Antagonism of morphine analgesia by nonopioid cold-water swim analgesia: Direct evidence for collateral inhibition

Judith L. Steinman, Patricia L. Faris, Phyllis E. Mann, John W. Olney, Barry R. Komisaruk, William D. Willis, Richard J. Bodnar

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The demonstrated existence of opioid and nonopioid forms of pain control has raised questions as to how they interact. Previous indirect evidence suggests that activation of one system inhibited the activation of the other. The present study assessed this directly using morphine as an opiate form of analgesia and continuous cold-water swims (CCWS, 4°C, 2 min) as the nonopioid form. A significant reduction in morphine (8 mg/kg, SC) analgesia on the tail-flick test was observed if rats were acutely exposed to CCWS immediately prior to morphine administration. The inability of naloxone (10 mg/kg, SC) to reduce CCWS analgesia verified its nonopioid nature. The antagonism of morphine (3 mg/kg, SC) analgesia was greater following preexposure to 2 min of CCWS than 1 min of CCWS. CCWS was also more effective in antagonizing analgesia induced by the 3 mg/kg than the 8 mg/kg dose of morphine. The antagonism of morphine analgesia by CCWS was dependent upon the temporal patterning of stimulus presentation: exposure to CCWS 20 or 60 min prior to morphine failed to alter subsequent morphine analgesia. A significant reduction in analgesia induced by intraperitoneal administration of morphine (10 mg/kg) was also observed when CCWS was presented immediately prior to injection, suggesting that pharmacokinetic factors such as altered drug absorbance by CCWS-induced vasoconstriction do not appear to explain these effects. These data provide direct support for the existence of collateral inhibitory mechanisms activated by CCWS and morphine, and suggests that these opioid and nonopioid forms of analgesia do not function synergistically, but instead involve some form of hierarchical order.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalNeuroscience and Biobehavioral Reviews
Issue number1
StatePublished - 1990

Bibliographical note

Funding Information:
ACKNOWLEDGEMENTS This research was supported in part by grants from NIH NS07022 (J.L.S.), NS22948 (B.R.K.), RSDA MH00595 (P.L.F.), RSA MH38894 (J.W.D.), NS09743 and NS 11255 (W.D.W.) and PSC/CUNY 6-67241, 6-68244 and 6-69213 (R.J.B.). We wish to thank the E. I. Du Pont Company and the Pennick Corporation for their generous gifts of naloxone and morphine, respectively, S. T. Cunningham and K. Repola for technical assistance, and an anonymous reviewer for suggesting the third experiment.


  • Collateral inhibition
  • Continuous cold-water swim
  • Morphine
  • Nonopioid analgesia
  • Opioid analgesia
  • Rats
  • Tail-flick test


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