Intrathecal clonidine in the neonatal rat: Dose-dependent analgesia and evaluation of spinal apoptosis and toxicity

Suellen M. Walker, Marjorie Grafe, Tony L. Yaksh

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

BACKGROUND: Neuraxial clonidine is used for perioperative analgesia in children of all ages. Preclinical studies in the postnatal rat allow comparison of the relative toxicity and safety of spinal analgesics throughout postnatal development. METHODS: Rat pups aged 3, 7, or 21 postnatal (P) days were briefly anesthetized for intrathecal injections of saline or clonidine. At each age, the maximum tolerated, antinociceptive (increased hindlimb mechanical withdrawal threshold) and antihyperalgesic (hindpaw carrageenan inflammation) doses were determined. Lumbar spinal cord sections were assessed for apoptosis and cell death (histology, activated caspase-3 immunohistochemistry, Fluoro-Jade C staining), histopathology (hematoxylin and eosin staining), and increased glial reactivity (microglial and astrocytic markers). P3 intrathecal ketamine sections served as positive controls. In additional groups, thermal latency and mechanical withdrawal threshold were measured at P35. RESULTS: Intrathecal clonidine produces age-and dose-dependent analgesia in rat pups. Maximal doses of clonidine did not alter the degree or distribution of apoptosis or increase glial reactivity in the neonatal spinal cord. No spinal histopathology was seen 1 or 7 days after injection at any age. Intrathecal clonidine did not produce persistent changes in reflex sensitivity to mechanical or thermal stimuli at P35. CONCLUSIONS: Intrathecal clonidine in the postnatal rat did not produce signs of spinal cord toxicity, even at doses much larger than required for analgesia. The therapeutic ratio (maximum tolerated dose/antihyperalgesic dose) was >300 at P3, >30 at P7, and >10 at P21. These data provide additional information to inform the clinical choice of spinal analgesic drug in early life.

Original languageEnglish (US)
Pages (from-to)450-460
Number of pages11
JournalAnesthesia and Analgesia
Volume115
Issue number2
DOIs
StatePublished - Aug 2012

Fingerprint

Clonidine
Analgesia
Apoptosis
Spinal Cord
Neuroglia
Analgesics
Hot Temperature
Staining and Labeling
Spinal Injections
Maximum Tolerated Dose
Carrageenan
Ketamine
Hematoxylin
Eosine Yellowish-(YS)
Hindlimb
Caspase 3
Reflex
Histology
Cell Death
Immunohistochemistry

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Intrathecal clonidine in the neonatal rat : Dose-dependent analgesia and evaluation of spinal apoptosis and toxicity. / Walker, Suellen M.; Grafe, Marjorie; Yaksh, Tony L.

In: Anesthesia and Analgesia, Vol. 115, No. 2, 08.2012, p. 450-460.

Research output: Contribution to journalArticle

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