Behavioural and neurochemical effects of long-lasting inflammatory pain
Author: Heilborn, Umut
Date: 2007-06-08
Location: Farmakologens Föreläsningssal, Nanna Svartz väg 2, Karolinska Institutet, Solna
Time: 09.00
Department: Institutionen för fysiologi och farmakologi / Department of Physiology and Pharmacology
View/ Open:
Thesis (1.112Mb)
Abstract
The treatment of chronic, inflammatory pain in humans is still unsatisfactory. In order to develop new anti-inflammatory and analgesic drugs, studies on the mechanisms underlying inflammatory pain in valid animal models, are of considerable importance. In the present thesis, we have investigated behavioural and neurochemical alterations in animal models of long lasting inflammatory pain. We have also addressed this field from a methodological perspective. In addition, we have investigated a pharmacological approach in animals which has been suggested to prevent the generation of chronic pain in humans.
Treatment with morphine prior to surgical interventions has been suggested to prevent the development of subsequent pain conditions. However, previous animal and human studies have shown contradictory results. We therefore examined the antinociceptive effect of morphine given before or after the induction of monoarthritis in rats. In order to investigate a possible correlation to the behavioural response, the plasma concentrations of morphine were followed. In the present preclinical setting, our data do not support an advantageous effect of administration of morphine prior to the induction of arthritis compared to morphine treatment after the onset of inflammatory pain.
The development of transgenic techniques has accentuated the need for valid disease models in mice. We therefore developed a model for joint inflammation in mice: adjuvant-induced monoarthritis. We estimated pain-related behaviour by scoring of gait and stance and we validated the model pharmacologically by administrating two different analgesic drugs, morphine and the non-steroid anti-inflammatory drug (NSAID) diclofenac. We conclude that adjuvant-induced monoarthritis, which has a limited effect on the general state of health of the animals compared to polyarthritic models, constitutes a robust and reproducible model in mice. This model is likely to be useful in patophysiological and pharmacological studies on inflammatory pain in transgenic mice. However, the choice of mouse strain is of importance for the results obtained.
Several human and animal studies indicate that the anterior cingulate cortex (ACC) plays an important role in the affective component of pain. The neuropeptide cholecystokinin (CCK) has been suggested to be involved in anxiety and in the modulation the antinociceptive effects of opioids in the spinal cord and medulla oblongata. However, its possible role in pain transmission or modulation in the brain is far less clear. CCK is particularly abundant in the ACC and we hypothesised that CCK in this brain region may play a role in pain, possibly in the affective component. Using a model for subchronic inflammatory joint pain in rats, we studied the effect of pain on the release of CCK in the ACC. We found that animals with inflammatory pain had a significantly increased release of CCK in the ACC compared to controls. We then proceeded by investigating whether the increased CCK release could be affected by morphine and diclofenac. Morphine, unlike diclofenac, is known to relieve the affective component of pain.
Surprisingly, we found that diclofenac but not morphine reduced the increased CCK release in the ACC of rats with inflammatory pain. Thus, our results argue against the hypothesis that CCK in the ACC is involved in the affective component of pain, but rather indicates that the observed increase in CCK could be mediated by an elevation in prostaglandin levels. Further studies on the interaction between prostaglandins and CCK in the brain may provide a future basis for the treatment of inflammatory pain in humans.
Treatment with morphine prior to surgical interventions has been suggested to prevent the development of subsequent pain conditions. However, previous animal and human studies have shown contradictory results. We therefore examined the antinociceptive effect of morphine given before or after the induction of monoarthritis in rats. In order to investigate a possible correlation to the behavioural response, the plasma concentrations of morphine were followed. In the present preclinical setting, our data do not support an advantageous effect of administration of morphine prior to the induction of arthritis compared to morphine treatment after the onset of inflammatory pain.
The development of transgenic techniques has accentuated the need for valid disease models in mice. We therefore developed a model for joint inflammation in mice: adjuvant-induced monoarthritis. We estimated pain-related behaviour by scoring of gait and stance and we validated the model pharmacologically by administrating two different analgesic drugs, morphine and the non-steroid anti-inflammatory drug (NSAID) diclofenac. We conclude that adjuvant-induced monoarthritis, which has a limited effect on the general state of health of the animals compared to polyarthritic models, constitutes a robust and reproducible model in mice. This model is likely to be useful in patophysiological and pharmacological studies on inflammatory pain in transgenic mice. However, the choice of mouse strain is of importance for the results obtained.
