Norepinephrine pathway

Figure 3. Norepinephrine pathways of human brain. Published with permission of Lundbeck Institute.

Table 2. Norepinephrine pathways, their targets and functions.

Fig. 2. Biosynthetic pathway for epinephrine, norepinephrine, and dopamine. The enzymes cataly2ing the reaction are (1) tyrosine hydroxylase (TH), tetrahydrobiopterin and O2 are also involved (2) dopa decarboxylase (DDC) with pyridoxal phosphate (3) dopamine-P-oxidase (DBH) with ascorbate, O2 in the adrenal medulla, brain, and peripheral nerves and (4) phenethanolamine A/-methyltransferase (PNMT) with. Cadenosylmethionine in the adrenal...

Analogous side-chain oxidations occur in various biosynthetic pathways. The neurotransmitter norepinephrine, for instance, is biosynthesized from dopamine by a benzylic hydroxylation reaction. The process is catalyzed by the copper-containing enzyme dopamine /3-monooxygenase and occurs by a radical mechanism. A copper-oxygen species in the enzyme first abstracts the pro-R benzylic hydrogen to give a radical, and a hydroxyl is then transferred from copper to carbon. 

Figure 25-7. Metabolism of adipose tissue. Hormone-sensitive lipase is activated by ACTH, TSH, glucagon, epinephrine, norepinephrine, and vasopressin and inhibited by insulin, prostaglandin E, and nicotinic acid. Details of the formation of glycerol 3-phosphate from intermediates of glycolysis are shown in Figure 24-2. (PPP, pentose phosphate pathway TG, triacylglycerol FFA, free fatty acids VLDL, very low density lipoprotein.)...

The conversion of tyrosine to epinephrine requires four sequential steps (1) ring hydroxylation (2) decarboxylation (3) side chain hydroxylation to form norepinephrine and (4) N-methylation to form epinephrine. The biosynthetic pathway and the enzymes involved are illustrated in Figure 42-10. 

Based on the modest ability of the (+)-isomers of MDMA and MBDB to inhibit the reuptake of norepinephrine (NE) into hypothalamic synaptosomes (Steele et al. 1987). it seemed possible that noradrenergic pathways might be involved in the eue. In ano er series of drug discrimination experiments designed to test this hypothesis, the specific NE uptake inhibitor (-)-tomoxctine was tested for stimulus transfer in doses up to 10 mg/kg in MDMA-trained rats. At 5 mg/kg, 67 percent of the animals responded on, the drug lever. However, pretreatment with tomoxetine in six rats trained to discriminate MDMA from saline had no effect on the discrimination of a subsequent dose of MDMA. 

Enhancing the positive effects of serotonin and norepinephrine in the afferent and efferent pathways of the micturition reflex... 

The endogenous release of the potent vasoconstrictor neuropeptide Y (NPY) is increased during sepsis and the highest levels are detected in patients with shock (A8). NPY is a 36-amino-acid peptide belonging to the pancreatic polypeptide family of neuroendocrine peptides (T2). It is one of the most abundant peptides present in the brain and is widely expressed by neurons in the central and peripheral nervous systems as well as the adrenal medulla (A3). NPY coexists with norepinephrine in peripheral sympathetic nerves and is released together with norepinephrine (LI9, W14). NPY causes direct vasoconstriction of cerebral, coronary, and mesenteric arteries and also potentiates norepinephrine-induced vasoconstriction in these arterial beds (T8). It appears that vasoconstriction caused by NPY does not counterbalance the vasodilatator effects of substance P in patients with sepsis. The properties of vasodilatation and smooth muscle contraction of substance P are well known (14), but because of the morphological distribution and the neuroendocrine effects a possible stress hormone function for substance P was also advocated (J7). Substance P, which is a potent vasodilatator agent and has an innervation pathway similar to that of NPY, shows a low plasma concentration in septic patients with and without shock (A8). 

Figure 1. Biosynthetic pathways for biogenic amines. In Drosophila and vertebrates decarboxylation of DOPA and 5-hydroxy-tryptophan is catalyzed by the same enzyme, DDC. In vertebrates this enzyme is called amino acid decarboxylase (AADC). Only vertebrates further metabolize dopamine to norepinephrine and epinephrine. TH, tryosine hydroxylase DDC, DOPA decarboxylase DBH, dopamine b-hydroxylase PNMT, phenylethanolamine N-methyltransferase. Tryp-OH tryptophan hydroxylase.

