Why Do Nerve Signals Get Crossed?

Why Do Nerve Signals Get Crossed?

We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

First off, I don't know if this is a normal healthy thing to occur. There have been many times where I have an itch on say my arm and I scratch it, only to feel the scratching elsewhere on my body. I assume somewhere along the transit of the touch signals to my brain the signal gets mixed up and is processed incorrectly.

So my questions are:

  • Why does this mixup happen? (chemical imbalance, damaged nerves, etc… )
  • How does my brain correspond the touch to somewhere else? (what is the process behind it)

Well nerve crossing or misinterpretation of nerve signal by the brain does not happen all the time. In case it happens frequently then I guess it would be Multiple Sclerosis or might be Fibromyalgia syndrome. In multiple sclerosis, the Myelin sheath surrounding neuron when gets damaged causes certain problem with nerve signal transmission to the brain. But that is not the main cause. The main cause can be found in Neuropathy:

When nerve cells are damaged, perhaps by a temporary restriction in their access to oxygen, they too atrophy or shrink a little, thus the synaptic junctions widens. Just like with a spark plug in your car or lawn mower, if this gap gets too wide, the spark cannot make the jump. A normal sized nerve signal cannot jump this enlarged gap either, so the signal either does not get through or it gets misdirected to another part of the body and is misinterpreted as pain.

So I can say that the nerve cells in the place where you feel real pain fails to transmit the signal to brain via its neighboring nerve cell instead that signal passes through some other node randomly (or it might take the same path every time you touch the pain area) and signal the brain which gets misinterpreted and make you feel that you have pain in the misinterpreted region.

This is part of a neuro issue… like seeing numbers in color, or touching something but feeling it in another part of your body. The sensations are processed in the brains communication area and ifeas/sensations get mixed or crossed. 4% of the population has these experiences. You aren't odd; you're exceptional.

How Does a Nerve Impulse Cross a Synapse?

Nerve impulses travel directly across connected synapses via electricity, while the impulses use special chemicals to cross non-touching synapses, according to the Science Museum of the South Kensington Museum in London. These chemicals are called neurotransmitters, and they can change the way nerves communicate with each other in the brain. The neuron that sends the message is usually called the presynaptic neuron, while the receiving neuron is called the postsynaptic neuron.

The Science Museum website explains that impulses that reach a synapse located at the end of a nerve cell, which necessitates that the impulse must travel across a gap, stimulate the neuron to produce and secrete a neurotransmitter. This neurotransmitter drifts across the gap, eventually contacting the postsynaptic neuron. When the neurotransmitter reaches the post-synaptic neuron, it converts the energy held in its chemical bonds into an electrical impulse. This impulse then continues down the post-synaptic neuron to its target. The postsynaptic neuron features a gap that only accommodates the correct neurotransmitter, eliminating the chance that it is stimulated inadvertently by the wrong neurotransmitter.

The body uses more than 50 neurotransmitters, according to the Science Museum. While electrical impulses are a quicker way to send and receive signals, neurotransmitters provide greater flexibility. For instance, neurotransmitters are better able to send more complex signals. Such abilities allow the human eye to distinguish between light and dark.

How do nerves control every organ and function in the body?

Nerves do not control every tissue and function in the human body, although they do play a large role. There are three main ways that bodily organs and functions are controlled:

  1. Through the central nervous system
  2. Through the endocrine system
  3. Through local self-regulation (which includes intracrine, autocrine, paracrine, and immune regulation)

Nerves carry orders from the brain and spinal cord in the form of electrical signals. Nerves also help sense the state of tissues and relay this information back to the brain and spinal cord, enabling us to experience pain, pleasure, temperature, vision, hearing, and other senses. The body uses electrical signals sent along nerves to control many functions because electrical signals can travel very quickly. At the end of each nerve's axon terminals the electrical signals are converted to chemical signals which then trigger the appropriate response in the target tissue. However, the control exerted by the nervous system inevitably resides in the brain and spinal cord, an not in the nerves, which just pass along the signals. Most signals get processed in the brain, but high-risk signals are processed and responded to by the spinal cord before reaching the brain in the effect we call "reflexes". Although the central nervous system plays a large role in controlling the body, it is not the only system that exerts control.

The endocrine system is a series of endocrine glands throughout the body that excrete certain chemical signals called hormones into the blood stream. The circulating blood then takes the hormones throughout the entire body where different tissues respond in characteristic ways to the hormones. The response of an organ or system to a hormone depends on how much of that hormone is present in the blood. In this way, endocrine glands can exert control over different organs and functions of the body by varying how much hormone they emit. In contrast to the central nervous system, the pathway of control for the endocrine system is purely chemical and not electrical. For example, the thyroid gland in the neck controls how quickly the body uses energy by secreting varying levels of thyroid hormone. Too much thyroid hormone, and you become restless, jittery, and unable to sleep. Too little thyroid hormone and you become sleepy, lethargic, and enable to think straight. A healthy body constantly monitors the activity level and adjusts the thyroid hormone levels as needed.

Other examples of endocrine glands are the adrenal glands, which prepare the body for facing an emergency, and the reproductive glands, which control body mass and reproduction. Hormones in the body control functions as diverse as libido, fertility, menstruation, ovulation, pregnancy, child birth, lactation, sleep, blood volume, blood pressure, blood sugar, the immune system, vertical growth in children, muscle mass, wound healing, mineral levels, appetite, and digestion. Ultimately, much of the endocrine system is subservient to the brain via the hypothalamus, but the endocrine system does operate somewhat independently using feedback loops.

Lastly, organs and functions in the body are controlled through local self-regulation. Rather than depend on the brain to dictate every single minute task, organs and cells can accomplish a lot on their own so that the brain is freed up for more important tasks. An organ can communicate regulatory signals through its interior using localized chemical signals such as paracrine hormone signalling. Typically, such hormones do not enter the blood stream, but are transported locally by simply flowing in the space between cells. This approach works because paracrine hormones are only meant to operate on nearby cells. For example, the clotting of blood and healing of wounds are controlled locally through an exchange of paracrine hormones. The organ with the highest degree of self-regulation is probably the liver. The liver hums along nicely, performing hundreds of functions at once without much direction from the rest of the body. An organ can also communicate through its interior electrochemically. For instance, the heart does not beat because a nerve is telling it to. The heart beats on its own through a cyclic wave of electrical impulses. While it is true that the brain can tell the heart to speed up or slow down, the actual beating of the heart is controlled locally.

