Month: November 2014

Transmembrane Enzymes Including Receptors

November 28, 2014 Pharmacology No comments , , , ,

1st_Marine_Division_insignia.svgIn general, there are five basic types of receptors. They include 1. a lipid -solube ligand that crosses the membrane and acts on an intracellular receptor (see detail here at http://www.tomhsiung.com/wordpress/2014/10/intracellular-receptors-for-lipid-soluble-agents/); 2. a transmembrane receptor protein whose intracellular enzymatic activity is allosterically regulated by a ligand that binds to a site on the protein’s extracellular domain; 3. a transmembrane receptor that binds and stimulates a protein tyrosine kinase; 4. a ligand-gated transmembrane ion channel that can be induced to open or closed by the binding of a ligand; and 5. a transmembrane receptor protein that stimulates a GTP-binding signal transducer protein (G protein, see the post of http://www.tomhsiung.com/wordpress/2014/09/g-protein-coupled-receptors/), which in turn modulates production of an intracellular second messenger.

Type 2 and type 3 receptors belong to transmembrane enzymes including receptors.

Transmembrane enzymes including receptors contain two types of receptors. One is called enzymes including receptors tyrosine kinases, the other is called cytokinesis receptors. Neoplastic disorders are often correlate with enhanced effects and activities of tyrosine kinases receptors since in these diseases excessive growth factor signaling is often involved (see below).

Enzymes Including Receptor Tyrosine Kinases

The class of transmembrane tyrosine kinases receptor molecules mediates the first steps in signaling by insulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), atrial natriuretic peptide (ANP), and many other trophic hormones. These receptors are polypeptides consisting of an extracellular hormone-binding domain and a cytoplasmic enzyme domain (effector element), which may be a protein tyrosine kinase, a serine kinase, or a guanylyl cyclase. In all these receptors, the two domains are connected by a hydrophobic segment of the polypeptide that crosses the lipid bilayer of the plasma membrane.

The receptor tyrosine kinase signaling pathway begins with binding of ligand, typically a polypeptide hormone or growth factor, to the receptors’ extracellular domain. This results in receptor conformation change that causes two receptor molecules to bind to one another (we call this phenomenon “dimerize”), which in turn brings together the tyrosine kinase domain. And subsequently the tyrosine kinases of the two receptor molecules become enzymatically active, thereafter they phosphorylate one another as well as additional downstream signaling proteins.

The function of the tyrosine kinase connected with the transmembrane receptor is to catalyze phosphorylation of tyrosine residues on different target signaling proteins (the downstream sinaling proteins just mentioned above), thereby allowing a single type of activated receptor (conformation change induced by the ligand) to modulate a number of biochemical processes. Some receptor tyosine kinases form oligomeric complexes larger than dimers upon activation by ligand, but the pharmacological significance of such higher-order complexes is presently unclear.

Regulation of Tyrosine Kinase Receptors

The intensity and duration of action of action of ligands of tyrosine kinase receptors that act via receptor tyrosine kinases are limited by a process called receptor down-regulation. Ligand binding often induces accelerated endocytosis of receptors from the cell surface, followed by the degradation of those receptors (and their bound ligands). When this process occurs at a rate faster than de novo synthesis of receptors, the total number of cell-surface receptors is reduced (down-regulation), and the cell’s responsiveness to ligand is correspondingly diminished.

A well-understood example is the EGF receptor tyrosine kinase, which undergoes rapid endocytosis followed by proteolysis in lysosomes after EGF binding; genetic mutations that interfere with this process cause excessive growth factor-induced cell proliferation and are associated with an increased susceptibility to certain types of cancer.

Endocytosis of other receptor tyrosine kinases, most notably receptors for nerve growth factor, serves a very different function. Internalised nerve growth factor receptors are not rapidly degraded and are translocated in endocytic vesicles from the distal axon, where receptors are activated by nerve growth factor released from the innervated tissue, to the cell body. In the cell body, the growth factor signal is traduced to transcription factors regulating the expression of genes controlling cell survival. This process effectively transports a critical survival signal from its site of release to its site of signalling effect, and does so over a remarkably long distance – up to 1 meter in certain sensory neurons.

