Friday, June 22, 2007

What is pain?

In a previous post Curious cat asked what pain was. The question is simple, but the answer certainly is not. I vaguely recalled sitting through some pharmacology lectures on pain, so thought I could make a post out of it.

Except, when I started looking up what pain was I found out that the whole phenomenon of pain is far, far more complex than what I can bottle down in a single article. However, I think my reductionist and simplistic knowledge of pain might suffice in providing a broad, very general outline of pain, so here goes.

Our sensory system is complex, and pain is amongst our most complex senses. The sensory systems (smell, taste, feeling (and pain), sight) all evolved primarily to help the organism survive better, by locating food better or sensing enemies or predators better and so on. Pain is one of the most obvious warning systems the body has. When something hurts, your body immediately responds by trying to get away from the pain.
Pain is also differentiated into acute and chronic pain. Acute pain is sudden, and is limited to a short time. For example, a stubbed toe hurts, but the pain subsides as soon. Chronic pain though can last a long time, and is indicative of a more serious ailment which may not be obvious, but could be extremely damaging.

But how is pain actually perceived at a molecular level? There are numerous nerve fibers throughout the body that sense pain, and these nerve fibers transmit information to the spinal chord, which in turn relays the information to the brain. These nerve cell receptors, which are unspecialized nerve endings that actually initiate the sensing of pain, are called “nociceptors”. The nociceptors themselves form two or three major classes (depending on how you classify them). There are mechanosensitive nociceptors (which sense pressure), mechanothermal nociceptors (temperature and pressure) and polynodal nociceptors. The nociceptors themselves are made up of A-fiber nociceptors, which mediate that fast, prickly sensation of pain, or C-fiber nociceptors, which conduct pain more slowly, and are responsible for the throbbing or burning sensation of pain. Now, many sensory nerve endings respond to nonpainful mechanical or thermal stimuli, but nociceptors are designed only to respond to high levels of mechanical or thermal stress, which subsequently cause pain. The threshold of activation of these nociceptors is very high, and they don’t respond when say you are exposed to lukewarm water, or to cool temperatures (like in the post describing the receptor for cool temperatures).

At a more molecular level, these different types of nociceptors all express different classes of ion channels, which provide the molecular specificity for sensing different pain. To give a molecular idea of how pain is perceived through these different channels, I’ll use a very recent example from a paper in Nature. Here, researchers describe the role of a very specific channel called Nav1.8. This is a “voltage gated sodium channel” that excites the nociceptors under extreme cold. Ion channels are proteins that form pores across cell membranes, and then specifically allow certain ions across. By doing so, they can maintain an electrochemical or voltage gradient across either side of the membrane. By opening and closing, the ion channels allow specific ions across, and thus change the electrochemical gradient. This results in an electrical impulse. In a nerve cell (including these nociceptor cells), when this happens, the cell releases molecules called neurotransmitters at the end point of the nerve, called a synapse. These neurotransmitter molecules can then go across to the next nerve cell at the synapse, and then pass on the information to the next nerve cell, and finally the information reaches the brain and is processed.

So, coming back to Nav1.8, this is a channel specific for Sodium ions, and only allows sodium ions across. Now, different stimuli open different ion channels, and this particular channel, found in nociceptors, responds to extreme cold. When exposed to extreme cold (which will cause pain), these channels remain open, and pass this information on to the brain. When the researchers started work on this ion channel, it was not known what role it played in extreme cold perception. So, what they did was to knock-out this protein in mice (just like the other experiments in the previous post on cold). Normal mice, when kept on a cold plate (at zero degrees Centigrade) will hop about, lift their feet, and be extremely uncomfortable. But in the mice where this Nav1.8 protein was removed, they would be impervious to cold, and calmly stand and freeze.

Similarly, for different stimuli (which can cause pain), there remain different proteins that sense them, and relay the information to the brain, usually saying “ouch” in different ways. Because pain works through these specific receptors and neurotransmitters, drugs can be designed to block them (opiods, including opium and morphine, work by blocking these neurotransmitters), and so we can “treat” pain.

