dynorphins and Brain-Injuries

Central nervous system (CNS) injury is a complex in which numerous neurochemicals and other vasoactive agents actively contribute towards the development of posttraumatic brain pathology and/or repair mechanisms. A focal trauma to the brain or spinal cord releases several endogenous neurodestructive agents within the CNS, resulting in adverse cellular reactions. Our laboratory is engaged in identifying these endogenous neurodestructive signals in the CNS following injury caused by trauma or hyperthermia. Our observations show that serotonin (5-HT), dynorphin A (Dyn A 1-17), nitric oxide synthase (NOS), and tumor necrosis factor-α (TNF-α) could be potential neurodestructive signals in the CNS injury. Thus, neutralization of these agents using monoclonal antibodies directed against 5-HT, NOS, Dyn A (1-17), and TNF-α in vivo will result in marked neuroprotection and enhance neurorepair after trauma. In addition, a suitable combination of monoclonal antibodies, for example, NOS and TNF-α, when applied 60-90 min after trauma, is capable to enhance neuroprotective ability and thwart cell and tissue injury after spinal cord insult. Taken together, our novel observations suggest a potential use of monoclonal antibodies as suitable therapeutic agents in CNS injuries to achieve neuroprotection and/or neurorepair.

Topics: Animals; Antibodies, Monoclonal; Antigen-Antibody Reactions; Brain Injuries; Disease Models, Animal; Dynorphins; History, 18th Century; History, 19th Century; History, 20th Century; Humans; Nerve Regeneration; Neuroprotective Agents; Nitric Oxide Synthase Type I; Serotonin; Spinal Cord Injuries; Tumor Necrosis Factor-alpha; Wound Healing

Traumatic brain injury (TBI) induces a cascade of primary and secondary events resulting in impairment of neuronal networks that eventually determines clinical outcome. The dynorphins, endogenous opioid peptides, have been implicated in secondary injury and neurodegeneration in rodent and human brain. To gain insight into the role of dynorphins in the brain's response to trauma, we analyzed short-term (1-day) and long-term (7-day) changes in dynorphin A (Dyn A) levels in the frontal cortex, hippocampus, and striatum, induced by unilateral left-side or right-side cortical TBI in mice. The effects of TBI were significantly different from those of sham surgery (Sham), while the sham surgery also produced noticeable effects. Both sham and TBI induced short-term changes and long-term changes in all three regions. Two types of responses were generally observed. In the hippocampus, Dyn A levels were predominantly altered ipsilateral to the injury. In the striatum and frontal cortex, injury to the right (R) hemisphere affected Dyn A levels to a greater extent than that seen in the left (L) hemisphere. The R-TBI but not L-TBI produced Dyn A changes in the striatum and frontal cortex at 7 days after injury. Effects of the R-side injury were similar in the two hemispheres. In naive animals, Dyn A was symmetrically distributed between the two hemispheres. Thus, trauma may reveal a lateralization in the mechanism mediating the response of Dyn A-expressing neuronal networks in the brain. These networks may differentially mediate effects of left and right brain injury on lateralized brain functions.

Topics: Analysis of Variance; Animals; Brain Injuries; Corpus Striatum; Dynorphins; Functional Laterality; Hippocampus; Male; Mice; Prefrontal Cortex; Radioimmunoassay

