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Pain, addiction, tortured rats, and sexism... who knew?

May 23, 2008 - 1 comments

Testosterone Increases Pain Threshold And Reduces Fear
By Robbie Durand, MA, CSCS

"Is that all you got b***h......." Marv replies and spits some blood out his mouth as he sits tied to a chair. Marv's face is covered in blood as Wendy a prostitute continually pistol-whips him across the face. Then after a series of conversations between the two, Marv casually gets up and unties the ropes that were supposed to have held him captive. Wendy replies: "You sat there and took it, when you could've taken my gun away from me any time you wanted to..." Marv: "Sure, but I thought I might be able to talk some sense into you. And I probably would've had to paste you one, getting the gun and I don't hurt dames."

Marv was the kind of guy who didn't take s**t from anyone and was one of the main characters in the movie: Sin City. Besides his incredible tolerance for pain, other honorable mentions were: routinely beat the **** out of the police, killing a few hitmen, and of course my favorite scene: he chops Toby Macguire into little pieces with a hacksaw! Marv was the kind of guy that loved the feel of pain but also liked to dish it out as well, in not so many ways bodybuilders are like Marv. What sane person would continually go to the gym doing drop-sets, supersets, and high rep squats to the point of almost passing out. The insane thing is that we go and do the same thing over the next day! Pain is something that comes along with the sport of bodybuilding. Arnold Schwarzenegger once said, "The last three or four reps is what makes the muscle grow. This area of pain divides the champion from someone else who is not a champion. That's what most people lack, having the guts to go on and just say they'll go through the pain no matter what happens." Bodybuilders are so used to pushing themselves beyond the pain threshold limit that we wear shirts titled, "HOUSE OF PAIN." So why is it that some men can handle a whole lot of pain and not even flinch and others stump their toe and scream like a little girl? I know its every bodybuilders dream to be an ***-kicking machine that feels no pain. Pain is one of the body's most important adaptive mechanisms, with its primary function being protection. The brain is quickly notified that tissue damage is occurring or that it is about to occur so that behavioral responses may intervene to avoid or minimize that damage. There is a rare condition called "congenital insensitivity to pain". This disease results in a malfunction of nervous system to not detect pain. You might be thinking how awesome!!!'s might sound like a cool disease but its not. For example, one case study documented a mother's horror as her daughter who was born with the disease came walking in from the backyard with her arm bent unnaturally to the side. She had fallen off the swing and broken her arm; she continued to play and caused further injury despite her arm being broken because it did not hurt. Other horror stories were that she had severe burns on her hands because she touched the stove one day and just left them their as her hands sizzled!!

Over the past decade, multiple pain inhibitory pathways have been discovered. Common painkilling substances
produced by the body are the enkephalins and endorphins. . Endorphins and enkephalins bind with the nerve cell
receptors required to send the electrical impulse across the synapse and thus, close the pain "gates," block the release of neurotransmitters responsible for increasing pain perception. They are so effective at suppressing pain that soldiers commonly would lose an arm or leg when a bomb explodes yet they feel no pain. Its mother nature's way of allowing a person to pass on to the pearly gates without excruciating pain. The enkephalins are found in many areas of the body, and the endorphins are primarily located within the brain itself. Enkephalins have been associated with addiction and withdrawal from morphine. Morphine intensely stimulates the enkephalin receptors which rapidly causes pain suppression. Drugs as: cocaine, amphetamines, and the opiates as heroin and morphine, are all potent stimulators of endorphin release. Is there any other way to get a high from endorphins without going to jail? Another common stimulation of endorphins is intense exercise. Numerous investigators have observed an increase in blood plasma levels of beta-endorphin following intense physical activity as running, cycling, ect. (30) The most popular action of endogenous opioids is their creation of a feeling of euphoria during exercise, which endurance athletes frequently refer to as "runner's high" however high intensity resistance exercise stimulates similar highs. Dr. Kraemer reported that when subjects performed six heavy-resistance exercise protocols, which consisted identically in order and total work but differed in repetitions (5 vs. 10 RM) and rest period length (1 vs. 3 min). Only the high intensity exercise protocol (i.e. 10 reps, 1 min. rest periods) demonstrated significant increases in plasma endorphin release. Additionally, the release of endorphins was correlated with the amount of lactic acid and cortisol released (32). The relationship between exercise intensity and plasma endorphins is a complex issue as not all researchers have found endorphins to increase after exercise. Plasma endorphins have not been found to increase proportionally with exercise intensity. This may be because beta-endorphins are produced directly in the brain itself and the blood levels of endorphins do not represent what is occurring in the brain. A common perceptual experience that occurs during exercise is that many aches and pains suddenly feel better during exercise. One study examined just how effective exercise was at increasing pain threshold in athletes compared to rest. Intense exercise produced a whooping +53% in the pain threshold in the athletes compared to rest (31). Endogenous pain suppressing opioids is one possible mechanism but another hormone has recently been discovered that also reduces pain...testosterone!!

