Hence, a complete understanding of the cellular and molecular processes involved in the development of neuropathic pain is essential for the development of novel therapies. In general, neuropathic pain is the result of abnormal activity of nociceptive neurons. transcription. In this chapter we review the diverse changes produced by inflammatory cytokines in the behavior of sensory neurons in the context of chronic pain syndromes. (pain evoked by a normally innocuous stimulus) and (enhanced pain evoked by a noxious stimulus). From the therapeutic point of view, neuropathic pain is an extremely intractable problem. Once established, pain of this type is not readily susceptible to treatment with nonsteroidal anti-inflammatory drugs. Moreover, although opiates may be employed acutely or for chronic pain states (e.g., terminal cancer), alleviation of neuropathic pain is more problematic as high doses are often required, narrowing the therapeutic index (Hempenstall et al. 2005). The remaining available drugs used to treat these syndromes (tricyclic antidepressants, antiepileptics) are not particularly effective and are also associated with a number of negative side effects (Watson 2000). Hence, a complete understanding of the cellular and molecular processes involved in the development of neuropathic pain is essential for the development of novel therapies. In general, neuropathic pain is the result of abnormal activity of nociceptive neurons. This activity is thought to initially result from the increased neuronal expression and activation of ion channels and receptors that mediate the abnormal generation of action potentials and synaptic transmission in primary afferent nociceptive neurons and/or other parts of the pain pathway. But what causes these changes to occur? It is presumed that some peripheral event provokes primary afferent nociceptive neurons to express different sets of genes, resulting in a new and abnormal chronically hyperexcitable pain phenotype. It has been shown that peripheral nerve injury (trauma-, disease-, or drug-induced) can trigger a wide variety of cellular changes in sensory neurons and, as we have discussed, neuropathic pain following peripheral nerve injury is a consequence of enhanced excitability associated with the chronic sensitization of nociceptive neurons in the peripheral and central nervous systems. Interestingly, following a peripheral nerve injury, not only a subset of injured (Wall and Devor 1983; Kajander et al. 1992; Kim et al. 1993; Amir et al. 1999), but also neighboring noninjured peripheral sensory neurons exhibit spontaneous, ectopic discharges (Tal and Devor 1992; Sheth et al. 2002; Ma et al. 2003; Obata et al. 2003; Liu and Eisenach 2005; Xie et al. 2005). Abnormal excitability of pain neurons may even extend to the spinal cord dorsal horn contralateral to the nerve injury (Sluka et al. 2001, 2007; Raghavendra et al. 2004; Tanaka et al. 2004; Twining et al. 2004; Romero-Sandoval et al. 2005; Bhangoo et al. 2007a; Jung et al. 2007). Although it is clear that molecular changes in the sensory ganglia and spinal cord dorsal horn are responsible for chronic pain, it remains a mystery as to what event(s) are critical for its development and maintenance. 2 Peripheral Nerve Injury and Swelling One important development in our understanding of the cellular and molecular processes that produce neuropathic pain concerns the part of the immune system. Immunity can be dissociated into two different phases C innate and acquired. Acquired immunity entails the trend of immunological 7CKA memory space and includes the antibody and lymphocyte reactions to specific antigens. The forerunner to acquired immunity is the innate immune response. This more basic type of immunity entails a generalized immune cell response to a variety of harmful or pathological intrusions into physiological homeostasis. Molecules such as Toll-like receptors (TLRs), Nod-like receptors, and RIG-like receptors indicated by several types of cells, including leukocytes, Schwann cells, neurons, astrocytes, and microglia, can identify shared molecular patterns indicated by infectious providers, cell debris, or other cellular detritus initiating a cascade of cytokine synthesis that orchestrates a general cellular response to these potential problems (Tanga et al. 2005; Creagh and O’Neill 2006; Kim et al. 2007; Tawfik et al. 2007; Watkins et al. 2007b). As mentioned before, this response.Measurements of pain hypersensitivity have demonstrated allodynia and hyperalgesia in HIV-1 infected individuals. as longer-term changes resulting from fresh gene transcription. With this chapter we review the varied changes produced by inflammatory cytokines in the behavior of sensory neurons in the context of chronic pain syndromes. (pain evoked by a normally innocuous stimulus) and (enhanced pain evoked by a noxious stimulus). From your therapeutic perspective, neuropathic pain is an extremely intractable problem. Once established, pain of this type is not readily susceptible to treatment with nonsteroidal anti-inflammatory medicines. Moreover, although opiates may be used acutely or for chronic pain claims (e.g., terminal malignancy), alleviation of neuropathic pain is definitely more problematic as high doses are often required, narrowing the restorative index (Hempenstall et al. 2005). The