Articles: hyperalgesia.
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Anesthesia and analgesia · Apr 2002
Spinal and peripheral mu opioids and the development of secondary tactile allodynia after thermal injury.
Local thermal injury to the paw leads to an increased sensitivity to a noxious stimulus applied to the site (primary thermal hyperalgesia) and an increased sensitivity to tactile stimuli in skin sites adjacent to the primary injury (secondary tactile allodynia; 2 degrees TA). We sought to define the peripheral and spinal actions of mu opioids in regulating 2 degrees TA. First, a mild thermal injury was induced on one heel, producing 2 degrees TA. This 2 degrees TA was blocked by pretreatment, but not posttreatment, with a topical mu-opioid agonist, loperamide (1.7%-5%). Second, 2 degrees TA was blocked by intrathecal morphine (0.1-10 microg) pre- and postinjury. 2 degrees TA reappeared when systemic naloxone was given before, but not after, injury in intrathecal morphine-pretreated rats. Intrathecal remifentanil, a short-lasting mu-opioid agonist, infused periinjury (3 microg/min), did not block subsequent primary thermal hyperalgesia, but it produced a dose-dependent (0.3-3 microg/min) abolition of 2 degrees TA. Local tissue injury leads to 2 degrees TA by the activation of opiate-sensitive afferents and the initiation of a cascade that persists in the absence of that initiating injury-induced stimulus. ⋯ Sensitivity to touch observed in areas adjacent to injury is blocked by opioids applied before, but not after, injury. This suggests that injury-activated opioid-sensitive fibers are responsible for sensitization and reveals a cascade that is diminished by pretreatment but not posttreatment, providing a rationale for adequate analgesia before injury (surgery) has occurred.
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Metabotropic glutamate receptor 5 (mGluR5) protein increased after sciatic nerve section in ipsilateral L4 and L5 DRG neuronal profiles, with most of the increase occurring in myelinated A-fiber somata. mGluR5 also increased in lamina II of the ipsilateral spinal cord and the proximal sciatic nerve stump in this model. After L5 spinal nerve ligation, mGluR5 immunoreactivity increased dramatically not only in damaged L5 but also in the neighboring undamaged L4. Interestingly, after partial sciatic nerve section, mGluR5 expression did not change in either L4 or L5 DRG neuronal profiles. ⋯ Furthermore, A-fibers in the uninjured L4 DRG after L5 spinal nerve ligation that have increased mGluR5 are the same A-fibers that newly express vanilloid receptor 1 after such injury. Together, these results suggest that, after L5 spinal nerve injury, mGluR5 expression on A-fibers is essential to the development of thermal hyperalgesia. After partial nerve section, however, it is unlikely that thermal responses are mediated through mGluR5 because no such increase in mGluR5 is detected in this model and MPEP is ineffective.
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Brain Res. Mol. Brain Res. · Mar 2002
Induction of connexin 37 expression in a rat model of neuropathic pain.
Activation of cutaneous C-fibers by capsaicin or sciatic nerve transection increases the number of astrocytic gap junctions as well as the levels of connexin 43 in the dorsal horn on the stimulated side. Changes in connexin 37 mRNA expression following nerve injury have not been previously documented. We examined the role of gap junction protein connexin 37 in neuropathic hypersensitivity following peripheral nerve injury. ⋯ Sciatic nerve connexin 37 mRNA increases were proportional to the extent of thermal hyperalgesia, but skin, muscle, and lumbar spinal cord connexin 37 mRNA showed no significant changes. Neuropathic pain relief correlated with downregulation of connexin 37 mRNA. Results indicate that upregulation of connexin 37 mRNA following sciatic nerve injury correlates with subsequent thermal hyperalgesia, which suggests that gap junctions (connexin 37) are responsible for the hyperexcitability following peripheral nerve injury.
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Anti-GD(2) antibodies have been shown to be effective for immunotherapy of neuroblastoma and other GD(2) enriched malignancies. Infusion of anti-GD(2) antibodies frequently causes spontaneous pain and allodynia for the duration of the immunotherapy and occasionally longer lasting neuropathic pain. Bolus intravenous injection of anti-GD(2) in rats initiates mechanical allodynia as measured by withdrawal threshold of the hindpaws. ⋯ Intrathecal pretreatment 48--72 h prior to the experiment with capsaicin at doses sufficient to cause a 50% depletion of dorsal horn CGRP, caused a total blockade of the mechanical allodynia indicating an involvement of peptidergic fine afferent fibers. It is likely that the antibody reacts with an antigen on peripheral nerve and/or myelin to initiate its effect. The lack of observed thermal hyperalgesia is surprising especially in light of the capsaicin-associated blockade, however, it is consistent with several other immune system related models of pain.
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Comparative Study
Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain.
Patients with sensory disturbances of painful and non-painful character show distinct changes in touch and/or pain sensitivity. The patterns of sensory changes were compared to those of human surrogate models of neuropathic pain to assess the underlying mechanisms. We investigated 30 consecutive in-patients with dysaesthesia of various origins (peripheral, spinal, and brainstem lesions) and 15 healthy subjects. ⋯ Our findings suggest that neuropathic pain is based on two distinct mechanisms: (I) central sensitization (neurogenic hyperalgesia; in patients with minor sensory impairment) and (II) partial nociceptive deafferentation (painful hypoalgesia; in patients with major sensory deficit). This distinction as previously postulated for postherpetic neuralgia, is obviously valid also for other conditions. Our findings emphasize the significance of a mechanism-based classification of neuropathic pain.