title: Streptozotocin-induced early thermal hyperalgesia is independent of glycemic state of rats: role of transient receptor potential vanilloid 1(TRPV1) and inflammatory mediators.
abstract: BACKGROUND
  Streptozotocin (STZ) is used as a common tool to induce diabetes and to study diabetes-induced complications including diabetic peripheral neuropathy (DPN). Previously, we have reported that STZ induces a direct effect on neurons through expression and function of the Transient receptor potential vanilloid 1 (TRPV1) channel in sensory neurons resulting in thermal hyperalgesia, even in non-diabetic STZ-treated mice. In the present study, we investigated the role of expression and function of TRPV1 in the central sensory nerve terminals in the spinal cord in STZ-induced hyperalgesia in rats.
  
  
  RESULTS
  We found that a proportion of STZ-treated rats were normoglycemic but still exhibited thermal hyperalgesia and mechanical allodynia. Immunohistochemical data show that STZ treatment, irrespective of glycemic state of the animal, caused microglial activation and increased expression of TRPV1 in spinal dorsal horn. Further, there was a significant increase in the levels of pro-inflammatory mediators (IL-1β, IL-6 and TNF-α) in spinal cord tissue, irrespective of the glycemic state. Capsaicin-stimulated release of calcitonin gene related peptide (CGRP) was significantly higher in the spinal cord of STZ-treated animals. Intrathecal administration of resiniferatoxin (RTX), a potent TRPV1 agonist, significantly attenuated STZ-induced thermal hyperalgesia, but not mechanical allodynia. RTX treatment also prevented the increase in TRPV1-mediated neuropeptide release in the spinal cord tissue.
  
  
  CONCLUSIONS
  From these results, it is concluded that TRPV1 is an integral component of initiating and maintaining inflammatory thermal hyperalgesia, which can be alleviated by intrathecal administration of RTX. Further, the results suggest that enhanced expression and inflammation-induced sensitization of TRPV1 at the spinal cord may play a role in central sensitization in STZ-induced neuropathy.
authors.affiliation: Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, 62702, USA.
authors.forename: Mahendra
authors.initials: M
authors.lastname: Bishnoi
authors.forename: Christine A
authors.initials: CA
authors.lastname: Bosgraaf
authors.forename: Mruvil
authors.initials: M
authors.lastname: Abooj
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhong
authors.forename: Louis S
authors.initials: LS
authors.lastname: Premkumar
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006930:Hyperalgesia / Q000097:blood* / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D006943:Hyperglycemia / Q000097:blood / Q000150:complications / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D007328:Insulin / Q000097:blood; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010146:Pain / Q000097:blood / Q000150:complications; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013311:Streptozocin; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D004224:Diterpenes; D018836:Inflammation Mediators; D007328:Insulin; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D013311:Streptozocin; C024353:resiniferatoxin; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin