Pain-- Biotechnology Companies -- Drugs in the pipeline

Pain

Pain is both a sensory and emotional experience, generally associated tissue damage, or inflammation. Pain is ultimately a perception, and not an objective bodily state.

Despite its unpleasantness, pain is a critical component of the body's defense system. It is part of a rapid warning and defence relay instructing the motor neurons of the central nervous system to minimize detected physical harm.

The gate control theory of pain offers insight into how cognitive and emotional factors might dramatically influence painful sensations. Developed by Ronald Melzack and Pat Wall, it focuses on different pain states at the brain, rather than at the perceived site of injury.

Nociception

Nociception is the physiological sense for perception of physiological pain. Nociception does not describe psychological pain.

Nociceptors are the free nerve endings of neurons that have their cell bodies outside the spinal column in the dorsal root ganglion and are named based upon their appearance at their sensory ends. These sensory endings look like the branches of small bushes.

The interpretation of pain occurs when the nociceptors are stimulated and subsequently transmit signals through sensory neurons in the spinal cord, which releases glutamate, a major exicitory neurotransmitter that relays signals from one neuron to another and ultimately to the thalamus, in which pain perception occurs. From the thalumus, the signal travels to the cerebrum, at which point the individual becomes fully aware of the pain.

Interestingly, the brain itself is devoid of nociceptive tissue, and hence cannot experience pain (thus a headache is not pain in the brain itself). Some evolutionary biologists have speculated that this lack of nociceptive tissue might be due to the fact that any injury of sufficient magnitude to cause pain in the brain has a sufficiently high probability of being fatal that development of nociceptive tissue therein would have little to no survival benefit.

If pain is defined as a signal of present or impending tissue damage effected by a harmful stimulus then the ability to experience pain or irritation is observable in most multi-cellular organisms. Even some plants have the ability to retract from a noxious stimulus. Whether this sensation of pain is equivalent to the human experience is debatable.

Interpretation of pain

The unpleasantness of pain encourages an organism to use any means at its disposal to disengage from the noxious stimuli that it assumes cause the pain. It may, of course, have incorrectly determined the cause. Preliminary pain can serve to indicate that an injury is imminent, such as the ache from a "soon-to-be-broken" bone. Pain may also promote the healing process as most organisms will protect an injured region from further damage in order to avoid further pain.

Despite its unpleasantness, pain remains an important part of human existence.

The study of pain has in recent years diverged into many different fields from pharmacology to psychology and neurobiology. Pain has also provided an interested take for the search for the neural correlates of consciousness, as pain has many subjective psychological aspects besides the physiological nociception.

Types of pain

Acute pain is defined as short-term pain or pain with an easily identifiable cause. Acute pain is the body's warning of present damage to tissue or disease. It is often fast and sharp followed by aching pain. Acute pain is centralized in one area before becoming somewhat spread out. This type of pain responds well to medications.

Chronic pain is medically defined as pain that has lasted 6 months or longer. This constant or intermittent pain has often outlived its purpose, as it does not help the body to prevent injury. It is often more difficult to treat than acute pain. Expert care is generally necessary to treat any pain that has become chronic. When opioids are used for prolonged periods drug tolerance, chemical dependency and even psychological addiction may occur. While drug tolerance and chemical dependency are common among opioid users, psychological addiction is rare.

The experience of physiological pain can be grouped into four categories according to the source and related nociceptors (pain detecting nerves).

Cutaneous pain is caused by injury to the skin or superficial tissues. Cutaneous nociceptors terminate just below the skin, and due to the high concentration of nerve endings, produce a well-defined, localised pain of short duration. Example injuries that produce cutaneous pain include paper cuts, minor (first degree) burns and lacerations.

Somatic pain originates from ligaments, tendons, bones, blood vessels, and even nerves themselves, and are detected with somatic nociceptors. The scarcity of pain receptors in these areas produces a dull, poorly-localised pain of longer duration than cutaneous pain; examples include sprained ankle and broken bones.

Visceral pain originates from body organs visceral nociceptors are located within body organs and internal cavities. The even greater scarcity of nociceptors in these areas produces a pain usually more aching and of a longer duration than somatic pain. Visceral pain is extremely difficult to localise, and several injuries to visceral tissue exhibit "referred" pain, where the sensation is localised to an area completely unrelated to the site of injury. Myocardial ischaemia (the loss of blood flow to a part of the heart muscle tissue) is possibly the best known example of referred pain; the sensation can occur in the upper chest as a restricted feeling, or as an ache in the left shoulder, arm or even hand.

