Experimental studies on the mechanisms and treatments of chronic pain

Chronic pain is a major concern for physical and mental health of a large patient population today while casting a significant economical burden on society. Work presented in this thesis deal with aspects of mechanisms and treatments of chronic pain using experimental models.

A common characteristic for many chronic pain conditions, particularly those after nerve injury, is hypersensitivity to cold stimulation. In the first part of the thesis, I presented a new method using a Peltier thermode to examine the responses of rats to quantitative thermal stimulation (heating and cooling). Using this method with temperature as end points, I showed that we can reliably detect cold hypersensitivity in spinally injured rats as well as study quantitatively the effects of analgesics again cold pain.

Sinomenine is a morphinan derivative alkaloid originally isolated from the root of the climbing plant Sinomenium Acutum that is native to Japan and China. The root of Sinomenium Acutum has long been used in East Asia as a remedy for disease conditions similar to rheumatism and sinomenine is currently used in China as an anti-rheumatic agent. In the second part of the thesis, we characterized the analgesic effect of sinomenine in a variety of experimental pain models. We showed that while sinomenine has modest effects on acute pain in normal rats, it produces marked analgesic effects in a wide-spectrum of models, including neuropathic pain in rats and mice after injury to the peripheral and central nervous system, acute inflammatory pain by carrageenan in mice as well as arthritic pain in mice using the collagen antibody-induced arthritis model (CAIA). We further showed that under chronic administration, sinomenine maintained its analgesic effect in neuropathic and arthritic pain models without producing tolerance or dependence. Our results thus suggested that sinomenine may be considered as a novel analgesic in treating neuropathic and arthritic pain.

One of the main clinical features of rheumatoid arthritis (RA) is sex difference in its prevalence and symptoms, including pain. The underlying mechanisms of sex differences in RA are still largely unknown. In the last part of the thesis, we studied sex differences in the development arthritis and pain-like behaviors in mice using the CAIA model. We observed a significant sex difference (females > males) in the development of joint inflammation and localized mechanical allodynia in the paws after CAIA in CBA strain of mice. Similarly, female CAIA mice also developed more persistent spread mechanical allodynia in their neck and flank areas. Following CAIA, the greater mechanical hypersensitivity in females was correlated to a higher expression of ionized calcium-binding adapter molecule 1, but lower expressions of activating transcription factor 3 and galanin, in dorsal root ganglion (DRG) compared with males. We conclude that sex differences in the CAIA model in CBA mice are similar to the clinical condition and sex dependent phenotypic changes in the DRG may be keys for the sex differences in RA and pain.

List of scientific papers

I. Gao T, Hao JX, Wiesenfeld-Hallin Z, Xu XJ. Quantitative test of responses to thermal stimulation in spinally injured rats using a Peltier thermode: a new approach to study cold allodynia. J Neurosci Methods. 2013; 212:317– 321.
https://doi.org/10.1016/j.jneumeth.2012.11.008

II. Gao T, Hao JX, Wiesenfeld-Hallin Z, Wang DQ, Xu XJ. Analgesic effect of sinomenine in rodents after inflammation and nerve injury. Eur J Pharmacol. 2013; 721:5-11.
https://doi.org/10.1016/j.ejphar.2013.09.062

III. Gao T, Shi T, Wang DQ, Wiesenfeld-Hallin Z, Xu XJ. Repeated sinomenine administration alleviates chronic neuropathic pain-like behaviors in rodents without producing tolerance. Scand J Pain. 2014; 5:249–55.
https://doi.org/10.1016/j.sjpain.2014.05.006

IV. Gao T, Shi T, Wiesenfeld-Hallin Z, Svensson CI, Xu XJ. The analgesic effect of sinomenine on experimental rheumatoid arthritis. [Submitted]

V. Gao T, Su J, Shi TJ, Hao JX, Hökfelt T, Wiesenfeld-Hallin Z, Svensson CI, Xu XJ. Sex differences in the development of arthritis and hypersensitivity in mice with collagen antibody-induced arthritis: correlation with phenotypic changes in dorsal root ganglia. [Submitted]