Characterization of spinal alpha-adrenergic modulation of nociceptive transmission and hyperalgesia throughout postnatal development in rats.
OBJECTIVE
The selective alpha(2)-adrenergic agonist dexmedetomidine is used clinically for analgesia and sedation, but effects in early life are not well characterized. Investigation of age-related effects of dexmedetomidine is important for evaluating responses to exogenously administered analgesics and provides insight into postnatal function of noradrenergic pathways.


METHODS
We examined effects of epidural dexmedetomidine in anaesthetized rat pups (3, 10 and 21 postnatal days) using a quantitative model of nociception and C-fibre induced hyperalgesia. Electromyographic recordings of withdrawal responses to hindpaw mechanical stimuli measured effects of dexmedetomidine upon the baseline reflex and the response to mustard oil application on the hindpaw (primary hyperalgesia) or hindlimb (secondary hyperalgesia). In addition, we compared epidural with systemic administration, examined effects of spinal transection and evaluated heart rate changes following dexmedetomidine.


RESULTS
Epidural dexmedetomidine dose-dependently prevented mustard oil-induced hyperalgesia at all ages but dose requirements were lower in the youngest pups. Higher doses also suppressed the baseline nociceptive reflex when given epidurally, but had no effect when given systemically. Analgesic efficacy was the same for primary and secondary hyperalgesia, and was not diminished by spinal cord transection.


CONCLUSIONS
Our laboratory studies predict that spinally mediated alpha(2)-agonist analgesia would be effective throughout postnatal development, dose requirements would be lower in early life and selective anti-hyperalgesic effects could be achieved with epidural administration at doses lower than associated with antinociceptive or cardiovascular effects. Clinical trials of alpha(2) agonists in neonates and infants should consider developmentally regulated changes.
Walker
S M
SM
Portex Anaesthesia Unit, UCL Institute of Child Health, University College London, London, UK. suellen.walker@ich.ucl.ac.uk
Fitzgerald
M
M
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000367:Age Factors; D000700:Analgesics / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D020927:Dexmedetomidine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004576:Electromyography; D006339:Heart Rate / Q000187:drug effects; D006614:Hindlimb; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007268:Injections, Epidural; D009149:Mustard Plant; D009412:Nerve Fibers / Q000187:drug effects; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects; D010938:Plant Oils; D051381:Rats; D013119:Spinal Cord Injuries
D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D010938:Plant Oils; D020927:Dexmedetomidine; C027793:mustard oil