The neurodevelopment of hippocampus and prefrontal cortex are known to influence different functions in normal and pathological conditions including cognition and sensorimotor functions. The neonatal lesion of the ventral hippocampus (VH) in rats has been established as an animal model of schizophrenia and is used to study postpubertal changes in behavior and neurobiology. In order to investigate whether early VH lesion in rats alters the expression of genes implicated in schizophrenia pre- and post-puberty, we studied the mRNA expression of neuropeptides (substance P, dynorphin and enkephalin), dopamine D1, dopamine D2, and NMDA (subunits NR1 and NR2A) receptors in this animal model.. Rat pups were lesioned at postnatal day 7 by injecting ibotenic acid into the VH bilaterally, and then sacrificed at age 35 (pre-puberty) and 65 (post-puberty) days. Another group of adult rats had the same lesion in the VH, to independently assess the effects of the lesion on the expression of genes, and then sacrificed at week 4 and 8 post lesion. Sham groups were injected with cerebrospinal fluid using the same procedure. Brains were removed and sectioned to study the mRNA expression using in situ hybridization (ISH).. The main results are the postpubertal onset of increased NR1 mRNA expression in all cortical regions and decreased dopamine D2 receptor, substance P and enkephalin mRNA expression in the striatum only in rats lesioned as neonates. These changes were not observed in the adult group with VH lesion.. Our results demonstrate that the postpubertal behavioral changes in this animal model (and possibly schizophrenia) are related to postpubertal onset of changes in the development of functions and interactions of the dopamine and glutamate receptors in the mesocortical system.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Brain Injuries; Dynorphins; Enkephalins; Female; Gene Expression Regulation, Developmental; Hippocampus; Ibotenic Acid; Male; Neuropeptides; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Substance P

Previous studies have observed that the recently described endogenous opioid, nociceptin/orphanin FQ (NOC/oFQ), contributes to impairment of N-methyl-D-aspartate (NMDA)-induced cerebrovasodilation following fluid percussion brain injury (FPI) via a cyclooxygenase (COX)-dependent generation of superoxide anion (O(2)(-)). This study was designed to investigate the relationship between NOC/oFQ, another opioid, dynorphin, and activation of the COX-2 isoform of the enzyme in such impaired dilation to NMDA after FPI in piglets equipped with a closed cranial window. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O(-)(2) generation. Under non-brain injury conditions, NOC/oFQ (10(-10) M), the CSF concentration observed after FPI, increased CSF dynorphin, while the NOC/oFQ antagonist [F/G] NOC/oFQ (1-13) NH(2) attenuated the stimulated release of dynorphin following FPI (34 +/- 3 and 97 +/- 6 vs. 36 +/- 3 and 68 +/- 8 pg/mol for CSF dynorphin before and after FPI in untreated and NOC/oFQ antagonist-pretreated animals). FPI increased SOD-inhibitable NBT reduction, but pretreatment with norbinaltorphimine, a dynorphin antagonist, or NS398, a COX-2 inhibitor, blunted such reduction (1 +/- 1 vs. 19 +/- 3 vs. 4 +/- 1 vs. 4 +/- 1 pmol/mm(2) for control, FPI, FPI-norbinaltorphimine and FPI-NS398, respectively). Under non-brain injury conditions, dynorphin, in a concentration observed in CSF after FPI, also increased SOD-inhibitable NBT reduction, which was blunted by NS398. NMDA-induced pial artery dilation was reversed to vasoconstriction following FPI, but pretreatment with norbinaltorphimine or NS398 partially protected such responses (9 +/- 1 and 16 +/- 1, control; - 8 +/- 1 and - 13 +/- 2, FPI; 6 +/- 1 and 12 +/- 1% FPI-norbinaltorphimine for NMDA 10(-8), 10(-6) M, respectively). These data show that NOC/oFQ modulates the CSF release of dynorphin after FPI. These data also show that dynorphin contributes to O(2)(-) generation after FPI via COX-2 activation. These data additionally indicate that dynorphin and COX-2 activation contribute to impairment of NMDA pial artery dilation after FPI. Finally, these data suggest that NOC/oFQ impairs NMDA dilation postinsult via the sequential release of dynorphin, activation of COX-2, and generation of O(2)(-).

