Differential control of hypothalamically elicited flight behavior by the midbrain periaqueductal gray in the cat

The purpose of the present study was to determine the role of the midbrain periaqueductal gray (PAG) and thalamic centrum medianum-parafascicular complex (CM-Pf) in the regulation of hypothalamically elicited flight behavior in the cat. The experimental paradigm involved a comparison of the differences in response latencies between single stimulation of the hypothalamus and concurrent stimulation of the hypothalamus and sites in the PAG or the CM-Pf. Dual stimulation of the ventral and dorsal aspects of the PAG resulted in differential modulation of flight behavior. Stimulation of the dorsal PAG suppressed hypothalamically elicited flight behavior while stimulation of the ventral aspects of the PAG facilitated flight behavior. Facilitation of flight behavior was also found from stimulation of ventral portions of the CM-Pf.     

Met-Enkephalin-Arg-Phe-like immunoreactive substances mediate electroacupuncture analgesia in the periaqueductal gray of the rabbit

The present study was undertaken to investigate whether the C-terminal extended Met-enkephalin heptapeptide (Met-enkephalin-Arg⁶-Phe⁷, MEAP) played a role in mediating the analgesic effect of electroacupuncture in rabbits. MEAP and its degrading enzyme inhibitor captopril as well as antiserum against MEAP were injected into the periaqueductal gray (PAG) via a previously implanted cannula. Their effects on nociception were tested by the escape response latency (ERL) elicited by radiant heat applied on the skin of the snout. (1) Microinjection of MEAP (30–240 nmol) into PAG produced a dose-dependent analgesic effect which was 2.5 times more potent than Met-enkephalin (MEK) and 3 times less potent than morphine. The complete reversal of the analgesia elicited by 240 nmol of MEAP by a small dose of naloxone (0.1 mg/kg, i.v.) indicates that the effect of MEAP is mediated by naloxone sensitive opioid receptors. (2) In rabbits, a dose-dependent analgesia was elicited by an intra-PAG injection of captopril (60–240 nmol). A single dose of 240 nmol captopril increased ERL by more than 100%. This effect could be reversed by 30 nmol of naloxone injected into the same site, or by antiserum recognizing MEAP (1 μL, titer 1:1500) but not by antiserum recognizing MEK (1 μl, 1:8000) suggesting that captopril was able to protect MEAP from degradation. (3) Intra-PAG injection of 60 nmol of captopril significantly potentiated the after effect of electroacupuncture (EA) induced analgesia. This effect could be blocked either by 30 nmol (but not 7.5 nmol) of naloxone, or by 1 μl (but not 0.1 μl) of MEAP antiserum. These results suggest that MEAP may cause analgesia by acting in PAG, and could be operative in EA analgesia.     

Increasing the work requirements lowers the threshold of naloxone for reducing self-stimulation in the midbrain of rats

Rats were trained to lever-press for intracranial self-stimulation (ICSS) with electrodes in the midbrain central gray area. The effects of naloxone (0.1-30.0 mg/kg, SC) on a continuous reinforcement (CRF) schedule were determined. Rats were then re-trained on higher fixed-ratio (FR) schedules, and naloxone was re-tested at FR: 5, 10, 15 and 20. Only moderate reductions in lever-pressing rates were obtained at the highest dose of naloxone under CRF and FR: 5 schedules. In contrast, pronounced, dose-dependent reductions in ICSS rates occurred at FR: 10, 15 and 20. The time-course for this reduction at FR: 20 was consistent with an opiate-antagonistic action of naloxone. The modest decrease in locomotor activity produced by naloxone in a matched group of control rats was not sufficient to account for the effects on ICSS. The threshold of naloxone for reducing the rate of ICSS lever-pressing was lowered by increasing the effort and/or time requirement for each reinforcement.     

Antinociception following microinjection of dibutyryl cyclic nucleotides into the caudal reticular formation and periaqueductal gray of the rat brain

The tail flick, paw pinch, and hot plate tests were used to assess changes in nociceptive threshold following microinjection of dibutyryl derivatives of cyclic nucleotides into areas of the central nervous system previously shown to be involved in modulation of nociceptive threshold and mediation of morphine analgesia. An elevation in the nociceptive threshold was observed on all three tests following administration of 10 μg dibutyryl cyclic 3':5' adenosine monophosphate (db cAMP) into the caudal brainstem reticular formation (CRF) and periaqueductal gray (PAG). Two μg db cAMP produced the same magnitude of analgesia but had a shorter duration of action. Twenty μg dibutyryl cyclic 3':5' guanosine monophosphate (db cGMP) produced analgesia on all three tests following microinjection at CRF sites but not at PAG sites. These data indicate that morphine analgesia and the antinociception produced by cyclic nucleotides may involve, at least in part, common neuronal substrates. However, the observed capacity of db cAMP to elevate nociceptive threshold does not support the hypothesis that the mechanism of morphine's analgesic action involves inhibition of adenylate cyclase.     