Gender Differences in Pain Threshold

Men have higher testosterone (T) levels and decreased incidence of depression and mood disorders compared to
women. Until the development of other anti-depressant therapies as SSRI's, T was used to treat depression up until
1940 (1). Additionally, in experimental studies, women present lower pain threshold and tolerance and evaluate
equivalent stimulus as being more painful than men (2). Men's brains respond differently to pain than women. In a study involving 14 men and women, Zubieta et al. (5) found significant differences in how the brains of men and women respond to pain. Volunteers were scanned over a period of 20 minutes as they received a moderately pain-causing but harmless injection of salt water in their jaw muscle. OUCH!!! The men experienced an increase amount of endorphins released in certain regions of their brains during the painful state of the experiment, while most of the women showed a decrease. Remember, endorphins are pain suppressing. The participants were asked to rate the intensity and unpleasantness of the pain. Women consistently gave higher ratings for both. Women are also more susceptible to present chronic pain conditions than men and use more pain relieving medications more often than men (3). The differences in pain threshold can be partly attributed to T.

Testosterone Increases Pain Threshold

For several years, evidence has accumulated indicating that T regulates pain perception in both males and females in humans, monkeys, rodents, and birds. The use of pain studies is unethical in humans so a majority of the research is performed on rats. There are several tests used in animals to determine pain threshold in rats. See Figure 1 for an explanation of the tests. When you give animals a little T, they become like Marv from Sin City and say, "That's all you got *****...." For example, when birds were given supplemental T, they left their feet in the hot water longer than control animals (6). When you castrate a male rat - (this is scientific terminology for "cutting his balls off.") he has pain threshold similar to that of female rats, but when you give him T his pain threshold increases (9, 18). In addition, if you give female rats T, they increase pain threshold levels similar to those of male rats. T reduces pain through many biochemical pathways, but a main contributing hormone is that T has an effect on increasing serotonin levels- "that feel good hormone" which may explain the extreme feelings of pleasure and euphoria during steroid use.

It has been documented that after intense stress, whether it is a physical or psychological stressor, T levels tend to decline in the plasma. If the stressor is great enough, also it's reduced in the brain and spinal cord. When rats were administered a drug called formalin into their front paws (i.e. formalin causes immediate pain in rodents) they had a depletion of T in their brain and spinal cord that persisted 24 hrs after injection. In contrast, the rats that were treated with good ole juice, there was a decrease in serum T levels but there was no elimination of T from the brain and spinal cord (12). The depletion in brain T levels maybe a contributing factor of depression that can occur after steroid withdrawal. Another study cut the "nads" off of rats and injected them with formalin, the rats showed significant signs of pain, however when rats were given T, they showed signs of pain but reactive response to pain was dampened (13). Ok, one more rat torture study!