Phantom limb pain is the sensation of pain from a limb that one no longer has or no longer gets physical signals from - an experience almost universally reported by amputees and quadriplegics.

Finally neuropathic pain ("neuralgia") can occur as a result of injury or disease to the nerve tissue itself. This can disrupt the ability of the sensory nerves to transmit correct information to the thalamus, and hence the brain interprets painful stimuli even though there is no obvious or documented physiologic cause for the pain.

Classification of Pain

Pain can be functionally classified into fast pain and slow pain.

Fast pain - Fast pain is felt within 0.1s of application of the pain stimulus. It can be described as sharp, acute, pricking pain and includes mechanical and thermal pain. It is mediated by type A &Delta fibres at rates of between 6-30m/s.
Slow pain - Slow pain is an aching, throbbing, burning, chronic pain. Chemical pain is an example of slow pain. It is mediated by slowed type C pain fibres at rates of between 0.5-2m/s

Pain Receptors

All pain receptors are free nerve endings. There are mechanical, thermal and chemical pain receptors. They are found in skin, on internal surfaces such as periosteum and joint surfaces. Deep internal surfaces are only weakly supplied with pain receptors and will propagate sensations of chronic, aching pain if tissue damage in these areas is experienced. Pain receptors do not adapt to stimulus. In some conditions, excitation of pain fibres becomes greater as the pain stimulus continues, leading to hyperalgesia.

Transmission of Pain Signals in the Central Nervous System

There are 2 pathways for transmission of pain in the CNS. These are the neospinothalamic tract (for fast pain) and the paleospinothalamic tract (for slow pain).

Pathway for Fast Pain - Fast pain travels via type A &Delta fibres to terminate on lamina I (lamina marginalis) of the dorsal horns. Second order neurons of the neospinothalamic tract then take off and give rise to long fibres which cross the midline through the anterior commisure and pass upwards in the contralateral anterolateral columns. These fibres then terminate on the Ventrobasal Complex (VBC) of the thalamus. From here, third order neurons communicate with the somatic sensory cortex. Fast pain can be localised easily if A &delta fibres are stimulated together with tactile receptors.
Pathway for Slow Pain - Slow pain is transmitted via slower type C fibres to lamina II and III of the dorsa horns, together known as the substantia gelatinosa. Second order neurons take off and terminatein lamina V, also in the dorsal horn. Third order neurons then take off and join fibres from the fast pathway, crossing to the opposite side via the anterior commisure, and travelling upwards through the anterolateral pathway. These neurons terminate widely in the brain stem, with one tenth of fibres stopping in the thalamus, and the rest stopping in the medulla, pons and mesencephalon. Slow pain is poorly localized .

The Analgesia System of the Central Nervous System

The analgesia system is mediated by 3 major components : the periaquaductal grey, the nuclear raphe magnus, and the pain inhibitory complex of the dorsal horns of the spinal cord.

Referred Pain

Referred pain is a phenomenon which arises when visceral pain fibres and pain fibres from the skin synapse on the same second order pain fibres. Thus pain arising from the viscera appear to come from the skin.

Pain and alternative medicine

A recent survey (http://nccam.nih.gov/news/2004/052704.htm) by NCCAM found pain was the most common reason to use complementary and alternative medicine (CAM). Among American adults who used CAM in 2002, 16.8% used CAM to treat back pain; 6.6% for neck pain; 4.9% for arthritis; 4.9% for joint pain; 3.1% for headache; and 2.4% used CAM to treat recurring pain. (Some survey respondents may have used CAM to treat more than one of these pain conditions.)

One such alternative, traditional Chinese medicine views pain as a qi "blockage" equivalent to electrical resistance, or as "stagnation of blood" – theorized as dehydration inhibiting metabolism. Traditional Chinese treatments such as acupuncture are relatively more effective for nontraumatic pain than with traumatic pain.

External links

International Association for the Study of Pain (http://www.iasp-pain.org/) - scientific multidisciplinany body
Sea Snails (Conus) harbour powerful new painkillers (http://www.thenakedscientists.com/html/columnists/barrygibbcolumn3.htm) - the ACV1 snail polypeptide appears to be a potential analgesic
Fish capable of experiencing pain (http://www.newscientist.com/news/news.jsp?id=ns99993673) (Rainbow Trout may show pain responses, contrary to popular belief) - New Scientist 2003
Developments in the neuroscience of pain (http://www.thenakedscientists.com/html/columnists/petermcnaughtoncolumn1.htm)