Potentiation of morphine analgesia by the cholecystokinin antagonist proglumide

Recent evidence has suggested that cholecystokinin (CCK) may act as a physiological opiate antagonist. Both the overlap of CCK and opiate systems within the central nervous system and the fact that exogenous CCK can antagonize opiate analgesia suggest that endogenous CCK systems interact with opiate-mediated pain inhibitory systems. In the present series of experiments, we examined the effect of the CCK receptor antagonist proglumide on various forms of morphine analgesia. We have observed that proglumide can potentiate morphine analgesia following systemic, intrathecal or intracerebral administration of these drugs. Endogenous CCK systems do not appear to be tonically active since neither systemic, intrathecal nor intracerebral proglumide typically produced measurable analgesia in the absence of morphine. These data suggest that CCK may be released in response to opiate administration and acts to return the organism toward its basal level of pain sensitivity. If such a hypothesis is in fact true, then CCK blockade may be of clinical value in the treatment of pain.     

The relationship of periaqueductal gray neurons to vocalization and laryngeal EMG in the behaving monkey

Summary The midbrain periaqueductal gray (PAG) of most higher animals has been shown by stimulation and lesion methods to be important in vocalization. In order to learn how the PAG is involved in vocalization, activity from single PAG neurons was recorded from 3 awake, vocalizing monkeys. From a population of 149 units that were temporally related to vocalization, 91 were analyzed with respect to specific parameters of vocalization and laryngeal EMG activity. Measures of the activity of 52 units were significantly correlated with vocalization or EMG activity. Units tended to be correlated with only a few measures of vocalization or EMG activity suggesting rather specific relationships between PAG units and vocalization measures. Microstimulation near recorded cells usually did not excite every muscle sampled, suggesting PAG projections to brainstem motor nuclei may be somewhat specific. The results confirm previous suggestions that the PAG may be involved in the coordination of brainstem motor nuclei during vocalization     

Ethanol preference following hypothalamic stimulation: relation to stimulation parameters and energy balance

Rats were given 5, 10, 20 and 30 min daily sessions of lateral hypothalamic stimulation. Approximately half of the rats showed a large and highly significant increase in their total intake of and preference for 10% v/v ethanol which was continuously available in their home cages. In terms of latency, total consumption and preference for ethanol, 10 min of daily stimulation produced a much greater enhancement than did 30 min. The ethanol drinking rats used more energy per unit of body weight which suggests that the stimulation and/or the ethanol itself may have increased energy expenditure. Simply changing the diet from powdered chow to identical composition pellets produced a large reduction in both total ethanol intake and preference. Reinstating the powdered diet produced a rapid reinstatement of ethanol drinking. These data are discussed in terms of ethanol's role in modulating stimulation induced changes in energy balance.     

Effects of apomorphine,clonidine or 5-methoxy-NN-dimethyltryptamine on approach and escape components of lateral hypothalamic and mesencephalic central gray stimulation in two inbred strains of mice

The effects of intraperitoneal injections of increasing doses of apomorphine, clonidine or 5-methoxy-NN-dimethyltryptamine (5-m-DMT) on approach and escape reactions induced by lateral hypothalamic (LH) or mesencephalic central gray (CG) stimulation were compared in BALB/c and DBA/2 mice. Apomorphine increased both the approach latency for LH stimulation and the escape latency for CG stimulation; the BALB/c strain was more reactive than DBA/2 animals. Clonidine reduced the approach latency for LH stimulation only in the BALB/c strain. 5-m-DMT increased escape latency both for LH and CG stimulation only in the DBA/2 strain. These results suggest that the neurochemical regulation of escape reactions respectively generated by LH or CG activation is partially different: dopamine seems to be involved only in CG aversion, whereas serotonin (5-HT) modulates both LH and CG escape reactions. Moreover, our results demonstrate a noradrenergic influence on the appetitive component of LH stimulation. Finally, they confirm that approach and escape reactions, particularly when induced from lateral hypothalamus, depend on distinct neuronal populations.     

Morphine and ACTH1–24: correlative behavioral excitations following microinjections in rat periaqueductal gray

Rats implanted with bilateral cannulas in the periaqueductal gray exhibited similar behavioral excitations following microinjections of morphine sulphate and ACTH_1–24. Injections were more effective when the sites were located within rather than below the periaqueductal gray. Analgesia was observed following morphine but not ACTH microinjection. These results confirm that morphine exerts a dual action, inhibitory (i.e. analgesic) and excitatory, with ACTH mimicking only the latter action.