Cytokine Receptors

Cytokine receptors respond to a heterogeneous group of peptide ligands, which include growth hormone, erythropoietin, several kinds of interferon, and other regulators of growth and differentiation. These receptors use a mechanism closely resembling that of receptor tyrosine kinases, except that in this case, the protein tyrosine kinase activity is not intrinsic to the receptor molecule. Instead, a separate protein tyrosine kinase, from the Janus-kinase (JAK) family, binds noncovalently to the receptor.

Cytokines first activate the cytosine receptors, then the JAK involved with the cytokine receptors are activated, resulting in phosphorylation of signal transducers and the resultant activation of transcription molecules like STAT. STAT dimers then travel to the nucleus, where they regulate transcription.

 

 

[Physiology] The Sense, The Coding, and The Ascending Tracts

November 27, 2014 Physiology and Pathophysiology No comments , , , , ,

First Part, Sense and Sensory Coding

Converting a receptor stimulus to a recongnizable sensation is termed sensory coding. All sensory systems code for four elementary attributes of a stimulus: 1.modality, the type of energy transmitted by the stimulus;2.location, the site on the body or space where the stimulus originated;3.intensity, which is signaled by the response amplitude or frequency of action;and 4.duration, that is the time from start to end of a response in the receptor.

There is a very important rule first enunciated by Johannes Muller in 1835, called the law of specific nerve energies. The law is that when the nerve from a particular sensory receptor is stimulated, the sensation evoked is that for which the receptor is specialized no matter how or where along the nerve the activity is initiated. For instance, if the sensory nerve from a Pancinian corpuscle in the hand is stimulated by pressure at the elbow or by irritation from a tumor in the brachial plexus, the sensation evoked is touch.

Table 1 Principle Sensory Modalities

Screen Shot 2014-11-26 at 11.38.16 PM

Modality

Humans have four basic classes of receptors based on their sensitivity to one predominant form of energy, including mechanoreceptors, thermorecetpros, chemoreceptor, and photoreceptors (mechanical, thermal, electromagnetic, and chemical). The particular form of energy to which a receptor is most sensitive is called its adequate stimulus. For example, the adequate stimulus for rods and cones in the eyes is light (an example of electromagnetic energy).

However, receptors do respond to forms of energy other than their adequate stimuli, but the threshold for these nonspecific responses is much higher. Pressure on the eyeball will stimulate the rods and cones, but the threshold of these receptors to pressure is much higher than the threshold of the pressure receptors in the skin.

Location

The term sensory unit refers to a single sensory axon and all of its peripheral branches. These branches vary in number but may be numerous, especially in the cutaneous senses. The receptive field of a sensory unit is the spatial distribution from which a stimulus produces a response in that unit.

If the skin is carefully mapped, millimeter by millimeter, with a fine hair, a sensation of touch is evoked from spots overlying these touch receptors. None is evoked from the intervening areas. Similarly, temperature sensations and pain are produced by stimulation of the skin only over the spots where the receptors for these modalities are located. Further more, the area supplied by one sensory unit usually overlaps and interdigitates with the areas supplied by others.

One of the most important mechanisms that enable localization of a stimulus site is lateral inhibition. Information from sensory neurons whose receptors are at the peripheral edge of the stimulus is inhibited compared to information form the sensory neurons at the center of the stimulus. Thus, lateral inhibition enhances the contrast between the center and periphery of a stimulated area and increases the ability of the brain to localize a sensory input. Note that two-point discrimination is based on lateral inhibition.

Intensity

The intensity of sensation is determined by the amplitude of the stimulus applied to the receptor. For example, as a greater pressure is applied to the skin, the receptor potential in the mechanoreceptor increases, and the frequency of the action potentials in a single axon transmitting information to the CNS is also increased. In addition to increasing the firing rate in a single axon, the greater intensity of stimulation also will recruit more receptors into the receptive field.

As the strength of a stimulus is increased, it tends to spread over a large area and generally not only activates the sense organs immediately in contact with it but also "recruits" those in the surrounding area. Furthermore, weak stimuli activate the receptors with the lowest thresholds, and stronger stimuli also activate those with higher thresholds. Some of the receptors activated are part of the same sensory unit, and impulse frequency in the unit therefore increases.

Because of overlap and interdigitation of one unit with another, however, receptors of other units are also stimulated, and consequently more units fire. In this way, more afferent pathways are activated, which is interpreted in the brain as an increase in intensity of the sensation.

