Neuroscience
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The role of endogenous opioid peptides and receptors has recently been investigated using knockout mice. Although the affinities of opioid peptides for opioid receptors has been known for many years there is still some uncertainty over which receptor is the endogenous target for each peptide. To address this issue we have studied using quantitative autoradiography the levels of all four opioid receptor subtypes (micro, delta, kappa and opioid receptor-like 1 [ORL1]) in brains sectioned from enkephalin and dynorphin knockouts, as well as from double knockouts. ⋯ Combinatorial double knockouts did not show any changes in addition to those observed in single knockouts. The largest changes were observed in limbic regions and our results suggest that proenkephalin peptides are tonically active at micro and delta-receptors predominantly in these areas. Prodynorphin peptides appear to regulate mostly the kappa-receptor but they are also modulators of micro- and delta-receptors.
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Comparative Study
Cyclooxygenase 2 in infiltrating inflammatory cells in injured nerve is universally up-regulated following various types of peripheral nerve injury.
We previously reported the up-regulation of cyclooxygenase 2 (COX2) in injured sciatic nerve of rats with partial sciatic nerve ligation (PSNL) and the reversal of PSNL-elicited tactile allodynia by local injection of the COX inhibitor ketorolac [Eur J Neurosci 15 (2002) 1037]. We further asked whether COX2 up-regulation in injured nerve is a universal phenomenon following various types of nerve injury. In the current study, we observed that abundant COX2 immunoreactive (IR) cell profiles appeared in injured nerves of rats following spinal nerve ligation (SNL), chronic constriction injury (CCI) and complete sciatic nerve transection. ⋯ Local ketorolac's anti-allodynia lasted much shorter when given 2-3 months after lesion. Local ketorolac failed to induce anti-allodynia 7 months after lesion, a time when COX2-IR cells completely disappeared from the injured nerve except a few cells at the injury site. Our data strongly suggest that during the initial several months after nerve injury, peripherally over-produced prostaglandins play an important role in the maintenance of neuropathic pain.
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Expression of pituitary adenylate cyclase activating polypeptide (PACAP) is increased in sensory neurons exposed to adjuvant induced peripheral inflammation. Local elevation in expression of the neurotrophin nerve growth factor (NGF) is a main factor contributing to the neuronal response to inflammation. ⋯ The results from this study show that inflammation triggered increases in PACAP expression occurs in small- to medium-sized dorsal root ganglion (DRG) neurons that also express trkA, and that this elevation in PACAP expression is prevented by systemic injection of anti-NGF. This supports a role for NGF as a positive regulator of PACAP expression during inflammation.
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Comparative Study
The proprotein convertase PC2 is involved in the maturation of prosomatostatin to somatostatin-14 but not in the somatostatin deficit in Alzheimer's disease.
A somatostatin deficit occurs in the cerebral cortex of Alzheimer's disease patients without a major loss in somatostatin-containing neurons. This deficit could be related to a reduction in the rate of proteolytic processing of peptide precursors. Since the two proprotein convertases (PC)1 and PC2 are responsible for the processing of neuropeptide precursors directed to the regulated secretory pathway, we examined whether they are involved first in the proteolytic processing of prosomatostatin in mouse and human brain and secondly in somatostatin defect associated with Alzheimer's disease. ⋯ However, the content and enzymatic activity of the PC2 mature form were similar in Alzheimer patients and controls. Therefore, the cortical somatostatin defect is not due to convertase alteration occuring during Alzheimer's disease. Further studies will be needed to assess the mechanisms involved in somatostatin deficiency in Alzheimer's disease.
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Comparative Study
Role of NR2B-containing N-methyl-D-aspartate receptors in haloperidol-induced c-Fos expression in the striatum and nucleus accumbens.
Administration of haloperidol in rats leads to a robust induction of immediate-early genes including c-Fos throughout the striatum, which is significantly attenuated by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. The striatum expresses mainly NR1/NR2A and NR1/NR2B subtypes of NMDA receptors, each having different functional and pharmacological properties. In this study, rats were pretreated with Ro 25-6981, a selective antagonist for NR2B-containing NMDA receptors, in order to determine the relative contribution of this NMDA receptor subtype in NMDA-dependent haloperidol-induced c-Fos expression. ⋯ Furthermore, the pattern of attenuation of raclopride-induced c-Fos expression following Ro 25-6981 pretreatment was similar to that of haloperidol-induced c-Fos expression, indicating that the NMDA receptor subtype dependence of haloperidol-induced c-Fos expression is a property of D2 antagonism. The results indicate that NR2B-containing NMDA receptors are mainly involved in mediating haloperidol-induced c-Fos expression in the medial or "limbic" striatum, and suggest that NR2A-containing NMDA receptors may preferentially mediate haloperidol induced c-Fos expression in the lateral or "motor" striatum. This may have implications in the treatment of schizophrenia because co-administration of a selective blocker of NR2A-containing NMDA receptors may be able to reduce the severity of extrapyramidal motor symptoms caused by haloperidol treatment without interfering with its therapeutic effect that is presumably mediated via the medial part of the striatum.