Electrical activity of the brain during the critical period in the rat was examined throughout the estrous cycle, using chronically implanted macro-micro electrodes. Slight circadian rhythms were observed in the basal level of the integrated multiple unit activity (MUA) in the basal hypothalamus and forebrain limbic area. In addition to these changes, a gradual increase of MUA in the basal hypothalamus was observed during the evening of diestrus day 2, while there was no change in the forebrain limbic preoptic area. However, a characteristic elevated pattern of MUA appeared for 12 to 25 min during the critical period (2 p.m. to 4 p.m.), both in the basal hypothalamus and forebrain limbic preoptic area, i.e., in the arcuate nucleus (ARC), ventromedial hypothalamic nucleus (VMH), medial preoptic area (MPO), septum (SEPT), amygdala (AMYG) and bed nucleus of stria terminalis (BST). The episodes of the characteristic pattern were also observed in the basal hypothalamus on the afternoons of diestrus day 2 and estrus, as well as in the forebrain limbic preoptic area on the day of estrus. To determine the possible relationship between the characteristic pattern and gonadotrophin release, electrochemical stimulation was applied to the areas of the brain where the characteristic pattern was observed during the critical period. Ovulation could be induced by stimulation of the ARC, MPO, SEPT, AMYG, and BST, but not by stimulation of the reticular formation (RF) and hippocampus (HPC). Furthermore, the results shed light on the facilitatory and inhibitory effects of progesterone on ovulation and the onset of the critical period.
Glutamate receptors are implicated in the genesis of opioid tolerance and dependence. Factors governing release of amino acids in systems chronically exposed to opiates, however, remain undefined. Using rats, each prepared with a spinal loop dialysis catheter and with a chronic lumbar intrathecal infusion catheter connected to a subcutaneous minipump, the release of amino acids before and during antagonist-precipitated withdrawal in unanesthetized rats was examined. Spinal infusion of morphine (20 nmol/micro l/hr) for 4 d had little effect on resting release of amino acids. In morphine-infused, but not saline-infused, rats naloxone (2 mg/kg, i.p.) evoked an immediate increase in the release of L-glutamate (299 +/- 143%) and taurine (306 +/- 113%) but not other amino acids. The magnitude and time course of the release of these amino acids significantly correlated with behavioral indices of withdrawal intensity. Acute intrathecal pretreatment immediately before naloxone with clonidine (20 microg; alpha2 agonist), MK-801 (3 microg; noncompetitive NMDA antagonist), or aminophosphonopentanoic acid (AP-5; 3 microg; competitive NMDA antagonist) suppressed naloxone-induced increases in spinal L-glutamate and taurine release and behavioral signs of withdrawal in spinal morphine-infused rats. Results point to a correlated increase in spinal L-glutamate release, which contributes to genesis of the opioid withdrawal syndrome. Agents such as clonidine that suppress opioid withdrawal may owe their action to an inhibition of excitatory amino acid release. The effects of MK-801 and AP-5 suggest a glutamate-evoked glutamate release.
Inflammation is often accompanied with hyperalgesia. This hyperalgesia is mediated partly by prostaglandin(s) produced in the CNS through the cyclooxygenase-2 (COX-2) dependent pathway. However, it remains unclear where COX-2 is induced in the CNS during inflammation, and how it is involved in hyperalgesia. We studied the precise site of COX-2 induction in the CNS, the relation between the time course of COX-2 induction and that of hyperalgesia, and the effect of COX-2-selective inhibitor by using a carrageenan model. Carrageenan injection induced expression of COX-2-like immunoreactivity in vascular endothelial cells throughout the CNS. This response became evident by 3 h, and was most prominent at 6 h after carrageenan injection. This COX-2 induction was associated with an elevation of prostaglandin E 2 in the cerebrospinal fluid, being evident at 3 h, larger at 6 h, and alleviated by a COX-2-selective inhibitor. Thermal hyperalgesia became evident at 1 h, further increased thereafter, and remained elevated until 6 h. Intrathecal administration of COX-2-selective inhibitor 2 h after the carrageenan injection exerted a prominent therapeutic effect on hyperalgesia. These results demonstrate that, during carrageenan-induced inflammation, endothelial cells are the major source of prostaglandin(s) in the CNS, and this endothelial expression of COX-2 is involved in the inflammation-induced hyperalgesia.
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