Topics: Animals; Animals, Newborn; Brain Injuries; Cyclooxygenase 2; Dynorphins; Enzyme Activation; Female; Glutamic Acid; Indomethacin; Isoenzymes; Male; N-Methylaspartate; Naltrexone; Nitrobenzenes; Nociceptin; Opioid Peptides; Pia Mater; Prostaglandin-Endoperoxide Synthases; Sulfonamides; Superoxides; Swine; Vasodilation

Previous studies in piglets show that opioid-induced pial artery dilation was impaired following fluid percussion brain injury (FPI). This study was designed to determine the role of the newly described opioid nociceptin orphanin FQ (NOC/oFQ) in such impaired dilation to other opioids after FPI. CSF NOC/oFQ concentration was elevated from 70+/-6 to 444+/-56 pg/ml ( approximately 10(-10) M) within 1 h of FPI. Coadministration of NOC/oFQ (10(-10) M) with methionine enkephalin (10(-10), 10(-8), 10(-6) M) attenuated pial dilation induced by this opioid (7+/-1, 13+/-2, and 19+/-2 vs. 2+/-1, 6+/-1, and 7+/-2%) under non-brain injury conditions. Similar inhibition by NOC/oFQ was observed for leucine enkephalin and dynorphin. Methionine enkephalin (10(-10), 10(-8), 10(-6) M)-induced pial artery dilation was also inhibited within 1 h of FPI, but such responses were partially restored in animals pretreated with the NOC/oFQ receptor antagonist [F/G] NOC/oFQ (1-13) NH(2) (10(-6) M) (8+/-1, 14+/-1, and 21+/-1 vs. 1+/-1, 3+/-1, and 4+/-1 vs. 7+/-1, 11+/-1, and 17+/-1% for sham control, FPI and FPI pretreated with the NOC/oFQ receptor antagonist). Leucine enkephalin and dynorphin-induced pial artery dilation were similarly altered by FPI and partially restored by [F/G] NOC/oFQ (1-13) NH(2). These data indicate that the NOC/oFQ released by FPI contributes to impaired dilation to other opioids observed following this insult.

Topics: Animals; Brain Injuries; Cerebral Arteries; Disease Models, Animal; Dynorphins; Enkephalin, Leucine; Enkephalin, Methionine; Female; Male; Nociceptin; Opioid Peptides; Pia Mater; Swine; Vasodilation

Traumatic brain injury conveys significant morbidity and mortality to infants and children. In the newborn pig, opioids contribute to pial artery vasconstriction after fluid percussion injury (FPI). FPI attenuates vasodilation and cGMP production by methionine enkephalin (Met) and leucine enkephalin (Leu) and reverse dynorphin (Dyn) from a dilator to a constrictor. Superoxide anion (O2-) production contributes to altered cerebral hemodynamics after FPI, and O2- scavengers partially restore decreased dilator responses after FPI. Endothelin-1 (ET-1), a purported mediator of cerebral vasospasm, has been suggested to alter nitric oxide function and cGMP concentration. The present study was designed to determine the contribution of ET-1 to altered opioid-induced dilation after FPI and the role of O2- in such altered responses.. Injury of moderate severity (1.9 to 2.3 atm) was produced by the lateral FPI technique in anesthetized newborn pigs equipped with a closed cranial window. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O2- generation.. FPI increased cerebrospinal fluid ET-1 from 20 +/- 2 to 93 +/- 6 pg/mL (approximately 10(-10) mol/L). Topical ET-1 (10(-10) mol/L) increased SOD-inhibitable NBT reduction from 1 +/- 1 to 16 +/- 3 pmol/mm2, similar to previously reported NBT reduction after FPI (14 +/- 2 pmol/mm2). BQ123 (10(-6) mol/L), an ET-1 antagonist, blunted the NBT reduction observed after FPI (4 +/- 1 pmol/mm2). Met produced pial vasodilation that was attenuated by FPI and partially restored by BQ123 pretreatment (7 +/- 1%, 11 +/- 1%, and 17 +/- 1% versus 3 +/- 1%, 6 +/- 1%, and 9 +/- 2% versus 5 +/- 1%, 9 +/- 1%, and 14 +/- 2% for 10(-10), 10(-8), and 10(-6) mol/L Met during control conditions, after FPI, and after FPI pretreated with BQ123, respectively). Met-induced dilation was associated with increased cerebrospinal fluid cGMP, and these biochemical changes were likewise blunted by FPI and partially restored by BQ123 (357 +/- 12, 455 +/- 15, 500 +/- 19, and 632 +/- 11 versus 264 +/- 4, 267 +/- 4, 295 +/- 12, and 305 +/- 15 versus 309 +/- 19, 432 +/- 11, 529 +/- 10, and 593 +/- 4 pg/mL for resting conditions, 10(-10), 10(-8), and 10(-6) mol/L Met during control conditions, after FPI, and after FPI pretreated with BQ123, respectively). Similar partial restoration of vascular and biochemical parameters was observed for Leu and Dyn.. These data show that ET-1, in concentrations similar to that present in cerebrospinal fluid after FPI, increases O2- production. These data also indicate the opioid-induced vasodilation and cGMP production are partially restored after FPI by ET-1 receptor blockade. These data suggest that ET-1 contributes to altered cerebral hemodynamics after FPI, at least in part, through elevated O2- production.

