Gabapentin prevents delayed and long-lasting hyperalgesia induced by fentanyl in rats.
BACKGROUND
Opioid-induced hyperalgesia can develop rapidly after opioid exposure. Neuropathic pain and opioid-induced hyperalgesia share common pathophysiologic mechanisms. Gabapentin is effective for the management of neuropathic pain and may therefore prevent opioid-induced hyperalgesia. This study tested the effectiveness of gabapentin for prevention of long-lasting hyperalgesia induced by acute systemic fentanyl in uninjured rats. Involvement of the alpha2delta auxiliary subunits of voltage-gated calcium channels in the prevention of opioid-induced hyperalgesia by gabapentin also was assessed.


METHODS
Hyperalgesia was induced in male Sprague-Dawley rats with subcutaneous fentanyl (four injections, 20, 60, or 100 microg/kg per injection at 15-min intervals). Intraperitoneal (30, 75, 150, or 300 mg/kg) or intrathecal (300 microg) gabapentin was administered 30 min before or 300 min after (intraperitoneal 150 mg/kg) the first fentanyl injection. Sensitivity to nociceptive stimuli (paw-pressure test) was assessed on the day of the experiment and for several days after injections. The effects combining gabapentin with intrathecal ruthenium red (20 ng) also were assessed.


RESULTS
Fentanyl administration was followed by an early increase (analgesia) and by a later and sustained decrease (hyperalgesia) in nociceptive thresholds. Gabapentin did not significantly modify the early analgesic component but dose-dependently prevented the delayed decrease in nociceptive threshold. Ruthenium red partially, but significantly, opposed the prevention of opioid-induced hyperalgesia by gabapentin.


CONCLUSIONS
Intraperitoneal and intrathecal gabapentin prevents the development of hyperalgesia induced by acute systemic exposure to opioids. This prevention may result, at least in part, from binding of gabapentin to the alpha2delta auxiliary subunits of voltage-gated calcium channels.
Van Elstraete
Alain C
AC
Université Paris-Sud, Assistance Publique-Hôpitaux de Paris, Département d'Anesthésie-Réanimation, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France.
Sitbon
Philippe
P
Mazoit
Jean-Xavier
JX
Benhamou
Dan
D
D000588:Amines / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000378:metabolism / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005283:Fentanyl / Q000633:toxicity*; D000077206:Gabapentin; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013995:Time; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000627:therapeutic use*
D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D005283:Fentanyl