When studying chronic pain in rats there is a surgery called a sciatic nerve resection (SNR) The sciatic nerve is the
largest single nerve in the body; it runs from each side of the lower spine through the rear and back of the thigh, and all the way down to foot, connecting the spinal cord with the leg and foot muscles. A SNR involves cutting the sciatic nerve which leaves the rat with a limp leg. The surgery pisses rats off and causes extreme pain, so they become like Hannibal Lecter and bite and scratch the self-mutilated dead leg, the phenomenon is called autotomy. Rats that are neutered and have SNR chow down on their leg like a bodybuilder hitting the buffet after a heavy day of squats, however, when you give the rats some "sauce" there is a delay in the autotomy for about 4 weeks (14).

Mechanisms of Testosterone Mediated Pain Threshold: Clear as Mud.

As you know, T can be converted into DHT by the enzyme 5α reductase, and DHT can be further converted into 3 α-androstanediol (3 α -diol). Furthermore, T can be converted to estrogen as well. So is it T causing these effects on pain threshold or a testosterone derivative? (i.e. estrogen, DHT, or 3 α -diol) Edinger and Frye found that all three (i.e. T, DHT, and 3 α -diol) metabolites caused rats less anxiety and pain in a behavioral series of open tests (10). It's interesting that female rats also demonstrate reduced pain threshold when their ovaries are removed to make them estrogen deficient, yet replacement of estrogen causes their pain threshold to be increased (7). It also of interest that when women are subjected to pain studies, they appear to have a higher pain threshold toward the beginning of their menstrual cycle when estrogen is the highest, pain threshold decreases during the later month when estrogen is lower (15). Both T and estrogen are producing pain-suppressing effects, but the combination of both may provide a superior effect than either one by itself. One study found that both T and estrogen were effective at increasing serotonin levels in the brain. In the male rats, after 3 days of T administration there was a 50% elevation in firing rate of serotonin neurons (26). Another study reported that if you castrate animals and give them T with an aromatase inhibitor the pain relieving effects are diminished ( ). This increase in serotonin in the brain may explain why men and women have feelings of euphoria while on steroids.
When looking at the mechanisms at which T reduces pain, it stimulates a host of inhibitory neurotransmitters that tell the brain to stop firing painful impulses. T has been shown to activate serotonin, GABA, and enkephalins, all of which are pain suppressing (4). One scientist decided to get to the bottom of the whole T or its metabolites debate and injected normal and neutered male and female rats with either T or estrogen. Interesting, the neutered male rats increased their pain threshold after T administration but not estrogen administration, whereas the in female rats, both estrogen and T increased pain threshold (16). The male rats that were left with intact testes did not experience any additional pain threshold increases from additional T supplementation. Thus T was far more effective than estrogen in reinstating both forms of analgesia in neutered rats, while generally failing to alter pain threshold in intact males. It should be of interest that the area of the brain that contains pain information called the periaqueductal gray has both androgen and estrogen receptors (10). It could be speculated that since T can convert to estrogen the activation of both T and estrogen receptors has a synergistic effect compared to estrogen alone.
T is currently being researched as a pharmacological means to reducing pain in patients with rheumatoid arthritis.
Rheumatoid arthritis is the result of an overactive immune system that causes inflammation of the joints, however T
reduces pain is and also suppresses the immune system. It has been documented that T may reduce the severity of pain by inhibiting inflammatory components (23). Furthermore, in neutered rats that are administered a bacterial drug that causes inflammation similar to rheumatoid arthritis; the effects of the drug are completely reversed by T administration (24). This may be the reason why men whom have rheumatoid arthritis may find substantial reductions in pain and inflammation after T administration (25).

