William T. Chance

Effects of medial raphe and raphe magnus lesions on the analgesic activity of morphine and methadone

The effects of lesions of the raphe nuclei on opiate-induced antinociception and brain serotonin (5-HT) levels were investigated. Lesions of the medial raphe nucleus effectively antagonized the analgesic effects of morphine, but not methadone, and lowered brain 5-HT. The decrement in analgesic activity of morphine was reversed by pretreatment with 5-hydroxytryptophan. Lesions of the raphe magnus, a descending 5-HT system, antagonized the analgesic potency of both morphine and methadone. These experiments indicate a differential effect of 5-HT manipulation on opiate-induced analgesia, suggesting a different mechanism of analgesic action for morphine and methadone.

Lack of effect of naloxone on autoanalgesia.

Autoanalgesia (behaviorally-induced antinociception) may be elicited by acute stress or clasically conditioned fear. Antinociception within both of these paradigms is reportedly associated with increased CNS opioid peptide activity. Large doses of naloxone (20 mg/kg) failed to modify antinociception elicited by acute footshock or conditioned fear in rats. Naloxone (4 mg/kg) was also ineffective against antinociception following footshock in mice. These data suggest that if an endorphin does mediate autoanalgesia, the affinity of its receptor for naloxone is very low. Alternatively, parallel opioid and non-opioid systems may be activated by autoanalgesic procedures, with antagonism of the opioid component being insufficient to reduce the antinociception.

Effect of autoanalgesia on CNS enkephalin receptors

Fear conditioning to foot shock (15 sec/day, 12 days) elicited autoanalgesia in 10 male (Sprague-Dawley) rats, while 17 non-shock control rats exhibited no analgesia as measured by the tail-flick assay. The binding of 3H-leu-enkephalin to synaptosomal preparations isolated from fear conditioned (experimental) and control animals was analyzed. At leu-enkephalin concentrations of 10(-9) M or less, both synaptosomal preparations demonstrated high affinity binding with dissociation constants on the order of 10(-10). Binding of leu-enkephalin could not be displaced by a hundred-fold excess of naloxone at leu-enkephalin concentrations less than 10(-9) M. However, the ability of naloxone to compete with leu-enkephalin for binding sites progressively increased at concentrations greater than 10(-9) M leu-enkephalin. At these ligand concentrations, the competition of naloxone for leu-enkephalin binding sites was more dramatic in the control than in the experimental animals. These data support the existence of two classes of receptors for leu-enkephalin, one of which is not blocked by opiate antagonists. Furthermore, changes in binding capacity associated with autoanalgesia produced by conditioned fear are consistent with the hypothesis of endogenous release of opiate-like peptides in response to stress.

Antinociception following lesion-induced hyperemotionality and conditioned fear☆

&NA; Hyperemotionality and antinociception (during hyperemotional states) followed lesioning of the septal area in rats. Both of these behaviors showed parallel decreases with daily handling as well as significant positive correlations between them. Tail‐flick latencies were also elevated when fear was conditioned to the environmental cues associated with the tail‐flick procedure. Fear‐induced antinociception was very resistant to extinction, being present across 9 daily extinction trials. These results are interpreted as demonstrations of the behavioral activation of endogenous antinociceptive mechanisms and are in agreement with the postulates of centrifugal control of nociception of the gate control theory of pain.

Lack of Cross-Tolerance Between Morphine and Autoanalgesia

The acquisition of autoanalgesia (behaviorally-induced antinociception) was investigated in morphine-tolerant and non-tolerant rats. Tolerance to morphine did not affect analgesia acutely-elicited by a brief (15 sec) schedule of footshock. Similarly, analgesia elicited by classically conditioned fear wasnot attenuated by morphine tolerance. These data suggest that endorphins may not be the principle mediators of autoanalgesic phenomena.