Duration

If a stimulus of constant strength is maintained on a sensory receptor, the frequency of the action potentials in its sensory never declines over time. This phenomenon is known as receptor adaptation or desensitisation. The degree to which adaptation occurs varies from one sense to another. Receptors can be classified into rapidly adapting (phasic) receptors and slowly adapting (tonic) receptors. Messier and Pacinian corpuscles are examples of rapidly adapting receptors, and Merkel cells and Ruffini endings are examples of slowly adapting receptors. Other examples of slowly adapting receptors are muscle spindles and nociceptors.

Different types of sensory adaptation likely have some value to the individual. Light touch would be distracting if it were persistent; and, conversely, slow adaptation of spindle input is needed to maintain posture. Similarly, inputs from nociceptor provides a warning that it would lose its value if it is adapted and disappeared.


Second Part, the Ascending Tracts

The sensation evoked by impulses generated in a sensory receptor depends in part on the specific part of the brain they ultimately activate. The ascending pathways from sensory receptors to the cortex are different for the various sensations. All somatosensory (touch, proprioception, temperature, pain, and itch) are mediated by two ascending sensory pathways.

Screen Shot 2014-11-27 at 12.38.26 AMTouch, vibratory sense, and proprioception are mediated by dorsal column medial lemniscal pathway. Pain and temperature are mediated by ventrolateral spinothalamic pathway.

Dorsal Column Pathway

The principal pathway to the cerebral cortex for touch, vibratory sense, and proprioception is the dorsal column pathway. Fibres mediating these sensations ascend ipsilaterally in the dorsal columns of the spinal cord to the medulla, where they synapse in the gracious nuclei (lower body, medial) and cuneate nuclei (upper body, lateral). Also, from peripheral to cerebral cortex, there are total three orders of neurons, like shown in the right figure.

Therefore, the second-order neurons from gracious and cuneate nuclei cross the midline and ascend in the medial lemniscus to the end in the contralateral ventral posterior lateral (VPL) nucleus and related specific sensory relay nuclei of the thalamus. Finally, the third-order neurons from VPL ascend to the cerebral cortex.

One interesting thing of dorsal column pathway is that there is a obvious characteristic, that is, the somatotopic organization. That is, within the dorsal columns, fibres arising from different levels of the cord are somatotopically organised. For instance, fibers from the sacral cord are positioned most medially (gracious nuclei) and those from the cervical cord are positioned most laterally (cuneate nuclei).

Somatotopic organization continues through the thalamus and cerebral cortex. VPL thalamic neurons (third-order neutrons)  carrying sensory information project in a highly specific way to the primary somatosensory cortex in the post central gyrus of the parietal lobe. The arrangement of projections to this region is such that the parts of the body are represented in order along the post central gyrus, with the legs on top and the head at the foot of the gyrus. Also, the size of the cortical receiving area for impulses from a particular part of the body is proportional to the use of the part.

Finally, in addition to the primary somatosensory cortex, there are two other cortical regions that contribute to the integration of sensory information, including sensory association area (located in the parietal cortex) and the secondary somatosensory cortex (located in the wall of the lateral fissure/sylvian fissure), which receive input from the primary somatosensory cortex.

Ventrolateral Spinothalamic Tract

Fibers from nociceptors and thermoreceptors synapse on neurons in the dorsal horn of the spinal cord (shown int the figure at right side). The axons from these dorsal horn neurons (second-order neurons) cross the middling and ascend in the ventrolateral quadrant of the spin cord, where they form the ventrolateral spinothalamic pathway. Then, fibers of second-order neurons synapse in the VPL and the third-order neurons from VPL project to the cortex. Whereas, some dorsal horn neutrons (second-order) that receive nociceptive input synapse in the reticular formation of the brain stem (spinoreticular pathway) and then project to the ventrolateral nucleus of the thalamus.

Studies show that noxious stimuli that did not induce a change in affect caused an increased metabolism in the primary somatosensory cortex, whereas stimuli that elicited motivational-affective responses activated a larger portion of the cortex. This showed that the pathway to the primary somatosensory cortex is responsible for the discriminative aspect of pain. In contrast, the pathway that includes synapses in the brain stem reticular formation and ventrolateral thalamic nucleus projects to the frontal lobe, limbic system, and insular cortex. This pathway mediates the motivational-affective component of pain.

Visceral sensation travels along the same central pathways as somatic sensation in the spinothalamic tracts and thalamic radiations, and the cortical receiving areas for visceral sensation are intermixed with the somatic receiving areas.