Also, each cell of the body has some degree of self-regulation internal to the cell itself. Some cells exert more internal control than others. For instance, white blood cells hunt down and destroy germs in a very independent fashion, as if they were autonomous organisms. Active white blood cells do not wait for the brain or a hormone to tell them to do their job. Sperm cells are so autonomous that they can continue to survive and function properly even after completely leaving the male's body.

In reality, the central nervous system, the endocrine system, and the local regulation systems are not independent, but exert control over each other in a complicated manner.

How is a message transferred across a synapse?

A synapse is a junction between the end of one neuron (known as the pre-synaptic neuron) and either another neuron (known as the post-synaptic neuron) or another tissue such as muscle (such as at the neuromuscular junction - the clue is in the name!). Either way, electrical signals are being transferred to chemical signals and then transferred back to electrical signals so that the original message can be passed on.
The word synapse ecompasses everything going on to transfer the signal at this junction. The synaptic cleft is the space in between the pre-synaptic terminal and the post-synaptic terminal. This space is tiny, only about 10-50nm (over 100 times smaller than a millimetre).
So how does it work?
The electrical signal - an action potential - arrives at pre-synaptic axon terminal. This opens channels that are known as voltage gated calcium channels. They are voltage gated becuase they respond to changes in voltage at the nerve terminal and they are calcium channels because only calcium ions can flow through them.
When these channels open, calcium flows into the pre-synaptic terminal. Calcium then binds to a protein called synaptotagmin which detects the rise in calcium. This then leads to proteins known as the SNARE proteins to fuse. This SNARE protein complex guides vesicles of acetylcholine (a neurotransmitter) right to the end of the nerve terminal where they bind with the membrane and are released into the synaptic cleft. This is known as exocytosis. Acetylcholine diffuses across the cleft to the post synaptic terminal where it binds with receptors known as nicotinic acetylcholine receptors. The cleft is small so that the neurotransmitter reaches its target easily. When binding occurs, sodium flows through the channels, depolarising the membrane and causing muscle contraction to occur.
When we have opertions, it is important that muscle contraction doesn't occur so drugs like tubocurarine act to block these receptors.
Botox is another example of disruption of the neuromuscular junction. Botox (actually called botulinum toxin) stops fusion of the vesicles with the membrane so exocytosis cannot occur. This paralyses the muscles and some people use this to smooth their skin or to stop twitches.
Why have synapses at all? Why not just have direct electrical connections between nerves and muscle? Well, synapses hugely increase the diversity of signals that can be sent within the body. The best example is in the brain. An adult brain has one hundred billion neurons and each one of these has roughly 7000 synapses connecting with other neurons. Messages are sent and filtered via these synapses to allow normal functioning of the brain. New synapses are made all the time when we create memories or learn something new. Synapses are more easily made when we're young so that's why people say it's easier to learn languages when you're young. Synapses can be lost too, especially in diseases like Alzheimer's Disease which affects your memory.
I hope that is helpful. Looking at a picture of the process can make it easier to understand so check out your textbook or look up on google images.

Cold Sensors

Photo Credit:

Why can you feel cold even when you're sitting in a warm room? Scientists may have discovered the answer.


Why chills are more than skin deep. I'm Bob Hirshon and this is Science Update.

You've heard of being chilled to the bone. But it turns out you can also be chilled from inside the bone&mdashthe spine, to be exact.

University of Florida neuroscientist Jiango Gu and his colleagues were looking for sensory molecules, called receptors, that can sense cold. And they found them not only in the nerve cells just under the skin, but also inside the spinal cord, which is insulated from chilly environments.

And so this is interesting: why (do) we need cool or cold receptors inside the spinal cord where the temperature is constant?

He suspects that this could explain chills that are unrelated to external temperatures, like the ones you feel when you're sick or scared. Next, Gu's team plans to look for natural chemicals in the body that can trigger these cold receptors.

This is the first big step, because there are so many substances inside your body, and to identify a single substance or a few substances that can activate these receptors is going to be a difficult task.

If they succeed, they can then find out if surges in these chemicals really do give you the chills. I'm Bob Hirshon for AAAS, the Science Society.

Making Sense of the Research

Does this sound familiar? You and a friend are sitting in the same room, wearing similar clothes, and one of you is perfectly comfortable, but the other feels chilly. And twenty minutes later, the difference might disappear. If the temperature in the room isn't making you feel cold, what is? That's the question this research sets out to answer.

Feelings like warmth and cold are triggered by electrical signals carried by sensory nerves. At the endings of these nerves are specialized cells called receptors, which are activated either by extreme temperatures or by certain chemicals. Peripheral nerve endings are located just under the skin, or in other places that can receive signals directly from the environment.

Central nerve endings, on the other hand, are located within the spinal cord. Because they're deep inside the body, they can't sense the temperature in the room, or a substance that's on your skin. Instead, they respond to chemical signals that happen inside you.

The receptors on peripheral nerve endings that can sense cold are well known to scientists. They respond to cold temperatures, whether it's the air on a winter day, an ice cube on your skin, or the water in a chilly swimming pool. Interestingly, they also respond to menthol&mdashthe active ingredient in cough drops. (That's why your mouth feels cool when you suck on them.)

What Dr. Gu has discovered is that these cold receptors are also found on the central nerve endings, deep inside the body. Since the temperature outside can't affect these receptors, and menthol isn't normally found inside the human body, why are they there? That's the question Dr. Gu wanted to answer.

The most likely possibility is that there are certain chemicals inside our body that can trigger these central cold receptors. Maybe some of these chemicals are released when we have a fever, which would explain why we get chills even though our body temperature is higher than normal. Maybe some of them are released in more ordinary circumstances. Dr. Gu notes that other scientists have identified a natural body chemical that activates heat receptors in the central nervous system. So it would make sense that other substances in our bodies can trigger the feeling of cold.

