Intrathecal pertussis toxin produces hyperalgesia and allodynia in mice.
Pertussis toxin (PTX), which causes the ADP-ribosylation and thereby inactivation of Gi-proteins, has been employed in analgesia testing to elucidate receptors that are coupled to inhibitory G-proteins, such as the mu-opioid receptor. Consistent with previous findings, the antinociceptive effects of morphine (1-10 microg) as measured by tail-flick latency using a 55 degrees C water bath, were blocked by a single intrathecal injection of 0.5 microg PTX 6 days prior to intrathecal morphine administration. In addition, mice treated intrathecally with 0.5 microg of PTX had significantly shorter baseline tail-flick latencies compared with vehicle treated mice using a 55 degrees C water bath when tested 6 days after PTX or vehicle administration. Morphine-induced antinociception was blocked in a dose-dependent manner by PTX with complete blockade of morphine following a 0.3-microg dose of PTX. Further, mice administered 0.1 microg or 0.3 microg PTX intrathecally had significantly shorter tail-flick latencies compared with vehicle injected mice using a 40, 45 or 50 degrees C water bath when tested 7 days after intrathecal injection. Shorter tail-flick latencies were observed at 45 degrees C as early as 48 h after intrathecal administration of 0.03, 0.1 or 0.3 microg PTX and these shorter tail-flick latencies were observed up to 90 days after intrathecal PTX administration. The intrathecal administration of PTX caused hyperalgesia and allodynia that appears similar to the symptoms reported by patients suffering from neuropathic pain, and suggests that deficiencies in inhibitory systems, as compared with increases in excitatory systems, may play a role in the pathophysiology of at least some central or neuropathic pain states.
Womer
D E
DE
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. womerdaniele@lilly.com
DeLapp
N W
NW
Shannon
H E
HE
D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000139:chemically induced*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology; D010147:Pain Measurement; D037342:Pertussis Toxin; D010812:Physical Stimulation; D011930:Reaction Time; D013997:Time Factors; D010566:Virulence Factors, Bordetella
D000701:Analgesics, Opioid; D010566:Virulence Factors, Bordetella; D009020:Morphine; D037342:Pertussis Toxin