Topics: Analysis of Variance; Animals; Animals, Newborn; Arterioles; Brain Injuries; Cerebral Arteries; Dynorphins; Endothelin Receptor Antagonists; Endothelin-1; Enkephalin, Leucine; Enkephalin, Methionine; Female; Male; Muscle, Smooth, Vascular; Peptides, Cyclic; Pia Mater; Superoxides; Swine; Vasoconstriction; Vasodilation

The current study was designed to investigate the influence of pretreatment with the oxygen radical scavengers polyethylene glycol superoxide dismutase and catalase (SODCAT) on altered opioid-induced pial artery dilation after fluid percussion brain injury (FPI) in the newborn pig. It has been observed previously that brain injury produces pial artery vasoconstriction in the piglet associated with elevated cerebrospinal fluid opioid levels. Furthermore, opioid-induced vasodilation and cyclic guanosine monophosphate production are attenuated following brain injury. Finally, oxygen free radicals have been implicated in the pathogenesis of brain injury.. Anesthetized piglets equipped with a closed cranial window were connected to a percussion device consisting of a saline-filled cylindrical reservoir with a metal pendulum. Fluid percussion brain injury of moderate severity (1.9-2.3 atm) was produced by allowing the pendulum to strike a piston on the cylinder. Superoxide dismutase-inhibited nitroblue tetrazolium reduction was determined as an index of superoxide generation.. Superoxide dismutase- inhibited tetrazolium was increased markedly after FPI and these increases were blunted by SODCAT (1,000 U/kg and 10,000 U/kg, respectively) treatment 30 min before FPI (1 +/- 1 vs. 14 +/- 2 vs. 1 +/- 1 pmol/mm(2) for control, FPI, and FPI pretreated with SODCAT, respectively). Methionine enkephalin, an endogenous mu opioid agonist, produced vasodilation that was attenuated by FPI and partially restored by SODCAT pretreatment (17 +/- 1, 8 +/- 1, and 14 +/- 1% for methionine enkephalin 10(-6)m during control conditions, after FPI and after FPI pretreated with SODCAT, respectively). Methionine enkephalin-induced dilation was associated with increased cerebrospinal fluid cycle guanosine monophosphate and these biochemical changes were likewise blunted by FPI and partially restored by SODCAT (342 +/- 12 and 640 +/- 13 vs. 267 +/- 6 and 321 +/- 17 vs. 301 +/- 9 and 504 +/- 43 fmol/ml for resting conditions and 10 (-6)M methionine enkephalin during control, after FPI, and after FPI pretreated with SODCAT, respectively). Leucine enkephalin, an endogenous delta agonist, induced pial dilation and associated changes incerebrospinal fluid cyclic guanosine monophosphate, which were similarly altered by FPI and partially restored by SODCAT. Dynorphin, an endogenous kappa agonist, which has been shown to revert from a dilator to a constrictor after FPI, was restored to a vasodilator by SODCAT (18 +/- 1, -11 +/- 4, and 17 +/-5% for dynorphin 10(-6)m during control conditions, after FPI, and after FPI pretreated with SODCAT, respectively). Dynorphin-induced vasodilation was associated with a large increase in cerebrospinal fluid cyclic guanosine monophosphate, which was blunted by FPI and partially restored by SODCAT.. These data show that superoxide anion is produced after brain injury and that opioid-induced vasodilation and cyclic guanosine monophosphate production are partially restored after brain injury in the presence of SODCAT. (Key words: Brain injury: newborn. Circulation: cerebral. Free radicals: oxygen. Gases: nitric oxide. Nucleotides cyclic.