The problem is figuring out what these chemicals are. Testing every known body chemical on these cold receptors would be like looking for a needle in a haystack. To narrow down the field, Dr. Gu's team looked at chemicals that are similar to the one that activates heat receptors.

Now try and answer these questions:

  1. What is the difference between central and peripheral nerve endings?
  2. What are receptors? How do they relate to feelings of warmth or cold?
  3. What is the key finding of this study? What was known previously? What remains unanswered?
  4. Imagine that scientists found a natural body chemical, called Frigidin, that activated these cold receptors. What experiment would you design to see if Frigidin causes the sensation of feeling cold?

Cool Menthol 1 and Cool Menthol 2, a pair of stories by the Australian Broadcasting Corporation's Dr. Karl Kruszelnicki, features more information about menthol and its effect on cold receptors.

Nerves in the Human Body

Would you like to write for us? Well, we're looking for good writers who want to spread the word. Get in touch with us and we'll talk.

This section is wholly dedicated to the nerves in our body that control and organize all the organs. They include:

  • Spinal Nerve
  • Common Plantar Digital Nerve
  • Facial Nerve
  • Femoral Nerve
  • Lateral Plantar Nerve
  • Medial Plantar Nerve
  • Musculocutaneous Nerve
  • Posterior Femoral Cutaneous Nerve
  • Pupandal Nerve
  • Saphenous Nerve
  • Sciatic Nerve
  • Sural Nerve
  • Ulnar Nerve

I shall begin with a detailed description on spinal nerves along with a nerve chart for the same.

Show/hide words to know

Cerebral Cortex: the outer layers of the brain responsible for important brain functions, like thinking and feeling. more

Cranial: relating to the skull (cranium) or brain. The cranial nerves carry signals between the brain and body.

Gland: an organ that releases materials for use in certain places in the body or on the outside of the body. more

Neurotransmitter: a chemical that acts as a messenger and communicates information throughout the brain and body. Nerve tissue uses neurotransmitters to communicate. more

Receptor: a molecule on the surface of a cell that responds to specific molecules and receives chemical signals sent by other cells.

Thalamus: is the part of the brain that works like a switching station. This part of the brain takes information coming from the body and sends it on to the cerebral cortex. more


Since acetylcholinesterase has an essential function, it is a potential weak point in our nervous system. Poisons and toxins that attack the enzyme cause acetylcholine to accumulate in the nerve synapse, paralyzing the muscle. Over the years, acetylcholinesterase has been attacked in many ways by natural enemies. For instance, some snake toxins attack acetylcholinesterase. The picture at the top shows a view straight down the active site tunnel, from PDB entry 1b41 , showing the active site serine in red. The middle picture shows how a lethal toxin from the eastern green mamba blocks the active site and poisons the action of the enzyme. For more information on snake toxins, take a look at the Protein of the Month at the European Bioinformatics Institute.

Doctors are now willfully poisoning acetylcholinesterase in an attempt to reverse the symptoms of Alzheimer's disease. People with Alzheimer's disease lose many nerve cells as the disease progresses. By taking a drug that partially blocks acetylcholinesterase, the levels of the neurotransmitter can be raised, strengthening the nerve signals that remain. One drug being used in the way is shown at the bottom, from PDB entry 1eve . It inserts into the active site pocket and temporarily blocks entry of acetylcholine. Other poisons, as shown next, take a more permanent approach.

Exploring the Structure

The nerve toxin sarin and insecticides such as malathion directly attack the active site machinery of acetylcholinesterase. The structure shown here, from PDB entry 1cfj , shows the active site triad of acetylcholinesterase after being poisoned by sarin. In the normal reaction, the serine amino acid forms a bond to the acetyl group of acetylcholine, breaking the molecule. Then, in a matter of microseconds, a water molecule breaks the new bond, releasing acetic acid and restoring the serine to its original form. Sarin, however, transfers a nasty methylphosphonate group (MeP in the picture) to the serine. The phosphonate is far more stable and will disable the enzyme for hours or days.

This picture was created with RasMol. You can create similar pictures by clicking on the accession codes and picking one of the options for 3D viewing.

Related PDB-101 Resources

  • More about Acetylcholinesterase
  • Browse Cellular Signaling
  • Browse Enzymes
  • Browse Toxins and Poisons
  • Browse You and Your Health
  • Browse Drugs and the Brain


  1. P. Taylor (1991) The Cholinesterases. Journal of Biological Chemistry 266, 4025-4028.
  2. P. Taylor and Z. Radic (1994) The Cholinesterases: From genes to Proteins. Annual Review of Pharmacology and Toxicology 34, 281-320.
  3. K. L. Davis (2002) Current and Experimental Therapeutics of Alzheimer Disease. In Neuropsychopharmacology, K.L. Davis, D. Charney, J.T. Coyle, C. Nemeroff editors. Lippincott, Williams and Wilkins, publishers.
  4. J. L. Sussman, M. Harel, F. Frolow, C. Oefner, A. Goldman, L. Toker and I. Silman (1991) Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science 253, 872-879.

About PDB-101

PDB-101 helps teachers, students, and the general public explore the 3D world of proteins and nucleic acids. Learning about their diverse shapes and functions helps to understand all aspects of biomedicine and agriculture, from protein synthesis to health and disease to biological energy.

Why PDB-101? Researchers around the globe make these 3D structures freely available at the Protein Data Bank (PDB) archive. PDB-101 builds introductory materials to help beginners get started in the subject ("101", as in an entry level course) as well as resources for extended learning.

Boston University Medical CampusSexual Medicine

Female sexual dysfunction is defined as disorders of sexual desire, arousal, orgasm and/or sexual pain, which results in significant personal distress and may have an impact on the quality of life and interpersonal relationships. Although each specific condition can be separately defined in medical terms, clinically there is significant overlap in afflicted patients. The limited available data on female anatomy, physiology, biochemistry and molecular biology of the female sexual response makes this field particularly challenging to clinicians, psychologists and basic science researchers alike.

