Antinociceptive effects of melatonin in a rat model of post-inflammatory visceral hyperalgesia: a centrally mediated process
Aaron Mickle, Manu Sood, Zhihong Zhang, Golbon Shahmohammadi, Jyoti N Sengupta, Adrian Miranda, Aaron Mickle, Manu Sood, Zhihong Zhang, Golbon Shahmohammadi, Jyoti N Sengupta, Adrian Miranda
Abstract
Previous reports suggest that melatonin may play an important role in visceral nociception and neurogenic inflammation. We aimed to examine the role of melatonin on visceral hypersensitivity and to explore the site of action using a rat model of post-inflammatory visceral hyperalgesia. In all rats, a baseline viscero-motor response (VMR) to graded colorectal distension (CRD; 10-60mmHg) was recorded prior and 1 week following tri-nitrobenzenesulfonic acid (TNBS) induced colonic inflammation. Melatonin (30, 45 or 60mg/kg, ip) was given 20min before testing the VMR in naïve and TNBS-treated rats. Extracellular single-unit recordings were made from CRD-sensitive pelvic nerve afferent (PNA) fibers and lumbosacral (LS) spinal neurons in TNBS-treated animals. The effect of melatonin (60mg/kg) was examined on responses of PNAs and spinal neurons to graded CRD. In separate experiments, luzindole (non-specific MT(1)/MT(2) receptor antagonist) or naltrexone (non-specific opiod receptor antagonist) was injected prior to melatonin. Following TNBS, there was a significant increase in the VMR to CRD compared to baseline. This increase was attenuated by melatonin (60mg/kg) at pressures >20mmHg. The same dose of melatonin had no effect on the VMR in naïve animals. In TNBS-treated rats, melatonin significantly attenuated the responses of CRD-sensitive spinal neurons to CRD, but had no effect in spinal transected rats or PNA fibers. Both luzindole and naltrexone blocked melatonin's effect on the VMR and LS spinal neurons. Results indicate melatonin's antinociceptive effects are not via a peripheral site of action but rather a supra-spinal process linked to the central opioidergic system.
Conflict of interest statement
Statement of Conflict of Interest: No conflicts of interest exist with any of the authors.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2884285/bin/nihms200198f1.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2884285/bin/nihms200198f2.jpg)
Figure 3
VMR represented as EMG activity…
Figure 3
VMR represented as EMG activity to graded CRD (20, 30, 40 mmHg) from…
Figure 4
The mean VMR to graded…
Figure 4
The mean VMR to graded CRD in TNBS-treated rats. Melatonin has no effect…
Figure 5
The mean stimulus-response function of…
Figure 5
The mean stimulus-response function of pelvic nerve afferents from TNBS-treated rats before and…
Figure 6
The mean SRF of LS…
Figure 6
The mean SRF of LS spinal neurons in naïve and TNBS-treated rats before…
Figure 7
The mean SRFs of LS…
Figure 7
The mean SRFs of LS spinal neuron showed that melatonin had not effect…
Figure 8
The mean SRFs of LS…
Figure 8
The mean SRFs of LS spinal neuron showed that melatonin had not effect…
Figure 9
The mean SRF of CRD-sensitive…
Figure 9
The mean SRF of CRD-sensitive LS spinal neurons in TNBS-treated, spinalized (C 1…
- Analgesic effect of minocycline in rat model of inflammation-induced visceral pain.Kannampalli P, Pochiraju S, Bruckert M, Shaker R, Banerjee B, Sengupta JN. Kannampalli P, et al. Eur J Pharmacol. 2014 Mar 15;727:87-98. doi: 10.1016/j.ejphar.2014.01.026. Epub 2014 Jan 28. Eur J Pharmacol. 2014. PMID: 24485889 Free PMC article.