remaining available medicines used to treat these syndromes (tricyclic antidepressants, antiepileptics) are not particularly effective and are also associated with a number of negative side effects (Watson 2000). Hence, a complete understanding of the cellular and molecular processes involved in the development of neuropathic pain is essential for the development of novel therapies. In general, neuropathic pain is the result of irregular activity of nociceptive neurons. This activity is definitely thought to in the beginning result from the improved neuronal manifestation and activation of ion channels and receptors that mediate the irregular generation of action potentials and synaptic transmission in main afferent nociceptive neurons and/or other parts of the pain pathway. But what causes these changes to occur? It is presumed that some peripheral event provokes main afferent nociceptive neurons to express different units of genes, resulting in a fresh and irregular chronically hyperexcitable pain phenotype. It has been demonstrated that peripheral nerve injury (stress-, disease-, or drug-induced) can result in a wide variety of cellular changes in sensory neurons and, as we have discussed, neuropathic pain following peripheral nerve injury is definitely a consequence of enhanced excitability associated with the chronic sensitization of nociceptive neurons in the peripheral and central nervous systems. Interestingly, following a peripheral nerve injury, not only a subset of hurt (Wall and Devor 1983; Kajander et al. 1992; Kim et al. 1993; Amir et al. 1999), but also neighboring noninjured peripheral sensory neurons show spontaneous, ectopic discharges (Tal and Devor 1992; Sheth et al. 2002; Ma et al. 2003; Obata et al. 2003; Liu and Eisenach 2005; Xie et al. 2005). Irregular excitability of pain neurons may even extend to the spinal cord dorsal horn contralateral to the nerve injury (Sluka et al. 2001, 2007; Raghavendra et al. 2004; Tanaka et al. 2004; Twining et al. 2004; Romero-Sandoval et al. 2005; Bhangoo et al. 2007a; Jung et al. 2007). Although it is definitely obvious that molecular changes in the sensory ganglia and spinal cord dorsal horn are responsible for chronic pain, it remains a mystery as to what event(s) are critical for its development and maintenance. 2 Peripheral Nerve Injury and Swelling One important development in our understanding of the cellular and molecular processes that produce neuropathic pain concerns the part of the immune system. Immunity can be dissociated into two different phases C innate and acquired. Acquired immunity entails the trend of immunological memory space and includes the antibody and lymphocyte reactions to specific antigens. The forerunner to acquired immunity is the innate immune response. This more basic type of immunity entails a generalized immune cell response to a variety of.TLR5 mediates the immune response to bacterial flagellins. 7CKA suggests that the upregulated expression of inflammatory cytokines in association with tissue damage or infection triggers the observed hyperexcitability of pain sensory neurons. The actions of inflammatory cytokines synthesized by DRG neurons and associated glial cells, as well as by astrocytes and microglia in the spinal cord, can produce changes in the excitability of nociceptive sensory neurons. These changes include quick alterations in the properties of ion channels expressed by these neurons, as well as longer-term changes resulting from new gene transcription. In this chapter we review the diverse changes produced by inflammatory cytokines in the behavior of sensory neurons in the context of chronic pain syndromes. (pain evoked by a normally innocuous stimulus) and (enhanced pain evoked by a noxious stimulus). From your therapeutic point of view, neuropathic pain is an extremely intractable problem. Once established, pain of this type is not readily susceptible to treatment with nonsteroidal anti-inflammatory drugs. Moreover, although opiates may be employed acutely or for chronic pain says (e.g., terminal malignancy), alleviation of neuropathic pain is usually more problematic as high doses are often required, narrowing the therapeutic index (Hempenstall et al. 2005). The remaining available drugs used to treat these syndromes (tricyclic antidepressants, antiepileptics) are not particularly effective and are also associated with a number of negative side effects (Watson 2000). Hence, a complete understanding of the cellular and molecular processes involved in the development of neuropathic pain is essential for the development of novel therapies. In general, neuropathic pain is the result of abnormal activity of nociceptive neurons. This activity is usually thought to in the beginning result from the increased neuronal expression and activation of ion channels and receptors that mediate the abnormal generation of action potentials and synaptic transmission in main afferent nociceptive neurons and/or other parts of the pain pathway. But what causes these changes to occur? It is presumed that some peripheral event provokes main afferent nociceptive neurons to express different units of genes, resulting in 7CKA a new and abnormal chronically hyperexcitable pain phenotype. It has been shown that peripheral nerve injury (trauma-, disease-, or drug-induced) can trigger a wide