The sexual response cycle consists of desire, arousal, orgasm and resolution (both physiologic and psychologic). Desire is the mental state created by external and internal stimuli that induces a need or want to partake in sexual activity. Desire may be said to consist of: 1) biologic roots, which in part are based on hormones such as androgen and estrogen, 2) motivational roots, which are in part based on intimacy, pleasure and relationship issues and 3) cognitive issues such as risk and wish. Arousal is the state with specific feelings and physiologic changes usually associated with sexual activity involving the genitals. Arousal may be said to consist of: 1) central mechanisms including activation of thoughts, dreams and fantasies, 2) non-genital peripheral mechanisms such as salivation, sweating, cutaneous vasodilation and nipple erection and 3) genital mechanisms such as clitoral, labial and vaginal engorgement. Orgasm is the altered state of consciousness associated with primarily genital sensory input. Orgasm consists of multiple sensory afferent information from trigger points such as clitoris, labia, vagina, periurethral glans, etc., which pass centrally to supraspinal structures likely involving the thalamic septum. Following sufficient sensory stimulation, central neurotransmitter discharge during orgasm results in repeated 1-second motor contractions of the pelvic floor (3 – 8/orgasm) followed in 2 – 4 seconds by repeated uterine and vaginal smooth muscle contraction. Pleasurable sensory information is also carried to the cortical pleasure sites.

Epidemiology of Female Sexual Dysfunction

Well-designed, random-sample, community-based epidemiologic investigations of women with sexual dysfunction are limited. Current data reveals that up to 76% of women have some type of sexual dysfuntion. U.S. population census data suggest that approximately 10 million American women ages 50-74 self-report complaints of diminished vaginal lubrication, pain and discomfort with intercourse, decreased arousal, and difficulty achieving orgasm. Recently, Laumann and Rosen found that sexual dysfunction is more prevalent in women (43%) than in men (31%) and is associated with various psychodemographic characteristics such as age, education, and poor physical and emotional health. More importantly, female sexual dysfunction is associated with negative sexual relationship experiences.

Anatomy and physiology of genital sexual arousal

There is a paucity of data concerning the anatomy, physiology, pathophysiology of sexual function in women. The female external genitalia consist of various structures. The vagina is a midline cylindrical organ that connects the uterus with the external genitalia. The vaginal wall consists of three layers: a) an inner mucous type stratified squamous cell epithelium supported by a thick lamina propia, that undergoes hormone-related cyclical changes, b) the muscularis composed of outer longitudinal smooth muscle fibers and inner circular fibers, and c) an outer fibrous layer, rich in collagen and elastin, which provides structural support to the vagina. The vulva, bounded by the symphysis pubis, the anal sphincter and the ischial tuberosities, consists of labial formations, the interlabial space, and erectile tissue. The labial formations are two paired cutaneous structures: a) the labia majora are fatty folds covered by hair-bearing skin that fuses anteriorly with the mons veneris, or anterior prominence of the symphysis pubis, and posteriorly with the perineal body or posterior commissure b) The labia minora are smaller folds covered by non-hearing skin laterally and by vaginal mucosa medially, that fuses anteriorly to form the prepuce of the clitoris, and posteriorly in the fossa navicularis. The interlabial space is composed of the vestibule, the urinary meatus, and vaginal opening and is bounded by the space medial to the labia minora, the fossa navicularis and the clitoris. The clitoris is a 7-13 cm Y shaped organ comprised of glans, body, and crura. The body of the clitoris is surrounded by tunica albuginea and consists of two paired corpora cavernosa composed of trabecular smooth muscle and lacunar sinusoids. Finally, the vestibular bulb consists of paired structures located beneath the skin of the labia minora and represents the homologue of the corpus spongiosum in the male.

There is limited understanding of the precise location of autonomic neurovascular structures related to the uterus, cervix, and vagina. Uterine nerves arise from the inferior hypogastric plexus formed by the union of hypogastric nerves (sympathetic T10-L1) and the splanchnic fibers (parasympathetic S2-S4). This plexus has three portions: Vesical plexus, the rectal plexus, and the uterovaginal plexus (Frankenhauser’s ganglion), which lies at the base of the broad ligament, dorsal to the uterine vessels, and lateral to the uterosacral and cardinal ligament. This plexus provides innervation via the cardinal ligament and uterosacral ligaments to the cervix, upper vagina, urethra, vestibular bulbs and clitoris. At the cervix, sympathetic and parasympathetic nerves form the paracervical ganglia. The larger one is called the uterine cervical ganglion. It is at this level that injury to the autonomic fibers of the vagina, labia, cervix may occur during hysterectomy. The pudendal nerve (S2-S4) reaches the perineum through Alcock’s canal and provides sensory and motor innervation to the external genitalia.

Large gaps exist in our knowledge of how the central nervous system controls female sexual function. Limited data suggest that descending supraspinal modulation of female genital reflexes emanates from: 1) brainstem structures such as the nucleus paragigantocellularis (inhibitory via serotonin), locus ceruleus (norepinephrine, nocturnal engorgement during REM sleep) and midbrain periaqueductal gray, 2) hypothalamic structures such as the medial pre-optic area, ventromedial nucleus and paraventricular nucleus and 3) forebrain structure such as the amygdala. Multiple factors interact at the supraspinal levels to influence the excitability of spinal sexual reflexes such as: 1) gonadal hormones, 2) genital sensory information via the mylenated spinothalamic pathway and the unmyelinated spinoreticular pathway and 3) input from higher cortical centers of cognition.

The sexual arousal responses of the multiple genital and non-genital peripheral anatomic structures are largely the product of spinal cord reflex mechanisms. The spinal segments are under descending excitatory and inhibitory control from multiple supraspinal sites. The afferent reflex arm is primarily via the pudendal nerve. The efferent reflex arm consists of coordinated somatic and autonomic activity. One spinal sexual reflex is the bulbocavernosus reflex involving sacral cord segments S 2,3 and 4 in which pudendal nerve stimulation results in pelvic floor muscle contraction. Another spinal sexual reflex involves vaginal and clitoral cavernosal autonomic nerve stimulation resulting in clitoral, labial and vaginal engorgement.

