Neuropathophysiology of Pain

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The conceptualization of the neurobiology of pain has undergone continuous refinement with increasing knowledge of multiple nociceptive targets and pathways.6'7 The psychophysical parameters used to describe nociceptive processing have thus been refined to differentiate acute withdrawal behaviors in response to dangerous (e.g., sharp or hot stimuli) stimuli in the environment (acute nociception) from increased sensitivity to mildly painful stimuli (hyperalgesia) or to otherwise innocuous stimuli (allodynia) (Figure 1).8 An increase in stimulus intensity in any sensory modality will eventually become noxious (Figure 1). Obviously, the sensation of noxious environmental stimuli (acute pain) is physiologically protective. However, following injury, this psychophysical function shifts such that previous noxious stimuli are now perceived as exceedingly painful (hyperalgesia). Additionally, tissue injury results in ongoing or spontaneous pain and the perception that normally nonnoxious stimuli are pain generating (allodynia). It is now

Hyperalgesia Stimulus Response Function

Figure 1 Psychophysical representation of hyperalgesia and allodynia sensory sensitivity. Following injury, being tissue or nerve injury, pain transmission and perception are changed so that a normally painful stimulus is going to be felt more painful (hyperalgesia) and a normally nonpainful stimulus is going to be felt as painful (allodynia). (Adapted from Cervero, F.; Laird, J. M., Pain 1996, 68, 13-23.)

Innocuous Noxious

Figure 1 Psychophysical representation of hyperalgesia and allodynia sensory sensitivity. Following injury, being tissue or nerve injury, pain transmission and perception are changed so that a normally painful stimulus is going to be felt more painful (hyperalgesia) and a normally nonpainful stimulus is going to be felt as painful (allodynia). (Adapted from Cervero, F.; Laird, J. M., Pain 1996, 68, 13-23.)

well appreciated that distinct sensory mechanisms contribute to physiological pain, to pain arising from tissue damage (inflammatory or nociceptive pain), and to pain arising from injury to the nervous system (neuropathic pain).9

Nociceptive pain is caused by the ongoing activation of A-S and C-nociceptors in response to a noxious stimulus (injury, disease, inflammation) (Figure 2). It can be further classified into visceral pain (deep cramping sensation associated with referred pain), superficial somatic pain (skin; well-localized sharp, pricking, or burning sensation), and deep somatic pain (muscle, joint capsules, and bone; diffuse dull or aching sensation). Under normal physiological conditions, there is a close correspondence between pain perception and stimulus intensity, and the sensation of pain is indicative of real or potential tissue damage. As the nervous system becomes sensitized (responding more strongly than normal to peripheral stimuli), in addition to spontaneous pain, nociceptive pain is also associated with evoked hyperalgesic and allodynic conditions.10-12 In general, nociceptive pain abates completely upon the resolution of injury if the disease process is controlled. Because of this, the use of disease-modifying therapies is being emphasized in the treatment of nociceptive chronic pain as illustrated in the treatment of rheumatoid arthritis not only by antiinflammatory agents but also by biological therapies such as tumor necrosis factor-a (TNF-a) antagonists.13

Unlike nociceptive pain, neuropathic pain can persist long after the initiating injurious event has been removed and any damage has healed. This then leads to abnormal processing of sensory information by the nervous system. Neuropathic pain can be classified as peripheral (painful peripheral mononeuropathy and polyneuropathy) or central (post stroke, following spinal cord injury) and can originate from nerve injury following a wide array of conditions/ events, e.g., direct trauma to nerves, inflammation/neuritis/nerve compression, diabetes, infections (herpes zoster, human immunodeficiency virus (HIV)), tumors (nerve compression/infiltration), toxins (chemotherapy), and primary neurological diseases.14'15 Following nerve injury, changes occur in the central nervous system (CNS) that can persist indefinitely. Under these conditions of sensitization, pain can occur without a specific stimulus or can be disproportionate to the stimulus intensity. The sensation of neuropathic pain may also be constant or intermittent and is felt in many different ways (e.g., allodynia or hyperalgesia associated with mechanical or thermal stimuli but also spontaneous sensations such as burning, tingling, prickling, shooting, deep aching, and spasm).14,15

