Heritability and sex differences in experimental neuropathic pain with special emphasis on the role of the major histocompatibility complex

Neuropathic pain caused by injury to the nervous system is a difficult clinical problem and a large proportion of patients experience no or only partial relief from existing treatments. Pain sensitivity and the development of neuropathic pain are complex biological and physiological entities that are known to be affected by genetics and sex. Although many theories have been put forward to explain neuropathic pain, the mechanisms are still largely unknown.

In the present thesis we have used a genetic approach to explore the potential involvement of the major histocompatibility complex (MHC) genes in the development of neuropathic pain-like behavior following a photochemically induced sciatic nerve or spinal cord injury in inbred and/or congenic rat strains with different MHC haplotypes. We were able to show that following peripheral nerve injury, certain allelic variants of MHC have stronger influence on the susceptibility for the development and maintenance of neuropathic pain in both males and females. We could also demonstrate that both MHC and non-MHC genes are implicated in the genetic regulation of susceptibility to neuropathic pain. However, after spinal cord injury, MHC genes do not appear to be involved in the development of central neuropathic pain.

We have also studied sex difference in the development of mechanical hypersensitivity and wide spread pain after infraorbital and sciatic nerve injury in Sprague-Dawley rats. Our results demonstrated that sex differences in the development of neuropathic pain-like behavior are dependent on site of injury as well as site of testing with females being more susceptible to develop widespread mechanical hypersensitivity, particularly after infraorbital nerve injury. This finding may lead to a rat model of the human condition of fibromyalgia and other forms of spread pain that is mostly observed in woman.

List of scientific papers

I. Dominguez CA, Lidman O, Hao JX, Diez M, Tuncel J, Olsson T, Wiesenfeld-Hallin Z, Piehl F, Xu XJ (2008). Genetic analysis of neuropathic pain-like behavior following peripheral nerve injury suggests a role of the major histocompatibility complex in development of allodynia. Pain. 136(3): 313-9. Epub 2007 Aug 30
https://pubmed.ncbi.nlm.nih.gov/17764842

II. Dominguez CA, Lidman O, Olsson T, Wiesenfeld-Hallin Z, Piehl F, Xu XJ (2008). Contrasting genetic effects of major histocompatibility complex on ischemic peripheral nerve and spinal cord injury in female rats. Neurosci Lett. 443(2): 95-8. Epub 2008 Jul 29
https://pubmed.ncbi.nlm.nih.gov/18675884

III. Dominguez CA, Li L, Lidman O, Olsson T, Wiesenfeld-Hallin Z, Piehl F, Xu XJ (2008). Both MHC and non-MHC genes regulate development of experimental neuropathic pain in rats. Neurosci Lett. 442(3): 284-6. Epub 2008 Jul 16
https://pubmed.ncbi.nlm.nih.gov/18640240

IV. Dominguez CA, Kouya PF, Wu WP, Hao JX, Xu XJ and Wiesenfeld-Hallin Z (2008). Sex difference in the development of localized and spread mechanical hypersensitivity in rats after injury to the infraorbital or sciatic nerves. [Submitted]