In the basal state, clitoral corporal and vaginal smooth muscles are under contractile tone. Following sexual stimulation, neurogenic and endothelial release of nitric oxide (NO) plays an important role in clitoral cavernosal artery and helicine arteriolar smooth muscle relaxation. This leads to a rise in clitoral cavernosal artery inflow, an increase in clitoral intracavernosal pressure, and clitoral engorgement. The result is extrusion of the glans clitoris and enhanced sensitivity.

In the basal state, the vaginal epithelium reabsorbs sodium from the submucosal capillary plasma transudate. Following sexual stimulation, a number of neurotransmitters including NO and vasoactive intestinal peptide (VIP) are released modulating vaginal vascular and nonvascular smooth muscle relaxation. Dramatic increase in capillary inflow in the submucosa overwhelms Na-reabsorption leading to 3-5 ml of vaginal transudate, enhancing lubrication essential for pleasurable coitus. Vaginal smooth-muscle relaxation results in increased vaginal length and luminal diameter, especially in the distal two-thirds of the vagina (Fig. 1). Vasoactive intestinal polypeptide is a non-adrenergic non-cholinergic neurotransmitter that plays a role in enhancing vaginal blood flow, lubrication and secretions.

Experimental models for investigation of female sexual genital arousal

I Results from in vivo animal studies:
The absence of established animal models to investigate female sexual genital arousal has hampered progress in this field. Recently, Park et al., investigated vaginal and clitoral hemodynamics in female New Zealand White rabbits in response to pelvic nerve stimulation (PNS) in order to mimic genital arousal in response to sexual stimulation. This elegant study showed that pelvic nerve-stimulation caused an increase in vaginal blood flow, vaginal wall pressure, vaginal length, clitoral intracavernosal pressure and clitoral blood flow and a decrease in vaginal luminal pressure. This study represents an approach to study genital arousal in an animal model and paved the way for the investigation of genital arousal in a laboratory setting. Using a rat model, Vachon et al., confirmed genital hemodynamic changes reported by Park et al., in the rabbit model. More recently, Giuliano et al., further demonstrated that PNS induced an increase in vaginal wall tension and a decrease in vaginal vascular resistance in the rat model. In addition, this study showed that atropine did not significantly affect vaginal blood flow response to pelvic nerve stimulation despite the fact that cholinergic fibers innervate vascular smooth muscle in the rat vagina, suggesting that acetylcholine may not be the primary neurotransmitter responsible for the increase in vaginal engorgement during sexual arousal. These studies documented that genital arousal is a neurovascular event characterized by increase in genital blood flow and smooth muscle relaxation. These hemodynamic changes are mediated by neurotransmitters and vasoactive agents and modulated by the hormonal milieu. Park et al., investigated the effects of estrogen deprivation and replacement on genital hemodynamics. They reported that ovariectomy significantly reduced vaginal and clitoral blood flow in response to pelvic nerve stimulation. We also investigated the effects of ovariectomy and estrogen and androgen treatment on genital blood flow using a novel, non-invasive laser oximetry technique. In contrast to the observations made by Park et al. we found that ovariectomy did not significantly alter genital blood flow in the rabbit model. The discrepancy may be attributed to differences in methodologies. In our studies, we determined genital blood flow two-weeks post ovariectomy, while Park et al. performed their studies six weeks after ovariectomy. The longer period of estrogen deprivation may have produced tissue structural changes that altered the engorgement response. Since the female rabbit remains in continuous diestrus until mounted, serum estrogen levels are normally low (32-38 pg/ml), and ovariectomy does not produce a dramatic decrease in estrogen levels (22-25 pg/ml). As a consequence, genital hemodynamic changes before and after ovariectomy may be minimal. In addition, laser oximetry was used in our studies to assess changes in genital blood flow, whereas Park et al., used laser Doppler-flowmetry. Further studies using other animal models that undergo menstrual cycling (e.g. rat) are necessary to investigate this discrepancy.

Park et al., also reported that estrogen replacement normalized genital hemodynamics to control levels. In our studies, treatment of ovariectomized animals with estradiol significantly increased pelvic nerve-stimulated genital blood flow above control levels (Fig.2). Interestingly, treatment with testosterone did not restore blood flow to that observed in control animals. Park et al., also noted marked thinning of the vaginal epithelial layers, decreased vaginal submucosal microvasculature, and diffuse clitoral cavernosal fibrosis in ovariectomized animals. In addition, the percentage of clitoral cavernosal smooth muscle was significantly decreased in ovariectomized animals. These studies suggest that estrogens modulate genital hemodynamics and are critical for maintaining tissue structural integrity.

Vaginal lubrication, an estrogen-dependent physiological process, is one of the indicators of genital arousal and tissue integrity. Min et al., showed that vaginal lubrication in ovariectomized animals under basal conditions and after pelvic nerve stimulation was reduced and normalized with estrogen treatment (Fig 3 and 4). In contrast, androgen treatment of ovariectomized animals with testosterone alone or in combination with estradiol did not restore vaginal lubrication to that observed in control animals. Finally, it was noted that ovariectomy caused vaginal atrophy and reduced vaginal epithelial cell maturation, which was normalized by estrogen but not androgen treatment.

In summary, data derived from in vivo animal models indicates that estrogen but not androgens modulate genital blood flow, vaginal lubrication and vaginal tissue structural integrity. It should be noted that estradiol levels used in these studies were supra-physiological with potential pharmacologic effects different from those achieved physiologically. Although estrogen replacement increases vaginal lubrication and restores vaginal epithelial integrity, this therapy may not be appropriate for all patients, due to associated risk of breast and endometrial cancer. An alternative to hormonal treatment is the utilization of P2Y2 receptor agonists, which have been shown to increase mucin production and blood flow in other systems. We investigated the effects of P2Y2 receptor agonists as a feasible non-hormonal alternative for the treatment of vaginal dryness in an animal model. P2Y2 receptors are expressed in cervical and vaginal tissues, and these agonists increased vaginal lubrication under conditions of estrogen deprivation.

