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Knock Knock! whos there... Roller Coaster Roller Coaster Who? |
Large Patch Transition Day
Trip out after dinner to Staples and Saveon
Romantic Cards....for a romantic gal shopping for her man..
Double bagged AKA Yoga sheik
New printer...and more TP
BATHTIME...Weighin
Things are what they are and they aren't so heavy unfortunately...
Three rounds of radiation have produced gains in tumour/mouth/throat swelling
but that have cost a dramatic net loss in weight
which has now put us in under 70lbs
BUBBLES and 70's FOLK POP Karaoke
Morphine itch Scratching takes a toll..
Itching is one of the most prevalent side effects of powerful,
pain-killing drugs like morphine, oxycodone and other opioids.
instead we offer to do it for her and use
calamine and benadryl to assist..
hydro-cortisone on the safe areas
The hair affair...one of the flights...a beautiful thing...
... Take it to the bridge.....mama!
And here is the list...
the one that don't tell you about....
until after you buy your cancer roller coaster ticket
and get over the first hump
(http://www.preciouslegacy.com/chap6.html)
6.02 Symptoms Related to Digestion
A. Nausea and Vomiting
B. Constipation
C. Diarrhea
D. Loss of Appetite and Weight Loss
E. Trouble Swallowing
F. Dry Mouth
G. Nutrition and Hydration
6.03 Problems with Breathing and the Lungs
A. Shortness of Breath
B. Cough
C. Hiccough
D. Secretions
6.04 Neurologic Problems
A. Insomnia
B. Confusion, Delirium and Dementia
C. Terminal Restlessness
D. Seizures
E. Headache
6.05 Conditions of the Skin
A. Itching
B. Bedsores
C. Edema
D. Odors
6.06 Bowel & Bladder Problems
6.07 Weakness and Other General Symptoms
6.01 Physical Symptoms Other than Pain; In General
Pain-free but itchy: Morphine’s alter ego
It is a truth universally acknowledged that a patient given a morphine epidural will experience itchiness as a side-effect. But why? Why should an effective analgesic make you itchy?
While this may sound like a simple question to answer, it has puzzled scientists for decades. Neurobiologists have long known the close nervous relationship between pain and itch, but until this month have been unable to separate the two. And if you can’t separate the symptom you are treating from the side-effect, you are left with an itch you can scratch but not eliminate.
What is an itch?
The itch response in animals depends generally on nerve circuits that sense stimuli (chemical, mechanical, electrical, or thermal) at the surface of the skin through “pruriceptive” receptors, and transmit a signal to the brain. Our response to a given stimulus is to scratch at the site of the itch. Scratching temporarily relieves the itch, and can often feel quite nice, however excessive scratching can damage the skin and ultimately be counter-productive.
In certain circumstances itching and scratching can occur in the absence of an external stimulus. In contrast to pruriceptive itch, neuropathic, neurogenic, or psychogenic itch do not rely on the activation of receptors beneath the surface of the skin. In these cases damage to the nervous system, psychiatric disturbance, or chemical perturbation of the normal itch pathway appear to be responsible. If the normal pruriceptive neurons are an incoming phone call, you can think of these abnormal signals as static on the line. It shouldn’t happen, but it means that something weird is having an effect on the circuit and causing it to malfunction.
I have been deliberately vague here. We really know very little about the molecular details of itch reception and transmission, but scientists DO know a fair amount about pain.
Ouch! That hurt!
Just like itch, pain is generally a response to an external stimulus. You experience pain when you step on a nail, or stub your toe, or grab hold of a hot skillet. And your immediate response is to withdraw from the source of pain very very quickly. Pain can also act as a warning that something in your body is not quite right; for example it is often a symptom of a cancerous growth. In this instance, withdrawal is not particularly effective, but thanks to the wonders of modern medicine we can attempt to make the pain go away.
So while itch is generally only unpleasant, pain is often life threatening. This is of course why we know a lot more about it. After all, you rarely find yourself in hospital with a nasty itch.
Step one in the pain response is detection. At the end of the sensory nerve fibers that respond to pain are “nociceptors”. These membrane proteins respond in a manner that reflects the severity of the stimulus to open calcium channels in the nerve membrane. This in turn generates an “action potential”, which is the electrical signal that travels along the length of the sensory neuron’s axon. This signal then travels to an area of the spinal cord called the dorsal horn. From the dorsal horn the signal travels to the thalamus, an area of the brain devoted to relaying signals to the cerebral cortex and the control of consciousness. Once the signal reaches the cerebral cortex the brain initiates a response, which includes the release of analgesic hormones from the hypothalamus and the stimulation of motor neurons to elicit withdrawal from the source of pain.