variety of cellular changes in sensory neurons and, as we have discussed, neuropathic pain following peripheral nerve injury is usually a consequence of enhanced excitability associated with the chronic sensitization of nociceptive neurons in the peripheral and central nervous systems. Interestingly, following a peripheral nerve injury, not only a subset of hurt (Wall and Devor 1983; Kajander et al. 1992; Kim et al. 1993; Amir et al. 1999), but also neighboring noninjured peripheral sensory neurons exhibit spontaneous, ectopic discharges (Tal and Devor 1992; Sheth et al. 2002; Ma et al. 2003; Obata et al. 2003; Liu and Eisenach 2005; Xie et al. 2005). Abnormal excitability of pain neurons may even extend to the spinal cord dorsal horn contralateral to the nerve injury (Sluka et al. 2001, 2007; Raghavendra et al. 2004; Tanaka et al. 2004; Twining et al. 2004; Romero-Sandoval et al. 2005; Bhangoo et al. 2007a; Jung et al. 2007). Although it is usually obvious that molecular changes in the sensory ganglia and spinal cord dorsal horn are responsible for chronic pain, it remains a mystery as to what event(s) are critical for its development and maintenance. 2 Peripheral Nerve Injury and Inflammation One important development in our understanding of the cellular and molecular processes that produce neuropathic pain concerns the role of the immune system. Immunity can be dissociated into two different phases C innate and acquired. Acquired immunity entails the phenomenon of immunological memory and includes the.It is likely that this binding portion of the IL-6 receptor can be provided knockout mice (Gillespie et al. well as by astrocytes and microglia in the spinal cord, can produce changes in the excitability of nociceptive sensory neurons. These changes include rapid alterations in the properties of ion channels expressed by these neurons, as well as longer-term changes resulting from new gene transcription. In this chapter we review the diverse changes produced by inflammatory cytokines in the behavior of sensory neurons in the context of chronic pain syndromes. (pain evoked by a normally innocuous stimulus) and (enhanced pain evoked by a noxious stimulus). From your therapeutic point of view, neuropathic pain is an extremely intractable problem. Once established, pain of this type is not readily susceptible to treatment with nonsteroidal anti-inflammatory drugs. Moreover, although opiates may be employed acutely or for chronic pain says (e.g., terminal malignancy), alleviation of neuropathic pain is usually more problematic as high doses are often required, narrowing the therapeutic index (Hempenstall et al. 2005). The remaining available drugs used to treat these syndromes (tricyclic antidepressants, antiepileptics) are not particularly effective and are also associated with PTPRR a number of negative side effects (Watson 2000). Hence, a complete understanding of the cellular and molecular processes involved in the development of neuropathic pain is essential for the development of novel therapies. In general, neuropathic pain is the result of abnormal activity of nociceptive neurons. This activity is usually thought to in the beginning result from the increased neuronal expression and activation of ion channels and receptors that mediate the abnormal generation of action potentials and synaptic transmission in main afferent nociceptive neurons and/or other parts of the pain pathway. But what causes these changes to occur? It is presumed that some peripheral event provokes main afferent nociceptive neurons to express different units of genes, resulting in a new and abnormal chronically hyperexcitable pain phenotype. It has been shown that peripheral nerve injury (trauma-, disease-, or drug-induced) can trigger a wide variety of mobile adjustments in sensory neurons and, as we’ve discussed, neuropathic discomfort pursuing peripheral nerve damage can be a rsulting consequence improved excitability from the chronic sensitization of nociceptive neurons in the peripheral and central anxious systems. Interestingly, carrying out a peripheral nerve damage, not just a subset of wounded (Wall structure and Devor 1983; Kajander et al. 1992; Kim et al. 1993; Amir et al. 1999), but also neighboring noninjured peripheral sensory neurons show spontaneous, ectopic discharges (Tal and Devor 1992; Sheth et al. 2002; Ma et al. 2003; Obata et al. 2003; Liu and Eisenach 2005; Xie et al. 2005). Irregular excitability of discomfort neurons could even extend towards the spinal-cord dorsal horn contralateral towards the nerve damage (Sluka et al. 2001, 2007; Raghavendra et al. 2004; Tanaka et al. 2004; Twining et al. 2004; Romero-Sandoval et al. 2005; Bhangoo et al. 2007a; Jung et al. 2007). Though it can be very clear that molecular adjustments in the sensory ganglia and spinal-cord dorsal horn are in charge of chronic discomfort, it continues to be a mystery in regards to what event(s) are crucial for its advancement and maintenance. 2 Peripheral Nerve Damage and Swelling One important advancement in our knowledge of the mobile and molecular procedures that make neuropathic discomfort concerns the part from the disease fighting capability. Immunity could be dissociated into two different stages C innate and obtained. Acquired immunity requires the trend of immunological memory space and contains the.