II. Effects of vasoactive substances on genital blood flow
Limited data are available on the effects of vasoactive substances on genital hemodynamics. Park et al., 1997 demonstrated that injection of papaverine hydrochloride and phentolamine mesylate into the vaginal spongy muscularis layer increased vaginal wall pressure and vaginal blood flow. Sildenafil, a PDE5-selective inhibitor, has been utilized in the treatment of women with sexual arousal disorders with mixed results and pre-clinical data supporting the use of this agent in the management of female sexual dysfunction remains equivocal. We have shown that sildenafil administration caused significant increase in genital blood flow and vaginal lubrication in intact and ovariectomized animals. However, this response was more pronounced in animals treated with estradiol. These data suggested that the NO-cGMP pathway is involved, at least in part, in the physiologic mechanism of female genital arousal and that sildenafil facilitates this response in an in vivo animal model.

The effects of apomorphine, a non-selective dopamine receptor agonist, on genital blood flow were investigated by Tarcan et al., who suggested that systemic administration of apomorphine improved clitoral and vaginal engorgement by increasing clitoral intracavernosal and vaginal wall arterial inflow.

In summary, data derived from in vivo animal models indicate that vasoactive agents play a role in genital arousal. Although sildenafil and apomorphine enhanced genital blood flow in the animal model, clinical use of vasoactive agents remains controversial.
Studies in organ baths:

Physiological studies of the arousal phase of the female sexual response involve, in part, an understanding of the various local regulatory mechanisms, which modulate tone in the clitoral erectile tissue and the vaginal muscularis. Immunohistochemical studies in human vaginal tissues have shown the presence of nerve fibers containing NPY, VIP, NOS, CGRP and substance P.10 Previous studies have suggested that VIP may be involved in the regulation of clitoral and vaginal smooth muscle tone but, as yet, no conclusive experimental evidence of its functional involvement has been forthcoming. There is physiological evidence supporting a role for the alpha-adrenergic system in female sexual arousal. The alpha-2 adrenergic agonist clonidine impaired both vaginal engorgement and lubrication when administered to healthy volunteers.

There is limited data on the functional activity of the inhibitory non-adrenergic non-cholinergic transmission in the clitoral corpus cavernosum. Cellek and Moncada have shown that electrical field stimulation induces NANC relaxation responses in the clitoral corpus cavernosum of the rabbit. These responses were inhibited by NG-nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) or tetrodotoxin. In addition, the inhibitory effect of L-NAME was partially reversed by L-arginine but not by D-arginine. EFS-induced relaxations were enhanced by an inhibitor of type V cyclic GMP phosphodiesterase, zaprinast. It was concluded that nitrergic neurotransmission is responsible for the NANC relaxation responses in the clitoral corpus cavernosum of the rabbit. Furthermore, the role of phosphodiesterase type 5 inhibition in the modulation of female sexual dysfunction was investigated by Vemulapalli and Kurowski. Pretreatment of clitoral corpus cavernosum strips with sildenafil enhanced the electrical field stimulation-induced relaxations, both in magnitude and duration. Thus, the NO pathway is critical for smooth muscle relaxation in the clitoris. However, in the vagina, this pathway plays only a partial role, as demonstrated by Ziessen et al. These investigators showed that in the rat and rabbit vaginal wall, NANC relaxations were partly mediated by nitric oxide. The remaining part was neurogenic since it could be inhibited by tetrodotoxin. This non-nitrergic NANC response was not associated with any known neuropeptides or purines. Thus, the nature of the non-adrenergic, non-cholinergic neurotransmitter in the vagina remains elusive.

We have carried out preliminary experiments in organ bath chambers to assess clitoral and vaginal tissue responses to: a) electric field stimulation b) alpha-adrenergic agonists c) NO donors and d) VIP. Electrical field stimulation resulted in a biphasic (contraction/relaxation) response in clitoral and vaginal tissue strips. Bretylium (inhibitor of NE release) abolished the contractile response induced by EFS in both tissues. Exogenously added norepinephrine caused a dose-dependent contraction in vaginal and clitoral tissues. These observations suggest that adrenergic nerves mediate the contractile response. Sodium nitroprusside and papaverine caused dose dependent relaxation of vaginal and clitoral strips pre-contracted with norepinephrine. Alpha-1 (prazosin and tamsulosin) and alpha-2 (delequamine) selective antagonists inhibited contraction of vaginal tissue strips to exogenous norepinephrine. Further studies using specific molecular probes and RNase protection assays have detected mRNA for both alpha 1A and alpha 2A adrenergic receptors in human clitoral and vaginal smooth muscle cells (Traish et al., unpublished data). Thus, vaginal and clitoral smooth muscle contraction is the result of activation of alpha-adrenergic receptors by norepinephrine released from adrenergic nerves. It remains to be determined if other vasoconstrictor agents, such as endothelin, neuropeptide Y (NPY), angiotensin or eicosanoids may play a role in regulating smooth muscle tone in these tissues.

Giraldi et al., have characterized the effect of experimental diabetes on neurotransmission in rat vagina. It was suggested that diabetes interferes with adrenergic-, cholinergic- and NANC-neurotransmitter mechanisms in the smooth muscle of the rat vagina.8 The changes in the nitrergic neurotransmission were attributed to reduction in NOS-activity, but may also be attributed to inhibition of various reactions in the L-arginine/NO/guanylate cyclase/cGMP system.

We investigated the effects of hormonal manipulations on vaginal smooth muscle contractility in response to electrical field stimulation (EFS) and vasoactive substances. Ovariectomy reduced norepinephrine-induced contractile response and treatment with estradiol or testosterone normalized the contractile response. Ovariectomy also attenuated EFS-induced relaxation response and treatment with testosterone facilitated EFS-induced smooth muscle relaxation. Moreover, VIP induced a dose-dependent relaxation response that was attenuated in tissues from ovariectomized animals or in animals treated with estradiol. In contrast, VIP-induced relaxation was facilitated in tissues from ovariectomized animals treated with testosterone. These observations suggest that testosterone and estradiol produce distinct physiological responses in vaginal smooth muscle and that androgens facilitate vaginal smooth muscle relaxation.