- The role of transient receptor potential vanilloid 1 in mechanical and chemical visceral hyperalgesia following experimental colitis.Miranda A, Nordstrom E, Mannem A, Smith C, Banerjee B, Sengupta JN. Miranda A, et al. Neuroscience. 2007 Sep 21;148(4):1021-32. doi: 10.1016/j.neuroscience.2007.05.034. Epub 2007 Aug 23. Neuroscience. 2007. PMID: 17719181 Free PMC article.
- Visceral analgesic effect of 5-HT(4) receptor agonist in rats involves the rostroventral medulla (RVM).Sengupta JN, Mickle A, Kannampalli P, Spruell R, McRorie J, Shaker R, Miranda A. Sengupta JN, et al. Neuropharmacology. 2014 Apr;79:345-58. doi: 10.1016/j.neuropharm.2013.12.006. Epub 2013 Dec 12. Neuropharmacology. 2014. PMID: 24334068 Free PMC article.
- Potential use of melatonergic drugs in analgesia: mechanisms of action.Srinivasan V, Pandi-Perumal SR, Spence DW, Moscovitch A, Trakht I, Brown GM, Cardinali DP. Srinivasan V, et al. Brain Res Bull. 2010 Mar 16;81(4-5):362-71. doi: 10.1016/j.brainresbull.2009.12.001. Epub 2010 Jan 19. Brain Res Bull. 2010. PMID: 20005925 Review.
- Melatonin: a hormone that modulates pain.Ambriz-Tututi M, Rocha-González HI, Cruz SL, Granados-Soto V. Ambriz-Tututi M, et al. Life Sci. 2009 Apr 10;84(15-16):489-98. doi: 10.1016/j.lfs.2009.01.024. Epub 2009 Feb 15. Life Sci. 2009. PMID: 19223003 Review.
- Modulation of melatonin to the thalamic lesion-induced pain and comorbid sleep disturbance in the animal model of the central post-stroke hemorrhage.Kaur T, Shih HC, Huang ACW, Shyu BC. Kaur T, et al. Mol Pain. 2022 Apr;18:17448069221127180. doi: 10.1177/17448069221127180. Mol Pain. 2022. PMID: 36065903 Free PMC article.
- The Relationship Between Daytime Salivary Melatonin and Gastrointestinal Symptoms in Young Adults Seeking Psychiatric Care.Söderquist F, Sundberg I, Ramklint M, Widerström R, Hellström PM, Cunningham JL. Söderquist F, et al. Psychosom Med. 2019 Jan;81(1):51-56. doi: 10.1097/PSY.0000000000000644. Psychosom Med. 2019. PMID: 30299401 Free PMC article.
- Neonatal bladder inflammation induces long-term visceral pain and altered responses of spinal neurons in adult rats.Kannampalli P, Babygirija R, Zhang J, Poe MM, Li G, Cook JM, Shaker R, Banerjee B, Sengupta JN. Kannampalli P, et al. Neuroscience. 2017 Mar 27;346:349-364. doi: 10.1016/j.neuroscience.2017.01.021. Epub 2017 Jan 23. Neuroscience. 2017. PMID: 28126369 Free PMC article.
- The anti-aging effects of LW-AFC via correcting immune dysfunctions in senescence accelerated mouse resistant 1 (SAMR1) strain.Wang J, Cheng X, Zhang X, Cheng J, Xu Y, Zeng J, Zhou W, Zhang Y. Wang J, et al. Oncotarget. 2016 May 10;7(19):26949-65. doi: 10.18632/oncotarget.8877. Oncotarget. 2016. PMID: 27105505 Free PMC article.
