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Pavlovian conditioning and tolerance to analgesia produced by electrical stimulation in the brainstem Paul, Dennis John


Stimulation of the periaqueductal gray (PAG) of the midbrain produces an analgesia that resembles opiate analgesia. There is considerable behavioral) pharmacological and physiological evidence to suggest a common underlying mechanism for stimulation produced analgesia (SPA) and opiate analgesia. Tolerance to the analgesic effect of opiate drugs has been shown to be subject to the laws of classical conditioning. Specifically, certain aspects of tolerance to opiates have been related to a compensatory physiological response elicited by cues that reliably predict the drug effect. Given the apparent similarity between SPA and opiate analgesia/ the present experiments test the hypothesis that tolerance to SPA is also subject to the laws of classical conditioning and show a compensatory physiological response. Experiment 1 sought to determine if tolerance to SPA can be extinguished. Electrical stimulation of the PAG was delivered for 5 min per day in the presence of distinctive environmental cues. Brain-stimulation increased tail-flick latencies/ and tolerance developed over seven daily sessions. Half of the rats were then given 12 extinction trials which consisted of exposure to the environmental cues, without brain-stimulation. The remaining subjects stayed in their home cages throughout this period. When tested again with brain-stimulation in the experimental environment, animals in the extinction group displayed significant SPA. The home cage group remained tolerant to the PAG stimulation. Reaquisition of tolerance was observed in the extinction group. Experiment 2 was designed to determine if tolerance to SPA is context specific. Half of the animals were stimulated in a distinctive experimental environment. The remaining animals were stimulated in their colony room. Stimulation of the PAG produced strong analgesia, with tolerance developing over seven daily sessions. On test days all animals were stimulated in the colony room. Animals that developed tolerance in the experimental environment showed significant analgesia when stimulated in the colony room. Animals given an eighth consecutive stimulation session in the colony room remained tolerant to the stimulation. Experiment 3 examined the hypothesis that tolerance to SPA should be accompanied by the development of a hyperalgesic response to environmental cues. PAG stimulation produced strong analgesia with complete tolerance developing over seven daily sessions. A nonstimulated control group was given daily tail-flick tests and showed a slightly increasing trend in latencies. On the test day half of the stimulated animals were tested without brain-stimulation and a hyperalgesic response was observed. The remaining stimulated rats received an additional stimulation session and did not show a decreased tail-flick latency. These results extend the generality of the conditioning model of tolerance to the tolerance that develops to SPA. The SPA paradigm may prove to be a valuable tool for examining physiological substrates of conditioned tolerance.

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