Topics: Animals; Blood Pressure; Brain Injuries; Catalase; Cerebral Arteries; Dynorphins; Female; Free Radical Scavengers; Male; Opioid Peptides; Polyethylene Glycols; Superoxide Dismutase; Swine; Vasodilation

Pial artery constriction following fluid percussion brain injury (FPI) is associated with elevated CSF dynorphin and beta-endorphin concentration in newborn pigs. Additionally, dynorphin is a dilator under control conditions and a vasoconstrictor under decreased cerebrovascular tone conditions. Vasopressin contributes to beta-endorphin-induced pial constriction and the constrictor potential for dynorphin. Recently, it has been observed that FPI reverses vasopressin from a dilator to a constrictor. The present study was designed to characterize the effect of FPI on beta-endorphin-induced constriction and the role of vasopressin in that constriction as well as in the reversal of dynorphin's vascular response following FPI. Brain injury of moderate severity (1.9 - 2.3 atm) was produced in anesthetized newborn pigs equipped with a closed cranial window. Dynorphin in physiologic and pharmacologic concentrations (10(-10), 10(-8), 10(-6) M) was reversed from a dilator to a constrictor following FPI (7 +/- 1, 11 +/- 1, and 16 +/- 1 vs -4 +/- 1, -7 +/- 1, and -11 +/- 1% before and after FPI, respectively). Dynorphin-induced vascular changes were accompanied by increased cortical periarachnoid CSF vasopressin and these biochemical changes were potentiated following FPI (24 +/- 4 vs 134 +/- 7 and 53 +/- 7 vs 222 +/- 14 pg/mliter for control and dynorphin (10(-6) M) before and after FPI, respectively). In contrast, in animals pretreated with the vasopressin receptor antagonist [1-(beta-mercapto-beta beta-cyclopentamethylene propionic acid) 2-(O-methyl)-Tyr-AVP] (MEAVP, 5 micrograms/kg iv), dynorphin-induced constriction following FPI was attenuated (6 +/- 1, 12 +/- 1, and 16 +/- 1, vs -2 +/- 1, -4 +/- 1, and -7 +/- 1% before and after FPI, respectively). Additionally, beta-endorphin-induced pial constriction was potentiated following FPI (-7 +/- 1, -10 +/- 1, -15 +/- 1 vs -10 +/- 1 -15 +/- 2, and -21 +/- 2% for beta-endorphin (10(-10), 10(-8), 10(-6) M) before and after FPI, respectively). beta-endorphin-induced CSF vasopressin release was similarly potentiated following FPI. Further, MEAVP blunted the augmented constrictor responses to beta-endorphin observed following FPI (-5 +/- 1, -9 +/- 1, -14 +/- 1 vs -2 +/- 1, -5 +/- 1, and -8 +/- 1% before and after FPI, respectively). These data indicate that FPI potentiates beta-endorphin-induced pial construction and reverses dynorphin from a dilator to a constrictor. Additionally, these data show that vasopressin contribu

