibited by opiate antagonists. Morphine analgesia in rats was measured by suppression of locomotion and vocalization responses to footshock. The ability of 1 to antagonize morphine analgesia in rats was similar to that of 3. Neither 1 nor 3 showed any evidence of agonist activity in rats at doses as high as 1.0 mg/kg (the highest dose tested). These results suggest that 1, labeled with 18F, may be useful for in vivo studies of the opiate receptor using positron emission tomography (PET)

Brief trains of electrical stimulation were applied to the tails of rats to evaluate pain thresholds in the presence and absence of concurrent brain stimulation. Lateral hypothalamic (LH) stimulation, particularly in the dorsolateral medial forebrain bundle, elevated threshold for eliciting a post-stimulus vocalization response. Thresholds for eliciting a simple vocalization and motor response--both of which are organized at lower levels of the CNS than post-stimulus vocalization--were not significantly affected. This restricted form of analgesia was reduced by the opioid antagonist, naltrexone. Rewarding effects of stimulation in these LH sites, as evaluated in tests of self-stimulation threshold, were not affected by naltrexone. These results suggest that LH stimulation activates an opioid analgesic mechanism that is selectively active at a supraspinal level and diminishes the affective consequences of otherwise noxious stimuli.

The analgesic effect of morphine in rats, as reflected in elevated thresholds for tail shock induced vocalizations, was markedly potentiated by the antihistamine, diphenhydramine. Intrinsic to the behavioral test paradigm employed are stressors which mobilize endogenous opioid activity as verified by the hyperalgesic effect of naloxone. Diphenhydramine failed to potentiate the analgesic effect of such endogenous opioid activity. The potentiating effect of antihistamines may therefore be mediated by mechanisms whose influence is restricted to systemically administered opiates