The Antinociceptive and Antihyperalgesic Effects of Topical Propofol on Dorsal Horn Neurons in the Rat

Abstract

Background Propofol (2,6-diisopropylphenol) is an IV anesthetic used for general anesthesia. Recent evidence suggests that propofol-anesthetized patients experience less postoperative pain, and that propofol has analgesic properties when applied topically. We presently investigated the antinociceptive effects of topical propofol using behavioral and single-unit electrophysiological methods in rats. Methods In behavioral experiments with rats, we assessed the effect of topical hindpaw application of propofol (1–25%) on heat and mechanically evoked paw withdrawals. In electrophysiology experiments we recorded from lumbar dorsal horn wide dynamic range (WDR)-type neurons in pentobarbital-anesthetized rats. We assessed the effect of topical application of propofol to the ipsilateral hindpaw on neuronal responses elicited by noxious heat, cold and mechanical stimuli. We additionally tested if propofol blocks heat sensitization of paw withdrawals and WDR neuronal responses induced by topical application of allyl isothiocyanate (AITC; mustard oil). Results Topical application of propofol (1–25%) significantly increased the mean latency of the thermally evoked hindpaw withdrawal reflex on the treated (but not opposite) side in a concentration-dependent manner, with no effect on mechanically evoked hindpaw withdrawal thresholds. Propofol also prevented shortening of paw withdrawal latency induced by AITC. In electrophysiological experiments, topical application of 10 and 25% propofol, but not 1% propofol or vehicle (10% intralipid), to the ipsilateral hindpaw significantly attenuated the magnitude of responses of WDR neurons to noxious heating of glabrous hindpaw skin with no significant change in thermal thresholds. Maximal suppression of noxious heat-evoked responses was achieved 15-min after application followed by recovery to the pre-propofol baseline by 30 min. Responses to skin cooling or graded mechanical stimuli were not significantly affected by any concentration of propofol. Topical application of AITC enhanced the noxious heat-evoked response of dorsal horn neurons. This enhancement of heat-evoked responses was attenuated when 10% propofol was applied topically after application of AITC. Conclusions The results indicate that topical propofol inhibits responses of WDR neurons to noxious heat consistent with analgesia, and reduced AITC sensitization of WDR neurons consistent with an antihyperalgesic effect. These results are consistent with clinical studies demonstrating reduced postoperative pain in surgical patients anesthetized with propofol. The mechanism of analgesic action of topical propofol is not clear, but may involve desensitization of TRPV1 or TRPA1 receptors expressed in peripheral nociceptive nerve endings, engagement of endocannabinoids, or activation of peripheral gamma-aminobutyric acid A receptors.

Thermosensitive Transient Receptor Potential (TRP) Channel Agonists and Their Role in Mechanical, Thermal and Nociceptive Sensations as Assessed Using Animal Models

“…Consistent with the heat hyperalgesia observed in humans, intraplantar CA (Tsagereli et al, 2009) and topical/intraplantar AITC (Takechi et al, 2013; Weng et al, 2012) induced heat hyperalgesia in rodents. Formalin also induced a delayed heat hyperalgesia in mice (Karim et al, 2006).…”

Propofol attenuates postoperative hyperalgesia via regulating spinal GluN2B‐p38MAPK/EPAC1 pathway in an animal model of postoperative pain

“…A consistency has been observed in the distribution of c‐Fos in the spinal cord after noxious stimulation, typically located in laminae I‐II of the dorsal horn, corresponding to the distribution of noci‐responsive neurons and terminal fields of primary nociceptive afferent fibers (Todd, ). The current findings that propofol suppressed the enhanced c‐Fos expression after incision in the superficial dorsal horn without interference in the deep layers of the dorsal horn indicate a selective analgesic effect of propofol that may be not associated with its general anesthetic effect (Takechi, Carstens, Klein, & Carstens, ).…”

General anaesthetic agents do not influence persistent pain after breast cancer surgery

“…This last point may also explain why perioperative strategies such as ketamine 33 or use of local anaesthesia have failed. 34 Finally, the preclinical data do not support a difference between propofol and the halogenated agents in terms of putative prevention of neuropathy, as both may act on the peripheral fibres 35,36 and may even have some neuroprotective effects. 37,38 Although it might be possible to explain the discrepancy between our results and those of Cho et al 10 by examining the mechanisms, it may also be explained by different methodologies.…”