How to Install Yosemite on Tonymacx86’s Custo Mac Pro (8GB*2 RAM)

November 23, 2014 Hackintosh No comments , , ,

My PC:

i7 4790k

Kingston 8GB*2 DDR3 1600 (the RAM oc to 1866 automatically)

Giga GTX760 4GB

Giga Z97X-UD3H

840 EVO 120G SSD

550W Power

Source: http://www.tonymacx86.com/yosemite-desktop-guides/145095-success-yosemite-ga-z97x-ud3h-i5-4690-gtx660.html

#1

Hello everyone, that is my guide to successfully install OS X Yosemite for the Gigabyte GA-Z97X-UD3H. It works everything except iMessage and FaceTime, you can enable them following this guide How to Fix iMessage

First of all, remove all the RAM sticks except one.

Follow this guide http://www.tonymacx86.com/445-unibea…-based-pc.html from step 1 to step 4.

IMPORTANT: when you will boot for the 1st time and when you just installed Yosemite (before installing drivers with MultiBeast) boot with these flags: “-x GraphicsEnabler=No”

Install MultiBeast with these options:

Quick Start > DSDT Free
Drivers > Audio > Realtek ALCxxx > ALC1150 (because that’s the audio card we have in our motherboard)
Drivers > Disk > 3rd Party SATA
Drivers > Misc > FakeSMC v6.11.1328
Drivers > Network > Intel > AppleIntelE1000e v3.1.0 (to enable the ethernet connection correctly)
Drivers > AppleRTC Patch for CMOS Reset
Bootloaders > Chimera v4.0.0
Customize > Boot Options > 1080p Display Mode (of course just if you have a 1080p display)
Customize > Boot Options > Basic Boot Options
Customize > Boot Options > Hibernate Mode – Desktop
Customize > Boot Options > IGPEnabler=No
Customize > Boot Options > Kext Dev Mode
Customize > Boot Options > Use KernelCache
Customize > System Definitions > Mac Pro > Mac Pro 3,1 (usually it’s better choose this to avoid kernel panic)
Customize > Themes > tonymacx86 Black (you can choose the one you want)

Then, just in case you have an SSD, check this option:
Drivers > Disk > TRIM Enabler > 10.10.0 TRIM Patch

Now cross your fingers and reboot! Press F12 when the PC is restarting and boot from the drive you installed Yosemite, everything should work fine! I’ll post the guide to enable HDMI audio ASAP. Hope this will help!

EDIT: just in case you have a kernel panic, boot up with -x in safe mode and install this MultiBeast driver:
Drivers > Misc > NullCPUPowerManagement

It is important that the USB3.0 driver must be installed. Otherwise the SD card reading via USB2.0 hub will cause freeze/panic definitely.

PS: The USB2.0 hub is connected to USB3.0 port on the motherboard. If your USB2.0 hub is connected with USB2.0 port on the motherboard, no such freeze/panic.

#2

I ordered the same motherboard/cpu as you have in your computer, so I’m glad I found your guide, because I’m quite a noob when it comes to computers . I will install everything sometime this weekend.

Just wondering, why remove the RAM-sticks except one?

#3

Quote Originally Posted by Steedy View Post

Just wondering, why remove the RAM-sticks except one?

Actually, I don’t know! If you won’t remove the RAM sticks except one, a kernel panic will pop up 

#4

I got two 8GB RAM sticks. So your advice would be to wait with installing the second one until I completed the entire installation?

#5

Quote Originally Posted by Steedy View Post

I got two 8GB RAM sticks. So your advice would be to wait with installing the second one until I completed the entire installation?

Exactly 

#18

Thank you,  agavasan You’re so great.

I follow your method and it works. Yes, the issue is the 16GB of RAM. And there is actually no need to disable on board graphics card (which will make the audio function abnormal).

And the boot flags of “-x GraphicsEnabler=No” is needed before the setup of MultiBeast. Otherwise you will not be able to reach the installer (both the 1st installation and the 2nd installation after the reboot).

Thank you so much. And after the setup of MultiBeast, I shut down my PC then plugged the other 8GB of RAM back then boot again. It’s a miracle that I am able to enter the system. But everyone should be patient that int the Apple bar screen it takes about 2 minute to start so do not turn off your PC. Finally, enjoy your Yosemite.

#20

However, I found a issue that after installation and multibeast setup and then I plugged the other RAM of 8GB back.