But pain is also perhaps the most subjective of all senses. The threshold for pain varies dramatically for different people. Some people can tolerate extreme pain, others can’t. This mental component of pain is far more complex (I hardly understand it fully, so cannot explain it well in this article), and a lot of pain is indeed purely from the mind. But given how important pain is to all of us, I think we’ll always remain interested in knowing how it happens.

10 comments:

CuriousCat said...

Thanks Sunil, that gives me the toe hold I was looking for...now, a question. You said that the pain killers that are opiates block the neurotransmitters. But, how do generic things like acetyl salicilic acid or acetamenophen work? By blocking the ion channel in the nociceptor? I mean, they should not affect the neurotransmitters right?

Sunil said...

Curious cat....all good questions, but the answers are not very simple, since pain is a complex phenomena.

Morphine and other opiod agonists work by acting on opoid receptors, and activating a bunch of downstream pathways that finally end up reducing neurotransmission from nociceptors.

However, asprin and other salicylates (which are all non-steroidal anti-inflammatory drugs or NSAIDs) work completely differently. They inhibit a group of enzymes called cyclooxygenases (Cox). These enzymes help make prostraglanding, which is critical in inflammation. So, by inhibiting these enzymes, asprin and other drugs help reduce inflammation substantially, and since inflammation triggers pain, lowering inflammation reduces pain.

Acetaminophen though is an interesting case, and the mechanism of action is still not fully clear. It was thought to inhibit these Cox enzymes, but does so only very weakly, and does not have too many anti-inflammatory effects. However, recent studies suggest that it might specifically inhibit a new Cox enzyme (Cox3), and the effects seen might be through that. The jury is still out for that. But acetaminophen is undoubtedly less effective than strong NSAIDs.

CuriousCat said...

Thanks Sunil.

Ashutosh said...

It's sort of interesting to think about the difference between acetaminophen and aspirin or other salicylates. If you assume that both of these acetylate serines in Cox, then you would intuitively think that aspirin would do the job better because since it's an ester, it has better leaving group ability than the amide in acetaminophen, and therefore would be more reactive. I wonder if that effect contributes to the relatively weak action of acetaminophen on Cox.

Sunil said...

ashutosh....that's an interesting point, and may well be true. At least in vitro, acetaminophen only weakly inhibits the Cox enzymes.....so some people think acetaminophen doesn't really work through Cox at all. It'll be interesting when it is all figured out.

Omnome said...

Great post!

sexy said...

情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,按摩棒,跳蛋,充氣娃娃,情境坊歡愉用品,情趣用品,情人節禮物,情惑用品性易購,A片,視訊聊天室,色情聊天室,聊天室

免費A片,AV女優,美女視訊,情色交友,免費AV,色情網站,辣妹視訊,美女交友,色情影片,成人影片,成人網站,A片,H漫,18成人,成人圖片,成人漫畫,情色網,日本A片,免費A片下載,性愛

A片,色情,成人,做愛,情色文學,A片下載,色情遊戲,色情影片,色情聊天室,情色電影,免費視訊,免費視訊聊天,免費視訊聊天室,一葉情貼圖片區,情色,情色視訊,免費成人影片,視訊交友,視訊聊天,視訊聊天室,言情小說,愛情小說,AIO,AV片,A漫,avdvd,聊天室,自拍,情色論壇,視訊美女,AV成人網,色情A片,SEX,成人論壇

情趣用品,A片,免費A片,AV女優,美女視訊,情色交友,色情網站,免費AV,辣妹視訊,美女交友,色情影片,成人網站,H漫,18成人,成人圖片,成人漫畫,成人影片,情色網