Several human and animal studies indicate that the anterior cingulate cortex (ACC) plays an important role in the affective component of pain. The neuropeptide cholecystokinin (CCK) has been suggested to be involved in anxiety and in the modulation the antinociceptive effects of opioids in the spinal cord and medulla oblongata. However, its possible role in pain transmission or modulation in the brain is far less clear. CCK is particularly abundant in the ACC and we hypothesised that CCK in this brain region may play a role in pain, possibly in the affective component. Using a model for subchronic inflammatory joint pain in rats, we studied the effect of pain on the release of CCK in the ACC. We found that animals with inflammatory pain had a significantly increased release of CCK in the ACC compared to controls. We then proceeded by investigating whether the increased CCK release could be affected by morphine and diclofenac. Morphine, unlike diclofenac, is known to relieve the affective component of pain.
Surprisingly, we found that diclofenac but not morphine reduced the increased CCK release in the ACC of rats with inflammatory pain. Thus, our results argue against the hypothesis that CCK in the ACC is involved in the affective component of pain, but rather indicates that the observed increase in CCK could be mediated by an elevation in prostaglandin levels. Further studies on the interaction between prostaglandins and CCK in the brain may provide a future basis for the treatment of inflammatory pain in humans.
List of papers:
I. Heilborn U, Schött E, Beck O, Arborelius L, Brodin E (1970). Effects of morphine on pain-related behaviour when given before or after induction of monoarthris and pharmacokinetics of morphine in rats. [Submitted]
II. Heilborn U, Berge OG, Arborelius L, Brodin E. (2007). Spontaneous nociceptive behaviour in female mice with Freund's complete adjuvant- and carrageenan-induced monoarthritis. Brain Res. 1143: 143-9
Pubmed
III. Erel U, Arborelius L, Brodin E. (2004). Increased cholecystokinin release in the rat anterior cingulate cortex during carrageenan-induced arthritis. Brain Res. 1022(1-2): 39-46
Pubmed
IV. Heilborn U, Rost BR, Arborelius L, Brodin E. (2007). Arthritis-induced increase in cholecystokinin release in the rat anterior cingulate cortex is reversed by diclofenac. Brain Res. 1136(1): 51-8
Pubmed
I. Heilborn U, Schött E, Beck O, Arborelius L, Brodin E (1970). Effects of morphine on pain-related behaviour when given before or after induction of monoarthris and pharmacokinetics of morphine in rats. [Submitted]
II. Heilborn U, Berge OG, Arborelius L, Brodin E. (2007). Spontaneous nociceptive behaviour in female mice with Freund's complete adjuvant- and carrageenan-induced monoarthritis. Brain Res. 1143: 143-9
Pubmed
III. Erel U, Arborelius L, Brodin E. (2004). Increased cholecystokinin release in the rat anterior cingulate cortex during carrageenan-induced arthritis. Brain Res. 1022(1-2): 39-46
Pubmed
IV. Heilborn U, Rost BR, Arborelius L, Brodin E. (2007). Arthritis-induced increase in cholecystokinin release in the rat anterior cingulate cortex is reversed by diclofenac. Brain Res. 1136(1): 51-8
Pubmed
Issue date: 2007-05-18
Rights:
Publication year: 2007
ISBN: 978-91-7357-175-3
Statistics
Total Visits
Views | |
---|---|
Behavioural ...(legacy) | 976 |
Behavioural ... | 126 |
Total Visits Per Month
February 2024 | March 2024 | April 2024 | May 2024 | June 2024 | July 2024 | August 2024 | |
---|---|---|---|---|---|---|---|
Behavioural ... | 0 | 1 | 1 | 0 | 3 | 1 | 1 |
File Visits
Views | |
---|---|
thesis.pdf(legacy) | 495 |
thesis.pdf | 261 |
thesis.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 439 |
China | 95 |
Sweden | 95 |
Germany | 71 |
South Korea | 17 |
Finland | 16 |
Denmark | 11 |
United Kingdom | 11 |
Russia | 11 |
Ireland | 8 |
Top cities views
Views | |
---|---|
Beijing | 38 |
Romeo | 35 |
Kiez | 24 |
Sunnyvale | 22 |
Stockholm | 19 |
Seoul | 17 |
Nürnberg | 12 |
Shenzhen | 11 |
Helsinki | 10 |
London | 9 |