Topics: Animals; Arteries; beta-Endorphin; Brain Injuries; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Dynorphins; Female; Male; Swine; Vasopressins

Previously, it has been observed that newborn pig pial artery constriction after fluid percussion brain injury was associated with elevated CSF dynorphin and beta endorphin concentration. Additionally, brain injury reversed dynorphin-induced pial artery vasodilation to vasoconstriction. The present study was designed to characterize the relationship between opioids and activation of phospholipase C (PLC) and protein kinase C (PKC) in brain injury-induced pial vasoconstriction. Anesthetized newborn pigs equipped with a closed cranial window were connected to a percussion device consisting of a saline-filled cylindrical reservoir with a metal pendulum. Brain injury of moderate severity (1.9-2.3 atm) was produced by allowing the pendulum to strike a piston on the cylinder. Brain injury decreased pial arteriolar diameter within 10 min of injury and continued to fall progressively for 3 h (130 +/- 5, 108 +/- 4 and 102 +/- 5 microns for 0, 10 and 180 min postinjury). In contrast, the PLC inhibitor, neomycin (10(-4) M), blunted brain injury-induced pial vasoconstriction (133 +/- 4, 129 +/- 4 and 135 +/- 5 microns for 0, 10 and 180 min postinjury, respectively). Similarly, staurosporine (10(-7) M), a PKC inhibitor, also blunted brain injury-induced vasoconstriction. beta endorphin (10(-8), 10(-6) M)-induced pial artery vasoconstriction was blunted by neomycin (12 +/- 1, 19 +/- 1 vs. 2 +/- 1, 4 +/- 2% constriction before and after neomycin, respectively). Staurosporine similarly blunted beta endorphin pial constriction (10 +/- 1, 15 +/- 1 vs. 1 +/- 1, 1 +/- 1% constriction before and after staurosporine, respectively). The constrictor potential for dynorphin was also inhibited by neomycin and staurosporine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Newborn; beta-Endorphin; Blood Gas Analysis; Blood Pressure; Brain Injuries; Cerebral Arteries; Dynorphins; Enzyme Activation; Female; Male; Opioid Peptides; Protein Kinase C; Swine; Type C Phospholipases; Vasoconstriction

The endogenous opioid peptide dynorphin has been implicated in the pathophysiology of secondary tissue injury after central nervous system (CNS) trauma. The detrimental effects of dynorphin appear to be mediated through both opioid receptors (probably kappa-receptors) and nonopioid mechanisms. However, both kappa-opioid agonists and antagonists have been reported to improve outcome in models of CNS trauma. To attempt to clarify this controversy, we examined the effects of centrally or systemically administered kappa-opioid agonists on neurological recovery after experimental fluid-percussion brain injury in the rat. Agonists included dynorphin A-(1-17) [Dyn A-(1-17)], which has actions at both kappa 1- and kappa 2-sites, and the selective kappa 1-agonists U-50,488H and U-69,593. des-Tyr-dynorphin A-(2-17) [Dyn A-(2-17)], which is inactive at opioid receptors, was also used. Microinjection of Dyn A-(1-17), but not Dyn A-(2-17) or U-50,488H, into the lateral ventricle 15 min before brain injury significantly worsened motor deficits over a 2-wk period. However, systemic administration of high doses of the kappa-agonists U-50,488H and U-69,593 also significantly worsened neurological outcome. These results fail to demonstrate any protective actions of kappa 1-agonists in this model of experimental traumatic brain injury and suggest that the opioid-related pathophysiological actions of dynorphin may be mediated by kappa 2-opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Behavior, Animal; Benzeneacetamides; Brain; Brain Injuries; Cardiovascular System; Dynorphins; Injections, Intravenous; Injections, Intraventricular; Male; Movement Disorders; Nervous System; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Survival Analysis