Today I modified a kext file in the SLE folder. I had to add my wireless card’s VEN and DEV ID into the IO80211Family.kext’s plist.

After I clicked “More to Tash” of IO80211Family.kext file in the SLE folder, my system freezes. So I wonder if this freeze is caused by the RAM of 8GB*2?

So next time, if I am going to change the SLE folder, I have to unplug a RAM first, then after the installation of the kext files, just plug the RAM back.

Have anyone experienced the same issue?

The Pain – The Basic Concepts

November 8, 2014 Critical Care, Physiology and Pathophysiology No comments , , , , ,

Pain is an unpleasant sensation localized to a part of the body. It is often described in terms of a penetrating or tissue-destructive process (e.g., stabbing, burning, twisting, tearing, squeezing) and/or of a bodily or emotional reaction (e.g., terrifying, nauseating, sickening). Furthermore, any pain of moderate or higher intensity is accompanied by anxiety and the urge to escape or terminate the feeling. These properties illustrate the duality of pain: it is both sensation and emotion. When it is acute, pain is characteristically associated with behavioral arousal and a stress response consisting of increased blood pressure, heart rate, pupil diameter, and plasma cortisol levels. In addition, local muscle contraction if often present.


The Pain Sensory System – The Anatomy

The nervous system has two anatomical divisions: the central nervous system (CNS) and the peripheral nervous system (PNS). CNS consists of the brain and the spinal cord, whereas PNS includes spinal nerves, their roots, and branches; cranial nerves and their branches; and components of the autonomic nervous system (ANS).

Collections of nerve cell bodies in the CNS form nuclei, meanwhile those in PNS form ganglia. Ganglia and nuclei contain either motor or sensory neurons.

Spinal Nerves

Spinal nerves are attached to the spinal cord. They transmit both motor and sensory impulses and are, thus, considered mixed nerves. Most cranial nerves are attached to the brain, of which some are either motor or sensory only, while others are mixed.

The spinal cord is composed of segments, as indicated by the 31 pairs of spinal nerves. Each segment has numerous dorsal and ventral rootlets that arise from the respective surfaces of the spinal cord and these respective rootlets unite to form dorsal and ventral roots. Dorsal rootlets contain neuronal processes that conduct afferent impulses to the spinal cord, whereas the ventral rootlets conduct efferent impulses from the spinal cord.

The dorsal root contains the central processes of sensory neuronal cell bodies that are located in the dorsal root ganglion (DRG). The peripheral processes of these sensory neuronal cell bodies are located in the spinal nerve, its rami, and their branches. These processes end at or form receptors. The ventral root contains motor fibers. Their neuronal cell bodies are found in the gray matter of the spinal cord: ventral horn if the axons innervate skeletal muscle; lateral horn if the axons supply smooth muscle, cardiac muscle, or glands.

Screen Shot 2014-11-03 at 5.08.36 PM

After that, the dorsal and ventral roots join to form a short, mixed spinal nerve. Almost immediately after its formation, the spinal nerve divides into mixed dorsal and ventral rami. Among them, the dorsal rami supply intrinsic (deep) muscles of the back and neck, joints of the vertebral column, and skin on the dorsal surface of the trunk, neck, and head. Ventral rami innervate all other muscles of the neck and trunk (including the diaphragm), skin of the anterior and lateral body walls, and all muscles, and skin of the limbs. Therefore in general, ventral rami are larger than dorsal rami.

Dermatomes

All spinal nerves, with the exception of C1, transmit sensory information from the skin. Most of the skin of the face and scalp is supplied by the trigeminal nerve (one of  12 pairs of cranial nerves).

Cranial Nerves

There are 12 pairs of cranial nerves. The spinal part of CN XI takes origin from upper cervical spinal cord, enters the cranial cavity through foramen magnum and, in the jugular foramen, joins a cranial root from the brain stem. CN II-XII are attached to the brain stem. Cranial nevers are sensory, motor, or mixed.

Autonomic Nervous System

Autonomic Nervous System (ANS) is functional divided rather than anatomic divided. Autonomic nervous system and somatic motor system consist make up the motor (efferent) portion of the PNS.

