Research into basic mechanisms underlying pain is an increasingly exciting and promising area. However, most of what is known about the anatomy and physiology of pain is from studies of experimentally induced cutaneous skin pain, while most clinical pain arises from deep tissues. Thus, while experimental studies provide fairly good models for acute pain, they are poor models for clinical syndromes of chronic pain. Not only do they provide little information about the muscles, joints, and tendons that are most often affected by chronically painful conditions, but they do not address the vast array of psychosocial factors that influence the pain experience profoundly.
To improve our understanding and treatment of pain we will need better animal models of human pain and better tools for studying clinical pain. Figure illustrates the major components of the brain systems involved in processing pain-related information. There are four major processes: transduction, transmission, modulation, and perception. Transduction refers to the processes by which tissue-damaging stimuli activate nerve endings.
Transmission refers to the relay functions by which the message is carried from the site of tissue injury to the brain regions underlying perception. Modulation is a recently discovered neural process that acts specifically to reduce activity in the transmission system. Perception is the subjective awareness produced by sensory signals; it involves the integration of many sensory messages into a coherent and meaningful whole.
Perception is a complex function of several processes, including attention, expectation, and interpretation. Diagrammatic outline of the major neural structures relevant to pain.
The sequence of events leading to pain perception begins in the transmission system with transduction lower left , in which a noxious stimulus produces nerve impulses in the primary more Transduction, transmission, and modulation are neural processes that can be studied objectively using methods that involve direct observation. In contrast, although there is unquestionably a neural basis for it, the awareness of pain is a perception and, therefore, subjective, so it cannot be directly and objectively measured. Even if we could measure the activity of pain-transmission neurons in another person, concluding that that person feels pain would require an inference based on indirect evidence.
Three types of stimuli can activate pain receptors in peripheral tissues: mechanical pressure, pinch , heat, and chemical. Mechanical and heat stimuli are usually brief, whereas chemical stimuli are usually long lasting.
Nothing is known about how these stimuli activate nociceptors. The nociceptive nerve endings are so small and scattered that they are difficult to find, let alone study. Nonetheless, there have been some studies of the effects of chemicals on the firing frequency of identified primary afferent nociceptors.
A variety of pain-producing chemicals activate or sensitize primary afferent nociceptors Bisgaard and Kristensen, ; Juan and Lembeck, ; Keele, Some of them, such as potassium, histamine, and serotonin, may be released by damaged tissue cells or by the circulating blood cells that migrate out of blood vessels into the area of tissue damage.
Other chemicals, such as bradykinin, prostaglandins, and leukotrienes, are synthesized by enzymes activated by tissue damage Armstrong, ; Ferreira, ; Moncada et al. All of these pain-producing chemicals are found in increased concentrations in regions of inflammation as well as pain. Obviously, the process of transduction involves a host of chemical processes that probably act together to activate the primary afferent nociceptor. In theory, any of these substances could be measured to give an estimate of the peripheral stimulus for pain.
In practice, such assays are not available to clinicians. It should be pointed out that most of our knowledge of primary afferent nociceptors is derived from studies of cutaneous nerves. Although this work is of general importance, the bulk of clinically significant pain is generated by processes in deep musculoskeletal or visceral tissues. Scientists are beginning to study the stimuli that activate nociceptors in these deep tissues Cervero, , ; Coggeshall et al.
In muscle, there are primary afferent nociceptors that respond to pressure, muscle contraction, and irritating chemicals Kumazawa and Mizumura, ; Mense and Meyer, ; Mense and Stahnke, Muscle contraction under conditions of ischemia is an especially potent stimulus for some of these nociceptors. Despite progress in our understanding of the physiology of musculoskeletal nociceptors, we still know very little about the mechanisms underlying common clinical problems such as low back pain.
Even when there is degeneration of the spine and compression of a nerve root—a condition generally acknowledged to be extremely painful—we do not know which nociceptors are activated or how they are activated. Neither do we know what it is about the process that leads to pain. The nociceptive message is transmitted from the periphery to the central nervous system by the axon of the primary afferent nociceptor. This neuron has its cell body in the dorsal root ganglion and a long process, the axon, that divides and sends one branch out to the periphery and one into the spinal cord Figure The axons of primary afferent nociceptors are relatively thin and conduct impulses slowly.
The primary afferent nociceptor.
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This is the route by which the central nervous system is informed of impending or actual tissue damage. Its peripheral process runs in peripheral nerves, and its peripheral terminals are present in most body structures more It is possible to place an electrode into a human peripheral nerve and record the activity of primary afferent nociceptors Fitzgerald and Lynn, ; Torebjork and Hallin, The nociceptor is characterized by its response to noxious heat, pressure, or chemical stimuli.
The ''pain'' message is coded in the pattern and frequency of impulses in the axons of the primary afferent nociceptors. There is a direct relation between the intensity of the stimulus and the frequency of nociceptor discharge Figure Furthermore, combined neurophysiological and psychophysical studies in humans have shown a direct relation between discharge frequency in a primary afferent nociceptor and the reported intensity of pain Fitzgerald and Lynn, ; LaMotte et al. Blocking transmission in the small-diameter axons of the nociceptors blocks pain, whereas blocking activity of the larger-diameter axons in a peripheral nerve does not.
