Rho-kinase inhibition enhances axonal plasticity and attenuates cold hyperalgesia after dorsal rhizotomy.
Dorsal rhizotomy results in primary deafferentation of the dorsal horn with concomitant sprouting of spared intraspinal monoaminergic axons. Because descending monoaminergic systems are thought to mitigate nociceptive transmission from the periphery and because dorsal rhizotomy can result in neuropathic pain, we sought to determine whether the rhizotomy-induced sprouting response could be further augmented. Because myelin-derived molecules mask endogenous plasticity of CNS axons and because myelin-inhibitory signaling occurs through the Rho-GTPase pathway, we inhibited Rho-pathway signaling after cervical dorsal rhizotomy in rats. An increase in the density of serotonergic- and tyrosine hydroxylase-positive fibers was seen in the dorsal horn 1 week after septuple rhizotomy, and axon density continued to increase for at least 1 month. One week after septuple rhizotomy, administration of intrathecal Y-27632, an antagonist of Rho-kinase (ROCK), increased the density of both fiber types over vehicle-treated controls. To examine behavioral effects of both cervical rhizotomy and ROCK inhibition, we examined responses to evoked pain: mechanical and thermal allodynia and cold hyperalgesia in the forepaw were examined after single, double, and quadruple rhizotomies of dorsal roots of the brachial plexus. The most notable behavioral outcome was the development of cold hyperalgesia in the affected forepaw after rhizotomies of the C7 and C8 dorsal roots. Application of Y-27632 both attenuated cold hyperalgesia and induced monoaminergic plasticity after C7/8 rhizotomy. Thus, inhibition of Rho-pathway signaling both promoted the sprouting of intact supraspinal monoaminergic fibers and alleviated pain after dorsal rhizotomy.
Ramer
Leanne M
LM
International Collaboration on Repair Discoveries, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4.
Borisoff
Jaimie F
JF
Ramer
Matt S
MS
D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001369:Axons / Q000473:pathology; D015415:Biomarkers; D001917:Brachial Plexus / Q000503:physiopathology; D002422:Causalgia / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D003080:Cold Temperature / Q000009:adverse effects; D004298:Dopamine / Q000502:physiology; D005552:Forelimb / Q000294:innervation; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D007278:Injections, Spinal; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009412:Nerve Fibers / Q000737:chemistry / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects*; D010147:Pain Measurement; D020671:Posterior Horn Cells / Q000502:physiology*; D011493:Protein Kinase C / Q000032:analysis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D019051:Rhizotomy; D012701:Serotonin / Q000502:physiology; D015398:Signal Transduction; D016037:Single-Blind Method; D013314:Stress, Mechanical; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis; D054460:rho-Associated Kinases
D000577:Amides; D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011725:Pyridines; C108830:Y 27632; D012701:Serotonin; D014446:Tyrosine 3-Monooxygenase; C087857:protein kinase C gamma; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D004298:Dopamine