Normal pain

Normal pain

Gamagatsu Ofset Haken

Ascending pain pathways

Pathophysiological pain

Right Heart Catheterization

Ascending pain pathways

Figure 2 Normal and pathophysiological transmission of pain. Under normal conditions, pain stimuli such as noxious heat are transmitted from the peripheral site (e.g., skin or joints) through the nociceptive primary afferent fibers to the spinal cord and the brain. Pathophysiological conditions are associated with peripheral and central sensitization. Peripheral sensitization can result from the sensitization of nociceptors by inflammatory mediators, neurotrophic factors released during tissue damage or by inflammatory cells. Peripheral sensitization is also associated with intense, repeated, or prolonged action potential generation in primary sensory afferents that is mediated by altered expression and activity of voltage-gated sodium and calcium channels. Consequences of peripheral sensitization are a lowering of the activation threshold of nociceptors and an increase in their firing rate. These changes result in the production of hyperalgesia and allodynia associated with nociceptive chronic pain. Central sensitization (long-lasting increases in dorsal horn neuron excitability and responsiveness) is associated with spontaneous dorsal horn neuron activity, responses from neurons that normally only respond to low intensity stimuli (altered neural connections following sprouting of Ab fibers to superficial laminae) and reduction in central inhibition. Central sensitization is associated with persistent pain, hyperalgesia, allodynia, and the spread of pain to uninjured tissue. In addition, it reflects a complex series of changes occurring in the spinal cord that may promote long-lasting increases in dorsal horn neuron excitability including the involvement of astrocytes and microglia activation.

Tissue injury results in the release of pronociceptive mediators that sensitize peripheral nerve terminals (peripheral sensitization), leading to phenotypic alterations of sensory neurons and increased excitability of spinal cord dorsal horn neurons (centralsensitization).7'9 Nerve injury may be associated with abnormal firing of the injured neurons, leading also to central sensitization and phenotypic changes in spinal cord neurons.16'17 In addition, descending supraspinal systems modulate nociceptive responses.18 A multitude of receptors, transmitters, second messenger systems, transcription factors, and other signaling molecules are now appreciated to be involved in pain pathways (Figures 2 and 3).6

As noted above, two mechanisms play a key role in the development and maintenance of chronic pain, namely peripheral and central sensitization.19 Peripheral sensitization can result from the sensitization of nociceptors by inflammatory mediators (e.g., prostaglandin E2 (PGE2), serotonin (5HT), bradykinin, epinephrine, adenosine), by neurotrophic factors released during tissue damage (e.g., nerve growth factor (NGF)) or by inflammatory cells (proinflammatory cytokines including interleukin-1 (IL1)). Peripheral sensitization is also associated with intense, repeated, or prolonged action potential generation in primary sensory afferents that is mediated by altered expression and activity of voltage-gated sodium and calcium channels.6 Consequences of peripheral sensitization are a lowering of the activation threshold of nociceptors and an increase in their firing rate. These changes result in the production of hyperalgesia and allodynia associated with nociceptive chronic pain. In addition, peripheral sensitization plays also an important role in the development and maintenance of central sensitization.6,17

Central sensitization (long-lasting increases in dorsal horn neuron excitability and responsiveness) is associated with spontaneous dorsal horn neuron activity, responses from neurons that normally only respond to low-intensity stimuli (altered neural connections following sprouting of Ab fibers to superficial laminae), expansion of dorsal horn neuron receptive fields, and reduction in central inhibition.20-22 Central sensitization is associated with persistent pain, hyperalgesia, allodynia, and the spread of pain to uninjured tissue, i.e., secondary hyperalgesia due to increased receptor

Peripheral terminal primary afferent fiber opioid

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