Articles: hyperalgesia.
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Descending controls on spinal nociceptive processing play a pivotal role in shaping the pain experience after tissue injury. Secondary hypersensitivity develops within undamaged tissue adjacent and distant to damaged sites. Spinal neuronal pools innervating regions of secondary hypersensitivity are dominated by descending facilitation that amplifies spinal inputs from unsensitized peripheral nociceptors. Cyclooxygenase-prostaglandin (PG) E2 signaling within the ventrolateral periaqueductal gray (vlPAG) is pronociceptive in naive and acutely inflamed animals, but its contributions in more prolonged inflammation and, importantly, secondary hypersensitivity remain unknown. In naive rats, PG EP3 receptor (EP3R) antagonism in vlPAG modulated noxious withdrawal reflex (EMG) thresholds to preferential C-nociceptor, but not A-nociceptor, activation and raised thermal withdrawal thresholds in awake animals. In rats with inflammatory arthritis, secondary mechanical and thermal hypersensitivity of the hindpaw developed and was associated with spinal sensitization to A-nociceptor inputs alone. In arthritic rats, blockade of vlPAG EP3R raised EMG thresholds to C-nociceptor activation in the area of secondary hypersensitivity to a degree equivalent to that evoked by the same manipulation in naive rats. Importantly, vlPAG EP3R blockade also affected responses to A-nociceptor activation, but only in arthritic animals. We conclude that vlPAG EP3R activity exerts an equivalent facilitation on the spinal processing of C-nociceptor inputs in naive and arthritic animals, but gains in effects on spinal A-nociceptor processing from a region of secondary hypersensitivity. Therefore, the spinal sensitization to A-nociceptor inputs associated with secondary hypersensitivity is likely to be at least partly dependent on descending prostanergic facilitation from the vlPAG. ⋯ After tissue damage, sensitivity to painful stimulation develops in undamaged areas (secondary hypersensitivity). This is found in many painful conditions, particularly arthritis. The periaqueductal gray (PAG) is an important center that controls spinal nociceptive processing, on which secondary hypersensitivity depends. Prostaglandins (PGs) are mediators of inflammation with pronociceptive actions within the PAG under normal conditions. We find that secondary hindpaw hypersensitivity in arthritic rats results from spinal sensitization to peripheral A-nociceptor inputs. In the PAG of arthritic, but not naive, rats, there is enhanced control of spinal A-nociceptor processing through PG EP3 receptors. The descending facilitatory actions of intra-PAG PGs play a direct and central role in the maintenance of inflammatory secondary hypersensitivity, particularly relating to the processing of A-fiber nociceptive information.
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The treatment of neuropathic pain remains a clinical challenge because of its unclear mechanisms and broad clinical morbidity. Matrix metalloproteinase (MMP)-9 and MMP-2 have previously been described as key components in neuropathic pain because of their facilitation of inflammatory cytokine maturation and induction of neural inflammation. Therefore, the inhibition of MMPs may represent a novel therapeutic approach to the treatment of neuropathic pain. ⋯ The administration of NAC blocked the maturation of interleukin-1β, which is a critical substrate of MMPs, and markedly suppressed the neuronal activation induced by CCI, including inhibiting the phosphorylation of protein kinase Cγ, NMDAR1, and mitogen-activated protein kinases. Finally, NAC significantly inhibited CCI-induced microglia activation but elicited no notable effects on astrocytes. These results demonstrate an effective and safe approach that has been used clinically to alleviate neuropathic pain through the powerful inhibition of the activation of MMPs.
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Review
Muscle Triggers as a Possible Source of Pain in a Sub-group of Tension Type Headache Patients?
Tension-type headache (TTH) is a common condition but the underlying etiology is not understood. Episodic TTH may develop into chronic TTH, and some possible triggers may be involved in generation and maintenance. Nociceptive generators and hyperexcitable spots in neck and shoulder regions may to some degree contribute to TTH. The current paper highlights some of the possible triggers and associated pain mechanisms involved in TTH and discusses whether inhibition of these possible triggers may provide new treatment options. ⋯ Understanding the possible triggers in TTH, muscle hyperalgesia, and widespread pain sensitization, may help to develop better management regimes and possibly prevent TTH from developing into more chronic conditions. Currently, there is a striking difference between the clinical observational studies favoring the role of muscle triggers in TTH and the intervention studies generally not supporting the role of muscle triggers in TTH.
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Although fibromyalgia (FM) is associated with a deficit in inhibitory conditioned pain modulation (CPM), the discriminative power of CPM procedures is unknown. Moreover, the high intersubject heterogeneity in CPM responses in FM raises the possibility that a sizeable subgroup of these patients may experience pain facilitation during CPM, but the phenomenon has not been explicitly studied. To address these issues, 96 patients with FM and 71 healthy controls were recruited. ⋯ Finally, the rate of patients with FM who reported pain facilitation during the CPM procedure was found to be significantly increased compared with that of controls (41.7% vs 21.2%). The good discriminative power of the composite pain index highlights the need for further validation studies using mechanistically relevant psychophysical procedures in FM. The low sensitivity of the CPM procedure, combined with the large proportion of patients with FM experiencing pain facilitation during CPM, strongly suggests that endogenous pain inhibition mechanisms are deeply impaired in patients with FM, but only in a subgroup of them.
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Several mechanisms of remifentanil-induced hyperalgesia in spinal cord mainly have been explained such as N-methyl-D-aspartate receptors activation, but the mechanism in dorsal root ganglion (DRG) is poorly understood. It has been reported that CCL3 may be a regulator in both inflammatory pain and hyperalgesia. In this paper we explored whether CCL3 and CCR5, the mainly receptor of CCL3, play a role in the remifentanil-induced hyperalgesia in DRG by using a rat model with remifentanil administration. ⋯ The results highlighted the fact that CCL3 and its receptor CCR5 in DRG might contribute to remifentanil-induced hyperalgesia. Thus CCL3/CCR5 signaling may be further considered in the development of new therapeutic strategies.