Although endogenous opioids have been implicated in the pathophysiology of spinal cord injury and brain ischemia, the role of specific opioid peptides and opiate receptors in the pathophysiology of traumatic brain injury remains unexplored. This study examined regional changes in brain opioid immunoreactivity and cerebral blood flow (CBF) after fluid-percussion brain injury in the cat and compared the effect of an opiate antagonist (Win 44,441-3 [Win-(-)]) with its dextroisomer Win 44,441-2 [Win-(+)] (which is inactive at opiate receptors) in the treatment of brain injury. Dynorphin A immunoreactivity (Dyn A-IR) but not leucine-enkephalin-like immunoreactivity accumulated in injury regions after traumatic injury; Dyn-IR increases also occurred predominantly in those areas showing significant decreases in regional CBF. Administration of Win-(-) but not Win-(+) or saline at 15 min after injury significantly improved mean arterial pressure, electroencephalographic amplitude, and regional CBF and reduced the severity and incidence of hemorrhage. Win-(-) also significantly improved survival after brain injury. Taken together, these findings suggest that dynorphin, through actions at opiate receptors, may contribute to the pathophysiology of secondary brain injury after head trauma and indicate that selective opiate-receptor antagonists may be useful in treatment of traumatic brain injury.

Topics: Animals; Azocines; Blood Flow Velocity; Blood Pressure; Brain; Brain Injuries; Cats; Cerebrovascular Circulation; Dopamine; Dynorphins; Electroencephalography; Endorphins; Enkephalin, Leucine; Female; Intracranial Pressure; Isomerism; Male; Narcotic Antagonists

Delayed injury following trauma to the central nervous system (CNS) may be due to the release or activation of endogenous factors. Endogenous opioid peptides have been proposed as one such class of injury factors, based on pharmacological studies demonstrating a therapeutic effect of naloxone and other opiate receptor antagonists following CNS injury. However, changes in brain opioid concentrations following injury have not been evaluated. In the present study, we measured regional alterations in dynorphin (ir-Dyn), leucine-enkephalin (ir-Enk) and beta-endorphin immunoreactivity (ir-End) following low- (1.0-2.0 atmospheres (atm)) or high- (3.0-4.0 atm) level fluid-percussion brain injury in the cat. A significant decrease in ir-End was observed in the hypothalamus at 2 h following high- but not low-level injury. No changes were observed in tissue ir-Enk following either level of injury. Severe brain trauma but not low-level injury caused a significant increase in ir-Dyn in the striatum, frontal cortex, parietal cortex, pons and medulla. In the anterior pituitary, a significant increase in ir-End and a significant decrease in ir-Dyn was observed at 2 h following both levels of injury. Pathological damage to brain tissue after injury was most pronounced in those regions showing significant increases in ir-Dyn but not other opioids. In the medulla, the increase in ir-Dyn but not ir-End or ir-Enk was also significantly correlated with a fall in systemic mean arterial pressure (MAP) at 2 h following high- but not low-level injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; beta-Endorphin; Blood Pressure; Brain Injuries; Cats; Dynorphins; Enkephalin, Leucine; Osmolar Concentration; Radioimmunoassay; Tissue Distribution

The present study examined the role of endogenous opioid peptides in the pathophysiological sequelae of fluid percussion head injury in the cat. Two hours following injury, tissue concentrations of dynorphin-like immunoreactive material (ir-Dyn) were significantly elevated in specific brain regions where injury, as evidenced by histological examination, was most severe. Changes in ir-Dyn but not beta-endorphin-like immunoreactive material (ir-End) were significantly correlated with a fall in regional cerebral blood flow (CBF) that occurred 2 h following injury. Administration of the opiate antagonist WIN44,441-3 (with enhanced activity at kappa-receptors) stereospecifically increased cerebral blood flow to the injured regions.

Topics: Animals; Azocines; beta-Endorphin; Brain Chemistry; Brain Injuries; Cats; Cerebrovascular Circulation; Dynorphins; Female; Male; Narcotic Antagonists; Receptors, Opioid