Behavioural and neurochemical effects and changes in gene expression in inflammatory and neuropathic pain

Chronic pain is a common clinical problem, which causes great suffering, and there is a great need for better analgesic drugs and strategies to counteract the transition of acute pain into chronic pain states. In studies of neurochemical mechanisms in animal models of chronic pain it is important to study also the development of spontaneous pain-related behaviour and sensory abnormalities (i.e. hyperalgesia and allodynia) as functional correlates. A novel method, to quantify the weight load of the hind paws in models of monoarthritis and mononeuropathy in the rat, was developed and compared with behavioural scoring methods. This weight bearing method was found to be a practical, useful and objective method to quantify the progression of the painrelated behaviour. A more graded response was obtained with the weight bearing measurements compared to behavioural scoring. Pre-administration of morphine (3 mg/ kg, s.c.) 30 min prior to an intra-articular carrageenan injection significantly reduced the summed behavioural score 3 to 48 hours after carrageenan injection, as compared to the control group, which received carrageenan only. In contrast, when morphine was given 2 h after carrageenan the summed behavioural score was not significantly different from the control group. Morphine did not affect the development of peripheral oedema. Morphine was detected in plasma up to 24 h after administration, even though only very low concentrations were detected after 3 h.

A significantly increased expression of mRNA for the immediate early genes (IEGs) c-fos, NGFI-A and jun B, was seen in superficial laminae of the ipsilateral lumbar dorsal horn within 30 min after partial nerve lesion surgery. Expression of rnRNA for c-fos and NGFI-A was also evident to a lesser degree in deeper laminae in the dorsal horn. Peak expressions occurred between 30 and 60 min and significant increases for c-fos, NGFI-A and jun B were observed up to 6, 3 and I h postoperatively, respectively. In the same rats, an elevation of SP-mRNA expression was significant at 1 and 2 days after partial nerve lesion, but returned to baseline levels at 3 days. Dynorphin rnRNA expression was significantly increased from 3 h to 3 days in superficial laminae. Significant mechanical allodynia was observed in the ipsilateral hind paw of lesioned animals at all time points from 2 to 28 days after partial ligation. Thus, there is no correlation between the expression of mRNAs for several IEGs and neuropeptides in the dorsal horn and the prolonged time course of allodynia in the PNL-model. The transient increase in IEG-mRNA expression appears primarily related to the ligation per se.

It has been suggested that a mechanism contributing to the relative resistance of neuropathic pain to treatment with opioids could be an enhanced release of the anti-opioid neuropeptide CCK in the dorsal following nerve lesion. However, in a microdialysis study the potassium induced in vivo release of CCK in the spinal dorsal horn was found to be markedly reduced in rats two weeks following axotomy, compared to control animals. The finding that the CCK-B-receptor antagonist Cl 988 restored the stimulated CCK levels suggests a regulatory mechanism involving the CCK-B-receptor binding site.

List of scientific papers

I. Schött E, Berge OG, Ängeby-Möller K, Hammarström G, Dalsgaard CJ, Brodin E (1994). Weight bearing as an objective measure of arthritic pain in the rat. J Pharmacol Toxicol Methods. 31(2): 79-83.
https://pubmed.ncbi.nlm.nih.gov/94305204

II. Schött E, Erel U, Beck O, Brodin E (1970). Differential behavioural effects of pre- and post-administration of morphine in monoarthritc rats. [Submitted]

III. DeLander GE, Schött E, Brodin E, Fredholm BB (1997). Spinal expression of mRNA for immediate early genes in a model of chronic pain. Acta Physiol Scand. 161(4): 517-525.
https://pubmed.ncbi.nlm.nih.gov/98091495

IV. DeLander GE, Schött E, Brodin E, Fredholm BB (1997). Temporal changes in spinal cord expression of mRNA for substance P, dynorphin and enkephalin in a model of chronic pain. Acta Physiol Scand. 161(4): 509-516.
https://pubmed.ncbi.nlm.nih.gov/98091494

V. Gustafsson H, de Araujo Lucas G, Schött E, Stiller CO, Alster P, Wiesenfeld-Hallin Z, Brodin E (1999). Measurement of cholecystokinin release in vivo in the rat spinal dorsal horn. Brain Res Brain Res Protoc. 4(2): 192-200.
https://pubmed.ncbi.nlm.nih.gov/99377293

VI. Gustafsson H, de Araujo Lucas G, Schött E, Stiller CO, Alster P, Wiesenfeld-Hallin Z, Brodin E (1998). Peripheral axotomy influences the in vivo release of cholecystokinin in the spinal cord dorsal horn-possible involvement of cholecystokinin-B receptors. Brain Res. 790(1-2): 141-150.
https://pubmed.ncbi.nlm.nih.gov/98256055