The ANS has sympathetic, parasympathetic, and enteric (ENS/Enteric Nervous System) divisions. The ENS is a network of neurons located within the wall of the gastrointestinal tract. This part of the ANS can function autonomously, although it interacts with the sympathetic and parasympathetic divisions. Somatic efferent impulses utilize a single neuron to transmit information from the CNS to skeletal muscle. In contrast, sympathetic and parasympathetic efferent information is transmitted through two neurons.

Visceral Afferent fiber conduct sensory information (pain or reflexive) from organs to the CNS. Their neuronal cell bodies are located either in dorsal root ganglia or a sensory ganglion associated with CN IX and X. They are considered part of the ANS, but not classified as sympathetic or parasympathetic.

Adrenal Medulla is unique in that it “acts” as the ganglion. The chromatin cells of the adrenal medulla are equivalent to postganglionic sympathetic neutrons. Upon stimulation by preganglionic sympathetic axons, they release neurotransmitters (epinephrine and norepinephrine) directly into the circulation.


How The Pain Generates?

The stimuli that activate pain receptors vary from one tissue to another. The adequate stimulus for skin is one that has the potential to injure tissue, i.e., pricking, cutting, crushing, burning, and freezing. These stimuli are ineffective when applied to the stomach and intestine, where pain is produced by an engorged of inflamed mucosa, distention or spasm of smooth muscle, and traction on the mesenteric attachment. In skeletal muscle, pain is caused by ischemia, necrosis, hemorrhage, and injection of irritating solutions as well as by injuries of connective tissue sheaths. Prolonged contraction of skeletal muscle evokes an aching type of pain. Ischemia is also the most important cause of pain i cardiac muscle. Joints are insensitive to pricking, cutting, and cautery, but pain can be produced in the synovial membrane by inflammation and by exposure to hypertonic saline. The stretching and tearing of ligaments around a joint can evoke severe pain. Injuries to the periosteum give rise to pain but probably not to other sensation. Blood vessels are a source of pain when pierced by a needle or involved in an inflammatory process. Distention of arteries or veins, as occurs with thrombotic or embolic occlusion, may be sources of pain; other mechanisms of headache relate to traction on arteries or inflammation to he meningeal structures by which they are supported. Pain from intraneural lesions probably arises from the sheaths of the nerves. Nerve root(s) and sensory ganglia, when compressed, give rise to pain.


Pain and The Sensitization

Heuristically, pain can be divided into several distinct sets of events, including acute nociception, tissue injury, nerve injury, and the affective dimensions. Primary afferents are classified by their diameter, degree of myelination, and conduction velocity. The largest-diameter afferent fibers, Aβ, respond maximally to light touch and/or moving stimuli. They are present primarily in nerves that innervate the skin. In normal individuals, the activity of these fibers dose not produce pain. There are two other classes of primary afferents: the small-diameter myelinated Aδ and the unmyelinated C fiber axons. These fibers are present in nerves to the skin and to deep somatic and visceral structures.

The acute activation of Aδ and C fibers generates transient input into the spinal cord, which in turn leads to activation of neurons that project contralaterally to the thalamus and thence to the somatosensory cortex. Besides, a parallel spinofugal projection is to the medial thalamus and from there to the anterior cingulate cortex, part of the limbic system.

PS: Ascending Pathway for Pain. A majority of spinal neurons contacted by primary afferent nociceptors send their axons to the contralateral thalamus. These axons form the contralateral spinothalamic tract, which lies in the contralateral anterolateral white matter of the spinal cord (where the change from one side to the other starts), the lateral edge of the medulla, and the lateral pons and midbrain.

When Aδ fibers are activated, glutamate is released as the neurotransmitter and pain is produced immediately. This type of pain is called first pain, or fast pain/epicritic pain, which is a rapid response and mediates the discriminative aspect of pain or the ability to localize the site and intensity of the noxious stimulus.

Activation of C fibers, which release a combination of glutamate and substance P, is responsible for the delayed second pain (also called slow pain or protopathic pain) which is the dull, intense, diffuse, and unpleasant feeling associated with a noxious stimulus. Itch and tickle are also related to pain sensation.

Molecular Mechanism of Pain

On the organizations and tissues on the endings of nociceptive sensory nerves that respond to noxious thermal, mechanical, or chemical stimuli, there are distribution of a variety of receptors. Many of these are part of a family of nonselective cation channels called transient receptor potential (TRP) channels. This includes TRPV1 receptors (the V refers to a group of chemicals called vanilloids) that are activated by intense heat, acid, and chemicals such as capsaicin. TRPV1 receptors can also be activated indirectly by initial activation of TRPV3 receptors in keratinocytes in the skin.