In summary, the data reported from several laboratories suggest that NO is a key pathway in mediating clitoral smooth muscle relaxation. However, in the vagina, NO appears to play only a partial role in mediating smooth muscle relaxation. VIP also induces vaginal smooth muscle relaxation yet its exact functional role remains to be determined. Functional alpha-adrenergic receptors are expressed in the vagina and mediate norepinephrine induced contraction. Hyperglycemia affects vaginal smooth muscle response to neurotransmission affecting multiple physiological pathways. We have observed that androgens but not estrogens at pharmacological doses enhanced smooth muscle relaxation. Further studies with hormonal manipulations at physiological doses are necessary to establish the role of hormones on vaginal smooth muscle relaxation.

Studies in cell culture:

Park et al. and Traish et al.recently sub-cultured and characterized human and rabbit vaginal and clitoral smooth muscle cells and investigated the synthesis of second messenger cyclic nucleotides in response to vasodilators and determined the activity and kinetics of phosphodiesterase (PDE) type 5.32,37 Cultured vaginal and clitoral cells exhibited growth characteristics typical of smooth muscle cells and immunostained positively with antibodies against alpha smooth muscle actin. The cells retained functional prostaglandin E, VIP and b adrenergic receptors as demonstrated by increased intracellular cAMP synthesis in response to PGE1, VIP or isoproterenol. The response to these vasoactive substances was augmented with forskolin, suggesting stabilization of G-protein activated adenylyl cyclases. Treatment with the nitric oxide donor, sodium nitroprusside, in the presence of sildenafil, a PDE type 5 inhibitor, enhanced intracellular cGMP synthesis and accumulation. Incubation of rabbit vaginal tissue with sildenafil, sodium nitroprusside and PGE1 or forskolin produced a marked increase in intracellular cGMP. These observations were similar to those obtained with cultured cells and suggest that sub-cultured cells retained functional characteristics exhibited in intact tissue. The cells retained phosphodiesterase type 5 expression as shown by specific cGMP hydrolytic activity. Sildenafil and zaprinast inhibited cGMP hydrolysis competitively and bound with high affinity (inhibition constants Ki= 7 and 250 nM, respectively). These observations suggest that cultured human and rabbit vaginal smooth muscle cells retained their metabolic functional integrity and this experimental system should prove useful in investigating the signaling pathways that modulate vaginal smooth muscle tone.

Investigation of the distribution of NOS in the rat vagina in response to ovariectomy and estrogen replacement was recently performed using immunohistochemical analyses with n-NOS and e-NOS antibodies. In intact cycling animals, e-NOS and n-NOS expression were found to be highest during proestrous and lowest during metestrous while in ovariectomized animals n-NOS and e-NOS expression declined substantially. Estrogen replacement resulted in significant increase in e-NOS and n-NOS expression, when compared with NOS in intact animals. It was suggested that estrogen plays a critical role in regulating vaginal NOS expression of the rat vagina and that NO may modulate both vaginal blood supply and vaginal smooth musculature. More recent studies have shown the opposite observation. They found that rabbit vaginal NOS activity was considerably reduced by treatment with estradiol or estradiol and progesterone. They also noted that progesterone treatment alone up-regulated vaginal NOS. NOS-containing nerves could be demonstrated in vagina by immunohistochemistry. Vaginal smooth muscle responded with relaxation after EFS, which was inhibited by NG-nitro-L-arginine. A tissue specific role for NOS in vagina was suggested based on NO-dependent response of vaginal smooth muscle, expression of relatively high NOS, which is down-regulation by estradiol and up-regulation by progesterone.

This discrepancy in NOS regulation by estrogen in these studies may be due to species differences or to methods for assessment of NOS expression and activity. We have used both immunochemical (Western blots) and enzymatic activity assays to determine regulation of vaginal NOS in the rabbit model. In this study we demonstrated that nitric oxide synthase was predominantly expressed in the proximal vagina. The reason for this tissue distribution is yet to be determined. We further observed that ovariectomy enhanced NOS activity in the proximal vagina suggesting specific regulation of NOS by sex steroid hormones. Treatment of ovariectomized animals with estrogens resulted in decreased expression and activity of NOS in vaginal tissue, consistent with the research by Al-Hijji et al. In contrast, treatment of ovariectomized animals with androgens resulted in increased NOS expression and activity. These observations suggest that NOS in vaginal tissue is regulated by androgens and estrogens in an opposite manner.


The psychosocial and relationship aspects of female sexuality have been extensively investigated. However, studies concerning the anatomy, physiology and pathophysiology of female sexual function and dysfunction are limited. The paucity of biological data may be attributed to lack of reliable experimental models and tools for the investigation of female sexual function, and to limited funding, which is critical for the development of experimental approaches.
Research efforts by a number of investigators in different laboratories are establishing experimental models needed for the investigation of the physiological mechanisms involved in the genital arousal response of sexual function. These experimental models have permitted assessment of genital hemodynamics, vaginal lubrication, regulation of genital smooth muscle contractility and signaling pathways, providing preliminary information on the role of neurotransmitters and sex steroid hormones in sexual function. Further research is needed to define the neurotransmitters responsible for vaginal smooth muscle relaxation, the role of sex steroid hormones and their receptors in modulating genital hemodynamics, smooth muscle contractility and neurotransmitter receptor expression. Finally, a global and integral understanding of the biologic aspects of female sexual function requires investigation of the vascular, neurological (central and peripheral) and structural components of this extremely complex physiological process.

How Does a Brain Cell Work

They are found in well-organised groups they communicate constantly through long ranging connections there are one hundred billion - 100,000,000,000 - of them, surrounded by at least 10 times that many supporting non-neuronal cells, and they are all inside your head.

They are of course brain cells. Of course there are many different types of cell in the brain most are concerned with protection and supportive functions like fighting disease and providing the necessary environment for the high maintenance nerve cells (also called neurones). We make sense of the world around us by the collective activity of these nerve cells and in turn they direct our response to that world violent rage and philosophical insight both begin with nerve cells but how exactly do they work?

