vasoactive-intestinal-peptide and Substance-Withdrawal-Syndrome

Some neurotrophins have the capability of enhancing neuropeptide expression in several regions of the brain. It was also recently shown that NGF, infused over 1 month, offsets the decreased synthesis and expression of vasopressin (VP) and vasoactive intestinal polypeptide (VIP) in the suprachiasmatic nucleus (SCN) of rats submitted to chronic ethanol treatment and withdrawal. In the present study we examined the effectiveness of neutrotrophin-3 (NT-3) in promoting such effects, given that SCN neurons express both the high and the low affinity receptors for this neurotrophin. NT-3 was intraventricularly infused during 10 days to rats withdrawn from prolonged ethanol treatment. The total number, and the mean somatic volume, of VP- and VIP-immunoreactive neurons was compared with the estimates obtained from control rats and withdrawn rats treated with either NGF or cerebrospinal fluid during the same period. The infusion of cerebrospinal fluid and of NT-3 did not prevent the reduction in the number of peptide-producing neurons induced by withdrawal from ethanol treatment. Conversely, NGF infusion increased their number to control levels and led to neuronal hypertrophy. Our results show that, unlike NGF, NT-3 does not display the capacity of enhancing neuropeptide expression in the SCN. Because SCN neurons express the low affinity p75(NTR), which is equally activated by both neurotrophins, our results additionally indicate that the effects of NGF upon SCN neurons are not receptor-mediated. Taken together, our data suggest that indirect mechanisms, rather than direct neutrophin signaling, are likely to mediate the trophic effects exerted by NGF upon SCN neurons.

Topics: Animals; Basal Nucleus of Meynert; Cell Size; Central Nervous System Depressants; Choline O-Acetyltransferase; Ethanol; Immunohistochemistry; Male; Nerve Growth Factor; Neurons; Neuropeptides; Neurotrophin 3; Rats; Rats, Wistar; Receptor, Nerve Growth Factor; Receptor, trkC; Substance Withdrawal Syndrome; Suprachiasmatic Nucleus; Vasoactive Intestinal Peptide; Vasopressins

Chronic ethanol treatment and withdrawal from alcohol decrease the synthesis and expression of neuropeptides in the hypothalamic suprachiasmatic nucleus. Given the existing evidence that neurotrophins modulate the synthesis and expression of neurotransmitters/neuromodulators in the mature brain, we have hypothesized that such alterations might result from the reduced biological activity or brain content of neurotrophic factors. To test this possibility, nerve growth factor (NGF) was delivered intraventricularly, over a 4-week period, to rats submitted to ethanol treatment for 6 months and to withdrawn rats. Vasopressin (AVP) and vasoactive intestinal polypeptide (VIP), and the respective mRNAs were detected by immunocytochemistry and in situ hybridization histochemistry, and their levels estimated using stereological methods and densitometry. In ethanol-treated and withdrawn rats, NGF produced increases in the number of AVP- and VIP-immunostained neurons to values identical to those of controls. Corresponding variations were detected in AVP and VIP mRNA levels, which indicates that NGF restored the expression of AVP and VIP by enhancing neuropeptide synthesis. These findings show that NGF can correct the changes induced by chronic ethanol treatment and withdrawal in the gene expression and protein content of the neuropeptides synthesized by suprachiasmatic neurons. They also reveal that NGF plays an important role in the maintenance of the neurochemical phenotype of the suprachiasmatic nucleus in the adult rat. Because suprachiasmatic neurons do not express trkA, NGF might have exerted its effects either through direct signalling of suprachiasmatic neurons via p75(NTR) activation or, indirectly, by enhancing the activity of the cholinergic and/or glutamatergic afferents to the suprachiasmatic nucleus, or both.

Topics: Alcohol-Induced Disorders, Nervous System; Animals; Arginine Vasopressin; Cell Count; Ethanol; Gene Expression Regulation; Immunohistochemistry; Male; Nerve Growth Factor; Neurons; Neuropeptides; Rats; Rats, Wistar; RNA, Messenger; Substance Withdrawal Syndrome; Suprachiasmatic Nucleus; Up-Regulation; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide (VIP) has numerous regulatory roles in peripheral, endocrine organs and in the central nervous system. The present study related to the effects of centrally (intracerebroventricularly) administered VIP on pain sensitivity and on opiate tolerance and dependence in intact male CFLP mice. VIP was analgesic when administered alone centrally. Naloxone treatment abolished this analgesic effect. VIP decreased the analgesic effect of a single subcutaneous morphine injection and the development of chronic tolerance to morphine. Morphine withdrawal signs were not significantly affected after VIP pretreatment. These findings indicate that VIP may play a role in pain sensitivity and that an opiate component may participate in this effect.

Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Drug Tolerance; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Morphine; Naloxone; Narcotic Antagonists; Pain Measurement; Substance Withdrawal Syndrome; Vasoactive Intestinal Peptide