Principles & Practice of Pain Medicine, 2e
These identified primary afferent nociceptors are thus necessary for detecting noxious stimuli. The relation of discharge frequency in primary afferent nociceptors to subjective pain intensity in human subjects. Top left: The skin of human subjects was subjected to brief, calibrated temperature increases. Subjects began to identify the temperature more Monitoring activity in identified primary afferent nociceptors is a potential tool for the evaluation of certain types of clinical pain.
In fact, this method has been used clinically to demonstrate pain-producing neural activity arising from a damaged nerve Nystrom and Hagbarth, At present, this method should be considered just a research tool; however, it is technically feasible and is of great potential value for evaluating pain patients. It raises the possibility of actually demonstrating nociceptor activity coming from a painful area. This method could be an advance over other correlative techniques for assessing pain because it measures the presumed noxious input, that is, the neural activity that ordinarily causes pain.
Most of the other measures assess responses that could be, but are not necessarily, caused by noxious stimuli. It is important to point out that 1 there can be pain without activity in primary afferent nociceptors, and 2 there can be activity in primary afferent nociceptors without pain. These phenomena occur when there has been damage to the central or peripheral nervous systems. In addition, the modulating system can suppress central transmission of activity elicited by nociceptor input. Thus, there is a variable relation between nociceptor input and perceived pain intensity.
For this reason the method of recording primary afferent nociceptors could be used to confirm the presence of an input, but it could not be used to prove that pain was not present. Besides these theoretical limitations of trying to assess subjective pain intensity by recording primary afferent nociceptors, there are important practical problems in measuring either pain-producing substances or primary afferent nociceptor activity. One is that the largest group of patients disabled by pain localize it to musculoskeletal structures in the lower back.
Because the nerves innervating these structures are not near the skin, they are difficult to find. Another problem is that pain arising from deep structures is often felt at sites distant from where the tissue damage occurs. In contrast to the pain produced by skin damage, which is sharp or burning and well localized to the site of injury, the pain that arises from deep tissue injury is generally aching, dull, and poorly localized Lewis, When the damage to deep tissues is severe or long lasting, the sensation it produces may be misperceived as arising from a site that is distant from the actual site of damage Head, ; Kellgren, ; Lewis, ; Sinclair et al.
This phenomenon, known as referred pain , helps to explain the frequent discrepancy between physical findings and patient complaints. The mechanism of referred pain is unknown for any particular case. Referred pain can be a major source of confusion in the examination of patients complaining primarily of pain.
The fact that pain is referred from visceral internal organs to somatic body structures is well known and commonly used by physicians. For example, the pain of a heart attack is not always localized to the heart but commonly is felt diffusely in the chest, the left arm, and sometimes in the upper abdomen. Less widely recognized is the fact that irritable spots, such as myofascial trigger points, in skeletal muscles also cause feelings of pain in locations distant from the irritable spot.
This was demonstrated experimentally in muscle and fascia by Kellgren in the late s Kellgren, Specific patterns of pain referred from particular muscles have been described clinically Travell and Rinzler, ; Travell and Simons, See Chapter 10 and Appendix. At least four physiological mechanisms have been proposed to explain referred pain: 1 activity in sympathetic nerves, 2 peripheral branching of primary afferent nociceptors, 3 convergence projection, and 4 convergence facilitation.
The latter two involve primarily central nervous system mechanisms. Sympathetic nerves may cause referred pain by releasing substances that sensitize primary afferent nerve endings in the region of referred pain Procacci and Zoppi, , or possibly by restricting the flow of blood in the vessels that nourish the sensory nerve fiber itself. Peripheral branching of a nerve to separate parts of the body causes the brain to misinterpret messages originating from nerve endings in one part of the body as coming from the nerve branch supplying the other part of the body. According to the convergence-projection hypothesis, a single nerve cell in the spinal cord receives nociceptive input both from the internal organs and from nociceptors coming from the skin and muscles.
The brain has no way of distinguishing whether the excitation arose from the somatic structures or from the visceral organs. It is proposed that the brain interprets any such messages as coming from skin and muscle nerves rather than from an internal organ.
The convergence of visceral and somatic sensory inputs onto pain projection neurons in the spinal cord has been demonstrated Milne et al. According to the convergence-facilitation hypothesis, the background resting activity of pain projection neurons in the spinal cord that receive input from one somatic region is amplified facilitated in the spinal cord by activity arising in nociceptors originating in another region of the body.
In this model, nociceptors producing the background activity originate in the region of perceived pain and tenderness; the nerve activity producing the facilitation originates elsewhere, for example, at a myofascial trigger point. This convergence-facilitation mechanism is of clinical interest because one would expect that blocking sensory input in the reference zone with cold or a local anesthetic should provide temporary pain relief.
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One would not expect such relief according to the convergence-projection theory. Clinical experiments have demonstrated both kinds of responses. This phenomenon of referred pain can present a serious problem to both patients and physicians when it goes unrecognized. Because the source of the pain lies overlooked at a distant location, the lack of any demonstrable lesion at the site of pain and tenderness often leads to the suspicion that the pain has a strong psychological component.
When health professionals insist that there is no reason for the pain, patients sometimes begin to wonder whether the pain is "all in their head.
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Primary afferent nociceptors transmit impulses into the spinal cord or if they arise from the head, into the medulla oblongata of the brain stem. In the spinal cord, the primary afferent nociceptors terminate near second-order nerve cells in the dorsal horn of the gray matter Willis, The primary afferent nociceptors release chemical transmitter substances from their spinal terminals. These transmitters activate the second-order pain-transmission cells.