AUTOANALGESIA: ACQUISITION, BLOCKADE AND RELATIONSHIP TO OPIATE BINDING *

Acquisition of autoanalgesia (behaviorally activated antinociception) was assessed across 7 consecutive days by shocking rats 10 sec after the determination of their tail-flick latencies. Thus the effect of conditioned fear on antinociception was being investigated, since each shock preceded the subsequent tail-flick test by 24 h. Autoanalgesia was acquired by the second fear-conditioning trial. Although pretreatment with naltrexone or diazepam had no effect, spinal cord transection at the thoracic level effectively obviated autoanalgesia. Investigations of opiate and opioid binding indicated significantly less binding in the fear-conditioned rats as well as an inverse relationship between binding and antinociception. These changes in binding are suggestive of partial mediation of autoanalgesia by an endogenous opiate peptide that is released by the fear-conditioning procedure.

A COMPARISON OF NICOTINE AND STRUCTURALLY RELATED COMPOUNDS AS DISCRIMINATIVE STIMULI

1 Of seven nicotine‐like compounds tested as discriminative stimuli in the rat, only 3‐pyridyl‐meth‐ylpyrollidine (3‐PMP) generalized to the stimulus effects of nicotine. 2 3‐PMP caused equivalent nicotine‐like responding at a dose (800 μg/kg) approximately 4 times that used for the original nicotine discrimination (200 μg/kg). The ED50 for 3‐PMP was about 5 times that for nicotine. 3 Testing of the compounds as possible antagonists of the nicotine‐elicited cue were negative. 4 The nicotine‐like cue produced by an 800 μg/kg injection of 3‐PMP was effectively blocked by mecamylamine but not by hexamethonium or atropine. Thus, 3‐PMP appears to produce generalization to the nicotine cue via action on central nicotinic‐cholinoceptors as has been previously reported for the nicotine discriminative stimulus. 5 Mecamylamine blocked the stimulus‐effects of 3‐PMP (800 μg/kg) and of nicotine (200 μg/kg) with an ED50 of 0.32 and 0.20 mg/kg respectively.

Investigation of pituitary influences on auto analgesia

Abstract (1) The effect of manipulations of pituitary hormonal systems on several paradigms of analgesia, as assessed by the tail-flick procedure, were investigated. (2) Systemic injection of ACTH did not elicit analgesia at 15, 30 or 60 min post injection. (3) Hypophysectomy had no effect upon analgesia elicited by acute foot shock. (4) Analgesia, elicited by classically conditioning fear to the tail-flick procedure, was slightly potentiated by hypophysectomy. (5) Hypophysectomy also potentiated morphine-induced analgesia at 2 and 3 hr, but not at 15, 30 or 60 min post injection. (6) These data suggest that neurochemical events in addition to pituitary-adrenal activation are necessary to elicit autoanalgesia (behaviorally-induced antinociception) and that CNS changes in opioid peptide activity which accompany autoanalgesia are independent of pituitary endorphins.

Eating following cholinergic stimulation of the hypothalamus

Stimulation of the perifornical hypothalamus of satiated rats with both crystalline carbachol and solutions of the drug elicited eating and drinking. The eating response did not appear to be a rebound phenomenon, since it paralleled the elicitation of drinking and was not inhibited by repeated applications of crystalline carbachol at 20-min intervals. Eating following the injection of various doses (0.5,1.0, 2.0, and 4.0 nanomoles) of carbachol also paralleled drinking, showing appropriate dose-response relationships. It is hypothesized that cholinergically elicited eating may involved excitatory interaction with adrenergic systems, with increased nicotinic cholinergic activity stimulating alpha-adrenergic neurons to elicit eating. Alternatively, cholinergic stimulation may be activating adrenergic systems through a direct presynaptic release of norepinephrine or epinephrine.

Autoanalgesia: acquisition, blockade and relationship to opiate binding

Acquisition of autoanalgesia (behaviorally activated antinociception) was assessed across 7 consecutive days by shocking rats 10 sec after the determination of their tail-flick latencies. Thus the effect of conditioned fear on antinociception was being investigated, since each shock preceded the subsequent tail-flick test by 24 h. Autoanalgesia was acquired by the second fear-conditioning trial. Although pretreatment with naltrexone or diazepam had no effect, spinal cord transection at the thoracic level effectively obviated autoanalgesia. Investigations of opiate and opioid binding indicated significantly less binding in the fear-conditioned rats as well as an inverse relationship between binding and antinociception. These changes in binding are suggestive of partial mediation of autoanalgesia by an endogenous opiate peptide that is released by the fear-conditioning procedure.