情趣用品,A片,免費A片,日本A片,A片下載,線上A片,成人電影,嘟嘟成人網,成人,成人貼圖,成人交友,成人圖片,18成人,成人小說,成人圖片區,微風成人區,成人文章,成人影城,情色,情色貼圖,色情聊天室,情色視訊,情色文學,色情小說,情色小說,臺灣情色網,色情,情色電影,色情遊戲,嘟嘟情人色網,麗的色遊戲,情色論壇,色情網站,一葉情貼圖片區,做愛,性愛,美女視訊,辣妹視訊,視訊聊天室,視訊交友網,免費視訊聊天,美女交友,做愛影片

av,情趣用品,a片,成人電影,微風成人,嘟嘟成人網,成人,成人貼圖,成人交友,成人圖片,18成人,成人小說,成人圖片區,成人文章,成人影城,愛情公寓,情色,情色貼圖,色情聊天室,情色視訊,情色文學,色情小說,情色小說,色情,寄情築園小遊戲,情色電影,aio,av女優,AV,免費A片,日本a片,美女視訊,辣妹視訊,聊天室,美女交友,成人光碟

情趣用品.A片,情色,情色貼圖,色情聊天室,情色視訊,情色文學,色情小說,情色小說,色情,寄情築園小遊戲,情色電影,色情遊戲,色情網站,聊天室,ut聊天室,豆豆聊天室,美女視訊,辣妹視訊,視訊聊天室,視訊交友網,免費視訊聊天,免費A片,日本a片,a片下載,線上a片,av女優,av,成人電影,成人,成人貼圖,成人交友,成人圖片,18成人,成人小說,成人圖片區,成人文章,成人影城,成人網站,自拍,尋夢園聊天室

信次 said...

