A53 CHRONIC MORPHINE TREATMENT CAUSES TOLERANCE AND INCREASES PAIN SIGNALING FOLLOWING ACUTE MORPHINE APPLICATION TO MOUSE VISCERAL SENSORY NERVES

• Published in: Journal of the Canadian Association of Gastroenterology Vol. 2; no. Supplement_2; pp. 105 - 106
• Main Authors: Jaramillo Polanco, J O, Lopez Lopez, C D, Yu, Y, Reed, D E, Lomax, A E, Vanner, S
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 15.03.2019
• Subjects: Posters Of Distinction
• ISSN: 2515-2084; 2515-2092
• DOI: 10.1093/jcag/gwz006.052

Abstract Background Opioid drugs are efficacious for treating abdominal pain but prolonged exposure to opioids in patients induces tolerance, which in turn can lead to escalating doses to achieve an analgesic effect. Furthermore, these increasing doses can activate pronociceptive signaling but the mechanisms are unclear. Aims To evaluate the short-term effect of morphine on the excitability of mouse colonic afferent nerve fibers and dorsal root ganglion (DRG) neurons, and determine whether chronic treatment with increasing doses of morphine modifies this effect. Methods C57BL/6 mice were intraperitoneally injected twice daily for 7 days with escalating doses of morphine (10, 20, 30 mg/kg for the first 3 days, then 40mg/kg on 4th to 7th day) or saline. The analgesic response to morphine injections was monitored daily using the tail-flick test. At day 8, mice were euthanized and the DRGs and colons were removed. Isolated DRG neurons were cultured and overnight incubated with 1µM morphine or media alone. Neuronal excitability was recorded by measuring the rheobase using perforated patch clamp. In vitro afferent recordings were performed on flat-sheet colon preparations to determine the effects of 1µM morphine (10 min perfusion) on basal firing frequency and response to probing with 1g von Frey hair. Results The tail flick test demonstrated morphine tolerance in morphine treated mice; the antinociceptive effect reached a maximum on day 4 and declined on the following days despite high doses. In patch clamp recordings, overnight incubation with 1µM morphine reduced the excitability of small DRG neurons from saline treated mice (rheobase increased 48%; p<0.01, unpaired t test), whereas this inhibitory effect was absent on neurons from morphine treated mice. Acute application of 1µM morphine inhibited the colonic afferent response to probing in saline treated mice (14.2 vs 8.5 Hz; p<0.01, paired t test, n=14), but not in morphine treated mice. Consistently, acute morphine decreased the basal activity of afferent axons in saline treated mice (0.46 vs 0.22 Hz; p<0.05), whereas it increased firing in morphine treated mice (0.08 vs 0.39 Hz; p<0.05, n=18). Chronic treatment with morphine reduced the inhibitory effect of acute morphine application on mechanosensitivity (12/14 vs. 6/18 units inhibited, P<0.05), and switched the effect of acute morphine on basal afferent firing from inhibition to excitation (0/14 vs. 6/12 units excited, P<0.05). Conclusions These findings suggest that chronic treatment with morphine impairs the antinociceptive effect of acute morphine application and increases firing in a subset of colonic afferents evoking a pronociceptive effect. This finding demonstrates a peripheral action of morphine underlying its ability to paradoxically increase pain signaling. Funding Agencies CCC