Chronic pain hypersensitivity depends on N-type voltage-gated calcium channels (CaV2.2). However, the use of CaV2.2 blockers in pain therapeutics is limited by side effects that result from inhibited physiological functions of these channels. Here we report suppression of both inflammatory and neuropathic hypersensitivity by inhibiting the binding of the axonal collapsin response mediator protein 2 (CRMP-2) to CaV2.2, thus reducing channel function. A 15-amino acid peptide of CRMP-2 fused to the transduction domain of HIV TAT protein (TAT-CBD3) decreases neurotransmitter release from nociceptive dorsal root ganglion neurons, reduces meningeal blood flow, reduces nocifensive behavior induced by subcutaneous formalin injection or following corneal capsaicin application, and reverses neuropathic hypersensitivity produced by the antiretroviral drug 2’,3’-dideoxycytidine. TAT-CBD3 was mildly anxiolytic but innocuous on sensorimotor and cognitive functions and despair. By preventing CRMP-2-mediated enhancement of CaV2.2 function, TAT-CBD3 alleviates inflammatory and neuropathic hypersensitivity, an approach that may prove useful in managing clinical pain.
Animal models of inflammation are used to assess the production of inflammatory mediators at sites of inflammation, the anti-inflammatory properties of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs), and the efficacy of putative analgesic compounds to reverse cutaneous hypersensitivity. This protocol details methods to elicit and measure carrageenan- and complete Freund’s adjuvant-induced cutaneous inflammation. Due to possible differences between the dorsal root sensory system and the trigeminal sensory system, injections of either the footpad or vibrissal pad are described. In this manner, cutaneous inflammation can be assessed in tissue innervated by the lumbar dorsal root ganglion neurons (footpad) and by the trigeminal ganglion neurons (vibrissal pad).
The subcutaneous air pouch is an in vivo model that can be used to study the components of acute and chronic inflammation, the resolution of the inflammatory response, the oxidative stress response, and potential therapeutic targets for treating inflammation. Injection of irritants into an air pouch in rats or mice induces an inflammatory response that can be quantified by the volume of exudate produced, the infiltration of cells, and the release of inflammatory mediators. The model presented in this unit has been extensively used to identify potential anti-inflammatory drugs.
It is well established that dorsal root ganglion (DRG) cells synthesize prostaglandin. However, the role that prostaglandin plays in the inflammatory hyperalgesia of peripheral tissue has not been established. Recently, we have successfully established a technique to inject drugs (3 μL) directly into the L5-DRG of rats, allowing in vivo identification of the role that DRG cell-derived COX-1 and COX-2 play in the development of inflammatory hyperalgesia of peripheral tissue. IL-1β (0.5 pg) or carrageenan (100 ng) was administered in the L5-peripheral field of rat hindpaw and mechanical hyperalgesia was evaluated after 3 h. Administration of a nonselective COX inhibitor (indomethacin), selective COX-1 (valeryl salicylate), or selective COX-2 (SC-236) inhibitors into the L5-DRG prevented the hyperalgesia induced by IL-1β. Similarly, oligodeoxynucleotide-antisense against COX-1 or COX-2, but not oligodeoxynucleotide-mismatch, decreased their respective expressions in the L5-DRG and prevented the hyperalgesia induced by IL-1β in the hindpaw. Immunofluorescence analysis demonstrated that the amount of COX-1 and COX-2, constitutively expressed in TRPV-1 + cells of the DRG, significantly increased after carrageenan or IL-1β administration. In addition, indomethacin administered into the L5-DRG prevented the increase of PKCe expression in DRG membrane cells induced by carrageenan. Finally, the administration of EP1/EP2 (7.5 ng) or EP4 (10 μg) receptor antagonists into L5-DRG prevented the hyperalgesia induced by IL-1β in the hindpaw. In conclusion, the results of this study suggest that the inflammatory hyperalgesia in peripheral tissue depends on activation of COX-1 and COX-2 in C-fibers, which contribute to the induction and maintenance of sensitization of primary sensory neurons.D uring tissue injury, prostaglandin-E 2 (PGE 2 ) is produced by the activation of the enzyme cyclooxygenase (COX) to play an important role in inflammatory hyperalgesia. PGE 2 sensitizes peripheral nociceptors through the activation of PGE 2 receptors (EP) (1). This sensitization, characterized by a reduction of nociceptive threshold and by an increase in peripheral afferent neuron responsiveness, is the main feature of inflammatory hyperalgesia in the peripheral tissue. The widespread use of nonsteroidal antiinflammatory drugs to control inflammatory hyperalgesia exemplifies the relevance of PGE 2 for the development of inflammatory hyperalgesia. These drugs decrease peripheral inflammatory hyperalgesia by inhibiting COX and, therefore, by preventing the synthesis of PGE 2 (2, 3).The COX enzyme is expressed in two major isoforms, COX-1 and COX-2, with different biological functions (4), although both play a role in the inflammatory hyperalgesia (5, 6). The isoform of COX constitutively expressed in dorsal root ganglion (DRG) is still unclear. Although COX-1 mRNA and, to a lesser extent, COX-2 mRNA have been detected in DRG cultures (7) under basal conditions, immunohistochemical studies have shown that DRG cells express only COX-1, but not C...
Our data provide important insight regarding the alterations in intercalated disc components resulting from severe septic injury. The intercalated disc remodeling under both protein expression and structural features in experimental severe sepsis induced by cecal ligation and puncture may be partly responsible for myocardial depression in sepsis/septic shock. Although further electrophysiological studies in animals and humans are needed to determine the effect of these alterations on myocardial conduction velocity, the abnormal variables may emerge as therapeutic targets, and their modulation might provide beneficial effects on future cardiovascular outcomes and mortality in sepsis.
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