Nerve cells need a lot of energy

The essential job of nerve cells is to send and receive messages, a process that uses electricity and intermittent chemical signals. This electrical signalling requires constant pumping of electrical charges between the inside and outside of the nerve cells to do this the brain uses a disproportionately large amount of energy compared to its size. The movement of electrical charges is performed by pumps or transporter proteins in the membrane of a cell and these are powered by the energy-rich molecule adenosine triphosphate (ATP) (see this link for a video of how a nerve cell works).

The purpose of all this pumping and transporting is to maintain large imbalances in the distribution of charged particles (ions) between the inside and outside of brain cells. Principally this involves keeping the levels of sodium and calcium inside the cell very low and keeping the level of potassium higher than the outside. In addition to producing large differences in concentration between inside and outside a cell, this distribution of ions causes an electrical potential difference - the inside of a brain cell is electrically negative by about, seventy thousandths of a volt (70 millivolts). It doesn't sound much, but when you take into account how thin is the cell membrane - 5 nanometres or 5 thousand millionths of a metre - this translates to an electrical potential gradient of 140,000 volts per centimetre! This is a very powerful electrical field and when combined with large differences in ion concentration, it acts as a powerful driving force to move ions across the cell membrane - but this can't happen until ion channels open.

What are ion channels.

Ion channels are proteins that sit in the cell membrane, the fatty layer that forms the boundary of a cell. They have a central pore, or channel, which allows ions to move between the inside and outside of the cell. Left to themselves these ions move from areas of high to lower concentration, and this is exactly what happens during the normal operation of brain cells.

Why study ion channels?

  • Malfunctioning ion channels are responsible for a large number of health disorders
  • Many drugs act on ion channels to produce their beneficial effects
  • This is particularly true for the nervous system. Tranquilizers, analgesics, anaesthetics and anti-epileptics are some examples of drugs which act directly on ion channels.
  • Anaesthetics open potassium channels,
  • anti-epileptic drugs modify sodium and calcium channel operation as well as some channels operated by inhibitory neurotransmitters.
  • Sodium and calcium channels are also targets of drugs used to improve heart function.
  • Stimulation of insulin release from the pancreas is caused by drugs which block potassium channels.
  • Epilepsy, muscular dystrophy, irregular heartbeat (long QT syndrome), cystic fibrosis, and some kidney ailments all result from inappropriate changes in the way ion channels work.

When ion channels open, charged particles flood across the membrane divide at a tremendous rate (several thousand each time the channel opens). This image conjures the idea of water flowing from the sluice of a dam, but it is more subtle than that. Instead, imagine a packet of vegetable soup with holes in it some holes only allow peas to pass through whereas others are selective for carrots and so on. Likewise a nerve cell possesses selective ion channels for the various different ions, so there are sodium channels and potassium channels etc which all have specific parts to play in the electrical behaviour of nerve cells. This rapid movement of electrically charged particles allows brain cells to produce large but brief electrical signals so they can send messages on a millisecond time scale. For example the basic unit of electrical signalling in the brain cell is a spike of activity lasting about 1 thousandth of a second called an action potential. Action potentials are caused by the sequential opening and closing of sodium channels and potassium channels. Nerve cells can produce a complex and diverse range of electrical signals. This ability stems from the opening and closing of the dozens of varieties of ion channels that have, so far, been discovered.

. and how are they controlled?

Two basic methods have evolved for opening ion channels. The first involves sensitivity to the powerful electrical field across the cell membrane. Changes in this electric field can alter the shape of some ion channels, causing a central channel to open - these are the voltage-dependent channels. The second system of control requires the attachment of a specific chemical signal to a receptor or recognition site on an ion channel this transmits a change in shape to the central channel. This is the way that neurotransmitters work these small molecules are secreted by nerve cells and transmit the signal in those places where the electrical signal won't work, such as the synapse.

What happens at a synapse?

Nerve cells make thousands of special connection points with each other called synapses. On one side is a store of neurotransmitter - the chemical signal. On the other side are the specialized ion channels that contain a recognition site for the neurotransmitter. The electrical signal is unable to cross the gap between the two sides of the synapse. When an action potential arrives at the synapse, the voltage change causes calcium channels to open and calcium pours into the cell. This rise in calcium is a trigger for release of neurotransmitters into the synaptic space where they open clusters of ion channels on the other side of the synapse. Different transmitters are used for increasing (glutamate, acetylcholine) or reducing (glycine, gamma-amino-butyric acid) the electrical activity of the recipient cell. The balance between excitatory and inhibitory activity from all synapses will determine the opening of voltage dependent ion channels and another round of electrical activity in the next cell.

Nature's poisonous bounty

Fish: tetrodotoxin - possibly the most renowned animal toxin named after the four-toothed puffer fish family Tetraodontidae. Famous also as the occasionally deadly raw fish delicacy fugu in Japan. Also found in the blue ringed octopus. Acts on sodium channels.

Plankton: saxitoxin - from the plankton which generate the marine "red tide". Causes paralytic shellfish poisoning of humans - after the shellfish consume the plankton. Acts on sodium channels. Considered sufficiently dangerous to be listed under the Chemical Weapons Convention.

Frogs: batrachotoxin - from Phyllobates terribilis, the name says it all, one of the range of poison arrow frogs. Acts on sodium channels.

Snails: conotoxins - a range of poisons from the venom of sea snails which use them to paralyse their prey (fish). Different forms of conotoxins act on sodium and calcium channels.

Snakes: from the krait family, alpha-bungarotoxin - prevents neurotransmitter from acting on acetylcholine receptors on muscle result paralysis. From the mamba family, dendrotoxin blocks potassium channels. Many snake venoms also contain other chemicals that disable prey by clotting the blood and digesting flesh as well as nerve cell poisons.

Spiders: agatoxins - which block calcium channels and atracotoxins which cause uncontrollable opening of sodium channels are components of the venom injected through the fearsome fangs of the funnel web spider family.

Scorpions: venom components have been found which block potassuim channels and modify sodium channel function.