Chemical pain intervention
Some of the hormones released by the hypothalamus are called “endorphins” (the derivation of the word is literally “endogenous morphines”, or morphines made by the body). These small molecules can bind to proteins on the surface of neurons, specifically at their pre-synaptic surfaces. The proteins they bind are called opioid receptors, which come in different flavors, with endorphins preferring μ-opioid receptors, or MORs. When an endorphin binds an MOR it inactivates the nerve signal by blocking the release of neurotransmitters across the synapse (a junction between nerves). Endorphins also cause the release of dopamine, the “feel good” hormone. These effects of endorphins block pain transmission to the brain and make us feel pretty good, allowing us to, if necessary, ignore our wounds as we run away from an attacking bear (for example).
But this effect is temporary. Pain returns after the situation has calmed down.
In 1804, morphine was isolated from opium (itself a natural derivative of poppies) by a pharmacist named Friedrich Sertürner, who got his inspiration for naming the compound from the Greek god of dreams, Morpheus. In 1927 a small chemists’ shop named Merck started to sell morphine as a pain medication, and the rest, as they say, is history.
Despite the numerous side effects of morphine, including addiction due to dopamine release, the drug has remained in clinical use thanks to its extremely potent effect on pain. Just like endorphins, morphine binds to MORs and blocks synaptic communication between neurons in the pain-sensing circuit.
But back to the itch
Imagine you have a bug bite on your arm. It’s really itchy, so you get up off the couch and go into the bathroom to find some anti-histamine ointment. But on the way you stub your toe. A few minutes later, as you wipe the tears of shock from your eyes and go back to watching Madmen, you realize that your bite has stopped itching.
This scenario, which plays out frequently in my house, illustrates nicely the overlap between pain and itch sensations. Neuroscientists thought that perhaps pain “wins” in the race along the neuronal highway, whereas the itch signal, which is not an indicator of life or death, “loses”.
It turns out that this is not the case, and recently published study in the journal Cell has finally managed to separate pain and itch in mice.
The work, which was conducted primarily at Washington University in St. Louis, MO, aimed to understand the link between morphine induced analgesia (MIA) and morphine induced scratching (MIS), with an eye to developing a treatment. They found that indeed both responses were reliant on MORs, but the exact type of MOR is crucial.
The modular nature of genes
Our genes, and the genes of many other organisms, are modular. That is, they are not one continuous string of information, but are spread in chunks across pieces of the genome. As an example I have made up a protein. It’s called Hypotheticin and is encoded in five chunks in the genome. Each chunk is called an exon, and between each exon the DNA sequence is referred to as an intron. When DNA is read and transcribed into a mRNA both introns and exons are included. While intronic sequences have crucial functions, they need to be removed from the mRNA before it is read and translated into protein by the ribosome. This removal process is called splicing. So in the most simple scenario, the four introns of Hypotheticin are removed and the five exons are spliced together.
However, the modular nature of the Hypotheticin gene means that the cell can engage in alternative splicing events. Instead of splicing out the four introns, it can instead remove one of the exons too. So instead of getting Hypotheticin 1-2-3-4-5, we now get Hypotheticin 1-2-4-5. And so these two proteins are functionally different (one has exon 3) and yet both are derived from the same gene.
This is exactly what is happening in the case of MIA and MIS. The authors of the study found that only one form of MOR (MOR1D) was responsible for MIS, whereas other distinct so-called splice isoforms were responsible for MIA.
Real world application
Having figured out this essential difference between pain and itch, the authors looked at the downstream consequences of activating the itch MOR rather than just the pain MOR. They found that MOR1D could interact with another membrane protein called GRPR (gastrin-releasing peptide receptor), a protein previously only implicated in gastrointestinal function. Using the genetic techniques at their disposal, the authors made a mouse that no longer makes GRPR and found that it still benefited from MIA, but was no longer susceptible to MIS. Furthermore, treating normal mice with drugs that inhibited downstream components of the GRPR pathway alleviated MIS, offering the promise of pharmacological treatment in humans.
And yes, due to the “contagious itch effect” I have been fighting the urge to scratch whilst writing this post…how was the reading experience?
Liu, X., Liu, Z., Sun, Y., Ross, M., Kim, S., Tsai, F., Li, Q., Jeffry, J., Kim, J., Loh, H., & Chen, Z. (2011). Unidirectional Cross-Activation of GRPR by MOR1D Uncouples Itch and Analgesia Induced by Opioids Cell, 147 (2), 447-458 DOI:10.1016/j.cell.2011.08.043
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