Noxious mechanical, cold, and chemical stimuli may activate TRPA1 receptors (A, for ankyrin) on sensory nerve terminals. Acid sensing ion channel (ASIC) receptors are activated by pH changes within a physiological range and may be the dominant receptors mediating acid-induced pain.

Purinergic receptors (P2X, an ionotropic receptor, P2Y, an a G protein-coupled receptor) are activated by indirect stimuli. For example, some nociceptive stimuli release intermediate molecules like ATP, etc, and these intermediate molecules then activate purinergic receptors. Another example is the tyrosine receptor kinase A (TrkA), which is activated by nerve growth factor (NGF) that is released as a result of tissue damage.

Itch and tickle can be produced by repeated local mechanical stimulation of the skin, also, a variety of chemical agents including histamine and kinins such as bradykinin, which are released in the skin in response to tissue damage, can produce itch and tickle. Kinins exert their effects by activation of two types of G protein-coupled receptor, B1 and B2. At present we know that the activation of bradykinin B2 receptors is a downstream event in protease-activated receptor-2 (PAR-2) activation, which induce both a nociceptive and a pruritogenic response.

PS: pain-producing substances include histamine, prostaglandins, serotonin, kinins, potassium ions, hight H+, and others.

Screen Shot 2014-11-08 at 11.02.40 PM

Sensitization

Following tissue injury or local inflammation (e.g., local skin burn, toothache, rheumatoid joint, etc.), an ongoing pain state arises that is characterized by burning, throbbing, or aching and an abnormal pain response. This abnormal pain response is called hyperalgesia, or the sensitization, which can be divided into peripheral sensitization and central sensitization. Peripheral sensitization is the results of some active factors such as substance P, prostaglandins, bradykinin, cytokines, H+ ions, and so on. When these substances are released into the injury site, they have the ability to activate the terminal of small high-threshold afferents (Aδ and C fibers) and to reduce the stimulus intensity required to activate these sensory afferents. In addition, the ongoing afferent traffic initiated by the injury leads to the activation of spinal facilitatory cascades, enhancing the excitability of nerve cells in the dorsal horn of the spinal corda and yielding a greater output to the brain for any given input. This facilitation is thought to underlie the hyperalgesic states, which we called it the central sensitization. The pain caused by sensitization usually is called the “nociceptive” pain.

Injury to the peripheral nerve yields complex anatomical and biochemical changes in the nerve and spinal cord that induce spontaneous dysesthesia. This nerve injury pain state may not depend upon the activation of small afferents, but may be initiated by low-threshold sensory afferents like Aβ fibers. Such nerve injuries result in the development of ectopic activity arising from neuromas formed by nerve injury and the dorsal root ganglia of the injured axons as well as a dorsal horn reorganization, such that low-threshold afferent input carried by Aβ fibers evokes a pain state. This dorsal horn reorganization reflects changes in ongoing inhibition and in the excitability of dorsal horn projection neurons. Note that this kind of pain is typically considered to respond less well to opioid analgesics.

Emotional effect

Interestingly, painful stimuli have the certain ability to generate strong emotional components that reflect a distinction between pain as a specific sensation subserved by distinct neurophysiological structures, and pain such as suffering (the original sensation plus the reactions evoked by the sensation, the affective motivational dimension). When pain does not evoke its usual responses such as anxiety, fear, panic, and suffering, a patient’s ability to tolerate the pain may be markedly increased, even when the capacity to perceive the sensation is relatively unaltered.

Besides, a tickling sensation or itch usually is regarded as pleasurable. And the simple scratching relieves itching because it activates large, fast-conducting afferents that gate transmission in the dorsal horn in a manner analogous to the inhibition of pain by stimulation of similar afferents.

Referred Pain

The fundamentals of referred pain is that the axon of each primary afferent contacts many spinal neurons, and each spinal neuron receives convergent inputs from many primary afferents. The convergence of sensory inputs to a single spinal pain transmission neuron is of great importance because it underlies the phenomenon of referred pain. All spinal neurons that receive input from the viscera and deep musculoskeletal structures also receive input from the skin.