- NMDA receptor mediates chronic visceral pain induced by neonatal noxious somatic stimulation.Miranda A, Mickle A, Bruckert M, Kannampalli P, Banerjee B, Sengupta JN. Miranda A, et al. Eur J Pharmacol. 2014 Dec 5;744:28-35. doi: 10.1016/j.ejphar.2014.09.034. Epub 2014 Sep 30. Eur J Pharmacol. 2014. PMID: 25281204 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Analgesics / pharmacology*
- Analgesics / therapeutic use
- Animals
- Colitis / complications
- Colitis / metabolism
- Colitis / physiopathology
- Disease Models, Animal
- Hyperalgesia / drug therapy*
- Hyperalgesia / etiology
- Hyperalgesia / physiopathology*
- Inflammation / drug therapy
- Inflammation / metabolism
- Inflammation / physiopathology
- Male
- Melatonin / metabolism
- Melatonin / physiology*
- Melatonin / therapeutic use
- Narcotic Antagonists / pharmacology
- Rats
- Rats, Sprague-Dawley
- Receptors, Melatonin / antagonists & inhibitors
- Receptors, Melatonin / metabolism
- Receptors, Melatonin / physiology*
- Tryptamines / pharmacology
- Visceral Afferents / physiopathology*
- Analgesics
- Narcotic Antagonists
- Receptors, Melatonin
- Tryptamines
- luzindole
- Melatonin
- Full Text Sources
- Medical
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![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2884285/bin/nihms200198f3.jpg)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2884285/bin/nihms200198f4.jpg)
Figure 5
The mean stimulus-response function of…
Figure 5
The mean stimulus-response function of pelvic nerve afferents from TNBS-treated rats before and…
Figure 6
The mean SRF of LS…
Figure 6
The mean SRF of LS spinal neurons in naïve and TNBS-treated rats before…
Figure 7
The mean SRFs of LS…
Figure 7
The mean SRFs of LS spinal neuron showed that melatonin had not effect…
Figure 8
The mean SRFs of LS…
Figure 8
The mean SRFs of LS spinal neuron showed that melatonin had not effect…
Figure 9
The mean SRF of CRD-sensitive…
Figure 9
The mean SRF of CRD-sensitive LS spinal neurons in TNBS-treated, spinalized (C 1…
- Analgesic effect of minocycline in rat model of inflammation-induced visceral pain.Kannampalli P, Pochiraju S, Bruckert M, Shaker R, Banerjee B, Sengupta JN. Kannampalli P, et al. Eur J Pharmacol. 2014 Mar 15;727:87-98. doi: 10.1016/j.ejphar.2014.01.026. Epub 2014 Jan 28. Eur J Pharmacol. 2014. PMID: 24485889 Free PMC article.
- The role of transient receptor potential vanilloid 1 in mechanical and chemical visceral hyperalgesia following experimental colitis.Miranda A, Nordstrom E, Mannem A, Smith C, Banerjee B, Sengupta JN. Miranda A, et al. Neuroscience. 2007 Sep 21;148(4):1021-32. doi: 10.1016/j.neuroscience.2007.05.034. Epub 2007 Aug 23. Neuroscience. 2007. PMID: 17719181 Free PMC article.
- Visceral analgesic effect of 5-HT(4) receptor agonist in rats involves the rostroventral medulla (RVM).Sengupta JN, Mickle A, Kannampalli P, Spruell R, McRorie J, Shaker R, Miranda A. Sengupta JN, et al. Neuropharmacology. 2014 Apr;79:345-58. doi: 10.1016/j.neuropharm.2013.12.006. Epub 2013 Dec 12. Neuropharmacology. 2014. PMID: 24334068 Free PMC article.
- Potential use of melatonergic drugs in analgesia: mechanisms of action.Srinivasan V, Pandi-Perumal SR, Spence DW, Moscovitch A, Trakht I, Brown GM, Cardinali DP. Srinivasan V, et al. Brain Res Bull. 2010 Mar 16;81(4-5):362-71. doi: 10.1016/j.brainresbull.2009.12.001. Epub 2010 Jan 19. Brain Res Bull. 2010. PMID: 20005925 Review.
- Melatonin: a hormone that modulates pain.Ambriz-Tututi M, Rocha-González HI, Cruz SL, Granados-Soto V. Ambriz-Tututi M, et al. Life Sci. 2009 Apr 10;84(15-16):489-98. doi: 10.1016/j.lfs.2009.01.024. Epub 2009 Feb 15. Life Sci. 2009. PMID: 19223003 Review.