情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣用品,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,情趣,美國aneros,rudeboy,英國rudeboy,英國Rocksoff,德國Fun Factory,Fun Factory,英國甜筒造型按摩座,甜筒造型按摩座,英國Rock Chic ,瑞典 Lelo ,英國Emotional Bliss,英國 E.B,荷蘭 Natural Contours,荷蘭 N C,美國 OhMiBod,美國 OMB,Naughti Nano ,音樂按摩棒,ipod按摩棒,美國 The Screaming O,美國TSO,美國TOPCO,美國Doc Johnson,美國CA Exotic,美國CEN,美國Nasstoy,美國Tonguejoy,英國Je Joue,美國Pipe Dream,美國California Exotic,美國NassToys,美國Vibropod,美國Penthouse,仿真按摩棒,矽膠按摩棒,猛男倒模,真人倒模,仿真倒模,PJUR,Zestra,適趣液,穿戴套具,日本NPG,雙頭龍,FANCARNAL,日本NIPPORI,日本GEL,日本Aqua Style,美國WET,費洛蒙,費洛蒙香水,仿真名器,av女優,打炮,做愛,性愛,口交,吹喇叭,肛交,魔女訓練大師,無線跳蛋,有線跳蛋,震動棒,震動保險套,震動套,TOY-情趣用品,情趣用品網,情趣購物網,成人用品網,情趣用品討論,成人購物網,鎖精套,鎖精環,持久環,持久套,拉珠,逼真按摩棒,名器,超名器,逼真老二,電動自慰,自慰,打手槍,仿真女郎,SM道具,SM,性感內褲,仿真按摩棒,pornograph,hunter系列,h動畫,成人動畫,成人卡通,情色動畫,情色卡通,色情動畫,色情卡通,無修正,禁斷,人妻,極悪調教,姦淫,近親相姦,顏射,盜攝,偷拍,本土自拍,素人自拍,公園露出,街道露出,野外露出,誘姦,迷姦,輪姦,凌辱,痴漢,痴女,素人娘,中出,巨乳,調教,潮吹,av,a片,成人影片,成人影音,線上影片,成人光碟,成人無碼,成人dvd,情色影音,情色影片,情色dvd,情色光碟,航空版,薄碼,色情dvd,色情影音,色情光碟,線上A片,免費A片,A片下載,成人電影,色情電影,TOKYO HOT,SKY ANGEL,一本道,SOD,S1,ALICE JAPAN,皇冠系列,老虎系列,東京熱,亞熱,武士系列,新潮館,情趣用品,情趣,情趣商品,情趣網站,跳蛋,按摩棒,充氣娃娃,自慰套,G點,性感內衣,情趣內衣,角色扮演,生日禮物,生日精品,自慰,打手槍,潮吹,高潮,後庭,情色論譠,影片下載,遊戲下載,手機鈴聲,音樂下載,開獎號碼,統一發票號碼,夜市,統一發票對獎,保險套,做愛,減肥,美容,瘦身,當舖,軟體下載,汽車,機車,手機,來電答鈴,週年慶,美食,徵信社,網頁設計,網站設計,室內設計,靈異照片,同志,聊天室,運動彩券,大樂透,威力彩,搬家公司,除蟲,偷拍,自拍,無名破解,av女優,小說,民宿,大樂透開獎號碼,大樂透中獎號碼,威力彩開獎號碼,討論區,痴漢,懷孕,美女交友,交友,日本av,日本,機票,香水,股市,股市行情, 股市分析,租房子,成人影片,免費影片,醫學美容,免費算命,算命,姓名配對,姓名學,姓名學免費,遊戲,好玩遊戲,好玩遊戲區,線上遊戲,新遊戲,漫畫,線上漫畫,動畫,成人圖片,桌布,桌布下載,電視節目表,線上電視,線上a片,線上掃毒,線上翻譯,購物車,身分證製造機,身分證產生器,手機,二手車,中古車,法拍屋,歌詞,音樂,音樂網,火車,房屋,情趣用品,情趣,情趣商品,情趣網站,跳蛋,按摩棒,充氣娃娃,自慰套, G點,性感內衣,情趣內衣,角色扮演,生日禮物,精品,禮品,自慰,打手槍,潮吹,高潮,後庭,情色論譠,影片下載,遊戲下載,手機鈴聲,音樂下載,開獎號碼,統一發票,夜市,保險套,做愛,減肥,美容,瘦身,當舖,軟體下載,汽車,機車,手機,來電答鈴,週年慶,美食,徵信社,網頁設計,網站設計,室內設計,靈異照片,同志,聊天室,運動彩券,,大樂透,威力彩,搬家公司,除蟲,偷拍,自拍,無名破解, av女優,小說,民宿,大樂透開獎號碼,大樂透中獎號碼,威力彩開獎號碼,討論區,痴漢,懷孕,美女交友,交友,日本av ,日本,機票,香水,股市,股市行情,股市分析,租房子,成人影片,免費影片,醫學美容,免費算命,算命,姓名配對,姓名學,姓名學免費,遊戲,好玩遊戲,好玩遊戲區,線上遊戲,新遊戲,漫畫,線上漫畫,動畫,成人圖片,桌布,桌布下載,電視節目表,線上電視,線上a片,線上a片,線上翻譯,購物車,身分證製造機,身分證產生器,手機,二手車,中古車,法拍屋,歌詞,音樂,音樂網,借錢,房屋,街頭籃球,找工作,旅行社,六合彩,水噹噹,台中隆鼻,果凍隆乳,改運整型,自體脂肪移植,新娘造型,婚禮顧問,下川島,常平,常平,珠海,澳門機票,香港機票,貸款,貸款,信用貸款,宜蘭民宿,花蓮民宿,未婚聯誼,網路購物,婚友,婚友社,未婚聯誼,交友,婚友,婚友社,單身聯誼,未婚聯誼,未婚聯誼, 婚友社,婚友,婚友社,單身聯誼,婚友,未婚聯誼,婚友社,未婚聯誼,單身聯誼,單身聯誼,白蟻,白蟻,除蟲,老鼠,減肥,減肥,在家工作,在家工作,水噹噹,台中隆鼻,果凍隆乳,改運整型,自體脂肪移植,新娘造型,婚禮顧問,下川島,常平,常平,珠海,澳門機票,香港機票,貸款,貸款,信用貸款,宜蘭民宿,花蓮民宿,未婚聯誼,網路購物,婚友,婚友社,未婚聯誼,交友,婚友,婚友社,單身聯誼,未婚聯誼,未婚聯誼, 婚友社,婚友,婚友社,單身聯誼,婚友,未婚聯誼,婚友社,未婚聯誼,單身聯誼,單身聯誼,白蟻,白蟻,除蟲,老鼠,減肥,減肥,在家工作,在家工作,婚友,單身聯誼,未婚聯誼,婚友,交友,交友,婚友社,婚友社,婚友社,大陸新娘,大陸新娘,越南新娘,越南新娘,外籍新娘,外籍新娘,台中坐月子中心,搬家公司,搬家公司,中和搬家,台北搬家,板橋搬家,新店搬家,線上客服,網頁設計,線上客服,網頁設計,植牙,關鍵字,關鍵字,seo,seo,網路排名,自然排序,網路排名軟體,交友,越南新娘,婚友社,外籍新娘,大陸新娘,越南新娘,交友,外籍新娘,視訊聊天,大陸新娘,婚友社,婚友,越南新娘,大陸新娘,越南新娘,視訊交友,外籍新娘,網路排名,網路排名軟體,網站排名優化大師,關鍵字排名大師,網站排名seo大師,關鍵字行銷專家,關鍵字,seo,關鍵字行銷,網頁排序,網頁排名,關鍵字大師,seo大,自然排名,網站排序,網路行銷創業,汽車借款,汽車借錢,汽車貸款,汽車貸款,拉皮,抽脂,近視雷射,隆乳,隆鼻,變性,雙眼皮,眼袋,牙齒,下巴,植牙,人工植牙,植髮,雷射美容,膠原蛋白,皮膚科,醫學美容,玻尿酸,肉毒桿菌,微晶瓷,電波拉皮,脈衝光,關鍵字,關鍵字,seo,seo,網路排名,自然排序,網路排名軟體,英語演講,托福,Toastmaster,汽車借款,汽車借款,汽車借款,汽車貸款,汽車貸款,借錢,借貸,當舖,借款,借貸,借錢,週轉,