The convergence patterns are determined by the spinal segment of the dorsal root ganglion that supplies the afferent innervation of a structure. For example, the afferents that supply the central diaphragm are derived from the third and fourth cervical dorsal root ganglia. Primary afferents with cell bodies in these same ganglia supply the skin of the shoulder and lower neck. Thus, sensory inputs from both the shoulder skin and the central diaphragm converge on pain-transmission neurons in the third and fourth cervical spinal segments.

Because of this convergence and the fact that the spinal neurons are most often activated by inputs from the skin, activity evoked in spinal neurons by input from deep structures is mislocalized by the patient to a place that roughly corresponds with the region of skin innervated by the same spinal segment.

Donnan Effect and The Equilibrium Potential

November 1, 2014 Physiology and Pathophysiology No comments , , , ,

244px-US_101st_Airborne_Division_patch.svgWhen an ion on one side of a membrane cannot diffuse through the membrane, the distribution of other ions to which the membrane is permeable is affected in a predictable way. For example, the negative charge of a nondiffusible anion hinders diffusion of the diffusible cations and favors diffusion of the diffusible anions. See example below:

Donnan Effect

In the example on the left, the membrane (we call it “m”) between compartments X and Y is impermeable to charged proteins (Prot) but freely permeable to K+ and Cl. Assume that the concentrations of the anions and of the cations on the two sides are initially equal. Cl diffuses down its concentration gradient from Y to X, and some K+ moves with the negatively charged Cl because of its opposite charge. Therefore,

[K+X] > [K+Y]

Furthermore,

[K+X] + [ClX] + [ProtX] > [K+Y] + [ClY]

that is, more osmotically active particles are on side X than on side Y. Donnan and Gibbs showed that in the presence of a nondiffusible ion, the diffusible ions distribute themselves so that at equilibrium their concentgration ratios are equal:

[K+X] * [ClX] = [K+Y] * [ClY]

This is the Gibbs-Donnan equation. It holds for any pair of cations and anions of the same valence.

Significance

The Donnan effect on the distribution of ions has tree effects in the body introduced here and discussed below.

1. Because of  charged proteins (Prot) in cells, there are more osmotically active particles in cells than in interstitial fluid, and because animal cells have flexible walls, osmosis would make them swell and eventually rupture if it were not for Na, K ATPase pumping ions back out of cells. Thus, normal cell volume and pressure depend on Na, K ATPase.

2. Because at equilibrium the distribution of permeant ions across the membrane (m in the example used here) is asymmetric, an electrical difference exists across the membrane whose magnitude can be determined by the Nernst equation. In the example of the figure, side X will be negative relative to side Y. The charges line up along the membrane, with the concentration gradient for Cl exactly balanced by the oppositely directed electrical gradient, and the same holds true for K+.

3. Because there are more proteins in plasma than in interstitial fluid, there is a Donnan effect on ion movement across the capillary wall.

Genesis of The Membrane Potential

The distribution of ions across the cell membrane and the nature of this membrane provide the explanation for the membrane potential. The resting membrane potential is -70 mV. The concentration gradient for K+ facilitates its movement out of the cell via K+ channels (chemical gradient), but its electrical gradient is in the opposite (inward) direction. Consequently, an equilibrium is reached in which the tendency of K+ to move out of the cell (chemical gradient) is balanced by its tendency to move into the cell (electrical gradient), and at that equilibrium there is a slight excess of cation on the outside and anions on the inside. The slight excess of cation on the outside and anions on the inside is maintained by Na, K ATPase, and because the Na, K ATPase moves three Na+ out of the cell for every two K+ moved in, therefore it also contributes to the membrane potential and thus is termed an electrogenic pump.

Attention must be paid that the number of ions responsible for the membrane potential is a minute fraction of the total number present and that the total concentrations of positive and negative ions are equal everywhere except along the membrane.

The resting membrane potential is -70 mV, and the equilibrium potential of Na+, K+, and Cl  are list in the figure below.Screen Shot 2014-11-01 at 1.54.43 PM According to the relationship between the equilibrium potential and the resting membrane potential, the electrical gradient of Na+ is inward, as same as the chemical gradient of it. Conversely, the electrical gradient of K+ is outward since the equilibrium potential of K+ is -90 mv and the actual resting potential is -90 mv, whose power is somewhat smaller than the force of chemical gradient.

Therefore, plenty of Na+ would come into the cell automatically, a few of K+ would come out of the cell spontaneously too. Thank goodness to the Na, K ATPase, which maintain the natural distribution of ions across the cell membrane, and the resting membrane potential.