Figure 9.2 Autonomic nerve pathways. All preganglionic neurons release acetylcholine (Ach), which binds to nicotinic receptors (N) on the postganglionic neurons. All postganglionic neurons in the parasympathetic system and some sympathetic postganglionic neurons innervating sweat glands release Ach that binds to muscarinic (M) receptors on the cells of the effector tissue. The remaining postganglionic neurons of the sympathetic system release norepinephrine (NE), which binds to alpha (a) or beta (P) receptors on cells of the effector tissue. The cells of the adrenal medulla, which are modified postganglionic neurons in the sympathetic system, release epinephrine (EPI) and NE into the circulation.

Beta receptors are also unevenly distributed with P2-receptors the more common subtype on the effector tissues. Beta-two receptors tend to be inhibitory for example, P2-receptor stimulation causes relaxation of vascular smooth muscle and airway smooth muscle, resulting in vasodilation and bronchodilation, respectively. Beta-two receptors have a significantly greater affinity for epinephrine than for norepinephrine. Furthermore, terminations of sympathetic pathways are not found near these receptors, so P2-receptors are stimulated only indirectly by circulating epinephrine instead of by direct sympathetic nervous activity. 

For neurons that synthesize epinephrine or norepinephrine, dopamine P-hydroxylase is the next step in the biosynthetic pathway 213... 

The catecholamines dopamine, norepinephrine and epinephrine are neurotransmitters and/or hormones in the periphery and in the CNS. Norepinephrine is a neurotransmitter in the brain as well as in postganglionic, sympathetic neurons. Dopamine, the precursor of norepinephrine, has biological activity in the periphery, most particularly in the kidney, and serves as a neurotransmitter in several important pathways in the CNS. Epinephrine, formed by the N-methylation of norepinephrine, is a hormone released from the adrenal gland, and it stimulates catecholamine receptors in a variety of organs. Small amounts of epinephrine are also found in the CNS, particularly in the brainstem. 

In cells that synthesize epinephrine, the final step in the pathway is catalyzed by the enzyme phenylethanolamine /V-methyltransferase. This enzyme is found in a small group of neurons in the brainstem that use epinephrine as their neurotransmitter and in the adrenal medullary cells, for which epinephrine is the primary hormone secreted. Phenylethanolamine N-methyltransferase (PNMT) transfers a methyl group from S-adenosylmethionine to the nitrogen of norepinephrine, forming a secondary amine [5]. The coding sequence of bovine PNMT is contained in a... 

FIGURE 12-3 Pathways of norepinephrine degradation. Unstable glycol aldehydes are shown in brackets. COMT, catechol-O-methyltransferase. 

The goal of treatment of SUI is to improve urethral closure by stimulating a-adrenergic receptors in the smooth muscle of the bladder neck and proximal urethra, enhancing supportive structures underlying the urethral epithelium, or enhancing serotonin and norepinephrine effects in the micturition reflex pathways. 

Duloxetine, a dual inhibitor of serotonin and norepinephrine reuptake indicated for depression and painful diabetic neuropathy, is expected to become first-line therapy for SUI. Duloxetine is thought to facilitate the bladder-to-sympathetic reflex pathway, increasing urethral and external urethral sphincter muscle tone during the storage phase. 

The sympathetic nervous system (SNS) and the hypothalamic-pituitary axis work together as important modulators of the immune system after exposure to stressors. Norepinephrine (NE) and epinephrine (EPI) (catecholamines from the SNS) and neuroendocrine hormones modulate a range of immune cell activities, including cell proliferation, cytokine and antibody production, lytic activity, and migration. This chapter will focus on these two major pathways of brain-immune signaling, briefly summarizing the evidence for SNS and hypothalamic-pituitary-adrenal (HPA) modulation of immune function, their influence on immune-mediated diseases, immune modulation in aging, and early life influences on these pathways. 

Known most famously for their part in the fight or flight response to a threat, challenge or anger, adrenaline (epinephrine) and dopamine from the adrenal medulla and noradrenaline (norepinephrine), mainly from neurones in the sympathetic nervous system are known collectively as catecholamines. Synthesis follows a relatively simple pathway starting with tyrosine (Figure 4.7). 

The first step is catalysed by the tetrahydrobiopterin-dependent enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), which is regulated by end-product feedback is the rate controlling step in this pathway. A second hydroxylation reaction, that of dopamine to noradrenaline (norepinephrine) (dopamine [3 oxygenase) requires ascorbate (vitamin C). The final reaction is the conversion of noradrenaline (norepinephrine) to adrenaline (epinephrine). This is a methylation step catalysed by phenylethanolamine-jV-methyl transferase (PNMT) in which S-adenosylmethionine (SAM) acts as the methyl group donor. Contrast this with catechol-O-methyl transferase (COMT) which takes part in catecholamine degradation (Section 4.6). 

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