Anonymous said...

^^ nice blog!! ^@^

徵信, 徵信, 徵信, 徵信社, 徵信社, 徵信社, 感情挽回, 婚姻挽回, 挽回婚姻, 挽回感情, 徵信, 徵信社, 徵信, 徵信, 捉姦, 徵信公司, 通姦, 通姦罪, 抓姦, 抓猴, 捉猴, 捉姦, 監聽, 調查跟蹤, 反跟蹤, 外遇問題, 徵信, 捉姦, 女人徵信, 女子徵信, 外遇問題, 女子徵信, 徵信社, 外遇, 徵信公司, 徵信網, 外遇蒐證, 抓姦, 抓猴, 捉猴, 調查跟蹤, 反跟蹤, 感情挽回, 挽回感情, 婚姻挽回, 挽回婚姻, 外遇沖開, 抓姦, 女子徵信, 外遇蒐證, 外遇, 通姦, 通姦罪, 贍養費, 徵信, 徵信社, 抓姦, 徵信社, 徵信, 徵信公司, 徵信社, 徵信, 徵信公司, 徵信社, 徵信公司, 女人徵信, 外遇

徵信, 徵信網, 徵信社, 徵信網, 外遇, 徵信, 徵信社, 抓姦, 徵信, 女人徵信, 徵信社, 女人徵信社, 外遇, 抓姦, 徵信公司, 徵信社, 徵信社, 徵信社, 徵信社, 徵信社, 徵信社, 女人徵信社, 徵信社, 徵信, 徵信社, 徵信, 女子徵信社, 女子徵信社, 女子徵信社, 女子徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社,

徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 外遇, 抓姦, 離婚, 外遇,離婚,

徵信, 外遇, 離婚, 徵信社, 徵信, 外遇, 抓姦, 徵信社, 徵信, 徵信社, 徵信, 外遇, 徵信社, 徵信, 外遇, 抓姦, 徵信社, 征信, 征信, 徵信, 徵信社, 徵信, 徵信社, 征信, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信, 徵信社, 徵信社, 徵信社, 徵信, 外遇, 抓姦, 徵信, 徵信社, 徵信, 徵信社,

Anonymous said...

I like a game which needs to use wonderland Gold, when you do not have wonderland online Gold, you must borrow wonderland money from friends, or you buy wonderland Gold. If you get cheap wonderland online Gold, you can continue this game.