- Modulation of melatonin to the thalamic lesion-induced pain and comorbid sleep disturbance in the animal model of the central post-stroke hemorrhage.Kaur T, Shih HC, Huang ACW, Shyu BC. Kaur T, et al. Mol Pain. 2022 Apr;18:17448069221127180. doi: 10.1177/17448069221127180. Mol Pain. 2022. PMID: 36065903 Free PMC article.
- The Relationship Between Daytime Salivary Melatonin and Gastrointestinal Symptoms in Young Adults Seeking Psychiatric Care.Söderquist F, Sundberg I, Ramklint M, Widerström R, Hellström PM, Cunningham JL. Söderquist F, et al. Psychosom Med. 2019 Jan;81(1):51-56. doi: 10.1097/PSY.0000000000000644. Psychosom Med. 2019. PMID: 30299401 Free PMC article.
- Neonatal bladder inflammation induces long-term visceral pain and altered responses of spinal neurons in adult rats.Kannampalli P, Babygirija R, Zhang J, Poe MM, Li G, Cook JM, Shaker R, Banerjee B, Sengupta JN. Kannampalli P, et al. Neuroscience. 2017 Mar 27;346:349-364. doi: 10.1016/j.neuroscience.2017.01.021. Epub 2017 Jan 23. Neuroscience. 2017. PMID: 28126369 Free PMC article.
- The anti-aging effects of LW-AFC via correcting immune dysfunctions in senescence accelerated mouse resistant 1 (SAMR1) strain.Wang J, Cheng X, Zhang X, Cheng J, Xu Y, Zeng J, Zhou W, Zhang Y. Wang J, et al. Oncotarget. 2016 May 10;7(19):26949-65. doi: 10.18632/oncotarget.8877. Oncotarget. 2016. PMID: 27105505 Free PMC article.
- NMDA receptor mediates chronic visceral pain induced by neonatal noxious somatic stimulation.Miranda A, Mickle A, Bruckert M, Kannampalli P, Banerjee B, Sengupta JN. Miranda A, et al. Eur J Pharmacol. 2014 Dec 5;744:28-35. doi: 10.1016/j.ejphar.2014.09.034. Epub 2014 Sep 30. Eur J Pharmacol. 2014. PMID: 25281204 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Analgesics / pharmacology*
- Analgesics / therapeutic use
- Animals
- Colitis / complications
- Colitis / metabolism
- Colitis / physiopathology
- Disease Models, Animal
- Hyperalgesia / drug therapy*
- Hyperalgesia / etiology
- Hyperalgesia / physiopathology*
- Inflammation / drug therapy
- Inflammation / metabolism
- Inflammation / physiopathology
- Male
- Melatonin / metabolism
- Melatonin / physiology*
- Melatonin / therapeutic use
- Narcotic Antagonists / pharmacology
- Rats
- Rats, Sprague-Dawley
- Receptors, Melatonin / antagonists & inhibitors
- Receptors, Melatonin / metabolism
- Receptors, Melatonin / physiology*
- Tryptamines / pharmacology
- Visceral Afferents / physiopathology*
- Analgesics
- Narcotic Antagonists
- Receptors, Melatonin
- Tryptamines
- luzindole
- Melatonin
- Full Text Sources
- Medical
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2884285/bin/nihms200198f5.jpg)
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2884285/bin/nihms200198f6.jpg)
Figure 7
The mean SRFs of LS…
Figure 7
The mean SRFs of LS spinal neuron showed that melatonin had not effect…
Figure 8
The mean SRFs of LS…
Figure 8
The mean SRFs of LS spinal neuron showed that melatonin had not effect…
Figure 9
The mean SRF of CRD-sensitive…
Figure 9
The mean SRF of CRD-sensitive LS spinal neurons in TNBS-treated, spinalized (C 1…
![Figure 7](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2884285/bin/nihms200198f7.jpg)
![Figure 8](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2884285/bin/nihms200198f8.jpg)
![Figure 9](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2884285/bin/nihms200198f9.jpg)
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