Aging and Pain Threshold

Aging is associated with a host of aches, pains, and diseases that can make life miserable for us men. We all make fun of the old geezer in movies who is screaming about his prostate is the size of a watermelon. Well the joke is on us, every man if he lives long enough will eventually develop prostate's not a matter of if you develop it, it's when you develop it. Prostate cancer is a slow growing disease; so many doctors overlook it if the patient is too old. As prostate cancer is the second leading cause of death among men, a common treatment for those men unlucky enough to develop prostate cancer is androgen deprivation therapy. Androgen deprivation therapy involves drugs that suppress T levels, in fact androgen deprivation therapy is a potent form of testosterone therapy it is similar to orchiectomy (another work for not having testicles.) When men are forced to take androgen deprivation therapy they experience physical symptoms just like post-menopausal women, they develop hot flashes and experience a loss of libido (19). T is needed for general health and normal physical functioning; one of the primary symptoms of men on androgen deprivation therapy is a low quality of life. It should be of no surprise that in addition to a poor quality of life, men's pain threshold decreases as we age. It could be due to a number neurochemical alteration but lowered T levels could be an additional mechanism. For example, older male rats have reduced pain suppressing opiate receptors in the area of the brain controlling pain compared which younger rats (17). Additionally, when older rats are subjected to pain studies they need more morphine to produce pain relief than younger rats.

Daredevil: The Man without Fear on Juice?

In addition to reducing pain, T has been shown to also reduce the fear response in males. That should be of no surprise to men, that's why your girlfriend jumps in your lap at scary movies. In all mammals, females in general tend to be more fearful. If you take castrate male rats, they elicit fear evoking responses similar to females (29). That's why we have to keep our T levels in the optimal range; nothing is more pathetic than a man jumping into his girlfriends lap during SAW!! So before puberty, if scientists expose rats to an open maze test (an open maze test is a measure of fear responses. The bolder an animal is, the further the animal will explore the maze) males and females have similar responses but after puberty when hormones start surging the males become bolder and explore while the females become timid (28). So here is an interesting study demonstrating how T can decrease one's level of fear. Scientists took female cows and divided them into a control group or a T injected group and exposed them to a series of fear experiments (i.e. maze exploration, feeding in an unfamiliar area, surprise effect, ect.) The female cattle exposed to T consistently demonstrated less signs of fear in all the experiments. In addition, the cattle on T had lower heart rates and demonstrated lower cortisol responses throughout the entire study. Another interesting side note, when the cattle did have the **** scared out of them they had a lower cortisol response than the control group (27). Human studies are few but a single dosage of T elicits reductions in fear in women just like animals. In one study, women were either given a placebo or were administered a single dosage of T. Okay, this is where psychologists get a little weird. They took women to a dimly lit cabin, with a device that administered shocks; they also wore an EMG for measuring brain activity. The women were told they were going to be administered three shocks in increasing amplitude. Based on EMG activity, the women that were administered T had a reduction in fear compared to the women who received nothing (34).


So how what is the evolutionary mechanism for testosterone leading to higher pain threshold? In the wild, males have to compete with each other over females. If higher T levels leads to more intensive fighting in males, it simultaneously increases the likelihood that the male will get injured and thus cause pain. The function of pain is to alert the organism of injuries and should be avoided in the future. Nevertheless the perception of pain during aggressive attacks might decrease aggressive behavior and lead to that animal not passing on his genes. It could be hypothesized that an additional role of T is to reduce pain threshold, as this would increase the willingness of an animal to fight with other animals and have successful reproduction. It has been proposed that the decreased pain perception in conjunction with higher aggression and physical strength is the physiological basis for the "winner" effect in males. So the million dollar question is, "Will taking supraphysiological dosages of T increase a person's pain threshold above normal? Studies are lacking, but in rats it seems that T does decrease pain threshold but taking additional T won't increase it further. For example, Aloisi et al. (20) gave male and female rat's supraphysiological dosages of T but only the females increased their pain threshold tolerance. In human studies, a physiological dose of steroids may be helpful in treating painful conditions. In one study, 16 male and 28 female patients experiencing moderately severe pain during episodes of sickle-cell disease were selected for a cross-over trial of low doses of steroids against saline solution. About 80% of the individuals on steroids' had good responses and reductions in pain while the placebo group had no effect (21). Another study reported that low-dose supplemental T treatment given to men with heart disease reduced chronic chest pain induced by exercise-exertion (22).

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by basir86, Nov 03, 2008
it is  very good.....but i want some update paper about the effects of physical activity on pain in rats....

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