title: Spinal gap junctions: potential involvement in pain facilitation.
abstract: Glia are now recognized as important contributors in pathological pain creation and maintenance. Spinal cord glia exhibit extensive gap junctional connectivity, raising the possibility that glia are involved in the contralateral spread of excitation resulting in mirror image pain. In the present experiments, the gap junction decoupler carbenoxolone was administered intrathecally after induction of neuropathic pain in response to sciatic nerve inflammation (sciatic inflammatory neuropathy) or partial nerve injury (chronic constriction injury). In both neuropathic pain models, a low dose of carbenoxolone reversed mirror image mechanical allodynia, while leaving ipsilateral mechanical allodynia unaffected. Ipsilateral thermal hyperalgesia was briefly attenuated. Critically, blockade of mechanical allodynia and thermal hyperalgesia was not observed in response to intrathecal glycyrrhizic acid, a compound similar to carbenoxolone in all respects but it does not decouple gap junctions. Thus, blockade of mechanical allodynia and thermal hyperalgesia by carbenoxolone does appear to reflect an effect on gap junctions. Examination of carbenoxolone's effects on intrathecal human immunodeficiency virus type 1 gp120 showed that blockade of pain facilitation might result, at least in part, via suppression of interleukin-1 and, in turn, interleukin-6. These data provide the first suggestion that spread of excitation via gap junctions might contribute importantly to inflammatory and traumatic neuropathic pain.
  
  
  CONCLUSIONS
  The current studies provide evidence for involvement of gap junctions in spinal cord pain facilitation. Intrathecal carbenoxolone, a gap junction decoupler, reversed neuropathy-induced mirror image pain and intrathecal gp120-induced allodynia. In addition, it decreased gp120-induced proinflammatory cytokines. This suggests gap junction activation might lead to proinflammatory cytokine release by distantly activated glia.
authors.affiliation: Department of Psychology & The Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado 90309-0345, USA.
authors.forename: Leah E
authors.initials: LE
authors.lastname: Spataro
authors.forename: Evan M
authors.initials: EM
authors.lastname: Sloane
authors.forename: Erin D
authors.initials: ED
authors.lastname: Milligan
authors.forename: Julie
authors.initials: J
authors.lastname: Wieseler-Frank
authors.forename: Diana
authors.initials: D
authors.lastname: Schoeniger
authors.forename: Brian M
authors.initials: BM
authors.lastname: Jekich
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Barrientos
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D002229:Carbenoxolone / Q000494:pharmacology; D002908:Chronic Disease; D017629:Gap Junctions / Q000187:drug effects / Q000502:physiology*; D019695:Glycyrrhizic Acid / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology; D006930:Hyperalgesia / Q000503:physiopathology; D007278:Injections, Spinal; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D009408:Nerve Compression Syndromes / Q000503:physiopathology; D010146:Pain / Q000503:physiopathology*; D020671:Posterior Horn Cells / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000503:physiopathology; D013047:Specific Pathogen-Free Organisms
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D015699:HIV Envelope Protein gp120; D007375:Interleukin-1; D019695:Glycyrrhizic Acid; D002229:Carbenoxolone