Unity vs. diversity of neuropathic pain mechanisms: Allodynia and hyperalgesia in rats selected for heritable predisposition to spontaneous pain.

Do contrasting neuropathic pain diagnoses share common pathophysiological mechanisms? Selective breeding was used to derive rat lines with a common genetic background but a striking difference in the degree of spontaneous pain behavior expressed in the neuroma model of neuropathic pain (HA rats (high autotomy) and LA rats (low autotomy)). The contrasting pain phenotype in these lines is attributable to allelic differences at a small number of genetic loci. Here we show that HA and LA rats also differ in their nocifensive response to applied stimuli in the Chung (spinal nerve ligation, SNL) model of neuropathic pain.

Sex-specific variability and a 'cage effect' independently mask a neuropathic pain quantitative trait locus detected in a whole genome scan.

Sex and environment may dramatically affect genetic studies, and thus should be carefully considered. Beginning with two inbred mouse strains with contrasting phenotype in the neuroma model of neuropathic pain (autotomy), we established a backcross population on which we conducted a genome-wide scan. The backcross population was partially maintained in small social groups and partially in isolation.

Mice congenic for a locus that determines phenotype in the neuroma model of neuropathic pain.

A common strategy for identifying physiological processes responsible for pain is to compare animal strains that show high versus low pain phenotype. However, this approach yields only weak inference because most strains differ from one another at a large number of genetic loci. We undertook a congenic breeding program aimed at transposing the gene(s) that confers dominant (low) pain phenotype in the neuroma model of neuropathic pain from mice of the C58/J strain onto a genetic background that normally expresses high pain phenotype (C3H/HeN).

pain1: a neuropathic pain QTL on mouse chromosome 15 in a C3HxC58 backcross.

We have produced a backcross (BC) population of 267 mice from the parental strains C3H/HeN and C58/J. The mice were phenotyped for neuropathic pain using the neuroma model. Subsequently all BC mice were genotyped in a region of chromosome 15 that has been previously suggested to contain a quantitative trait locus (QTL) for this trait.

Heritability of symptoms in the neuroma model of neuropathic pain: replication and complementation analysis.

Applying genetic selection pressure to an outbred population of albino rats, we have derived lines that show consistently high versus low pain phenotype in the neuroma model of neuropathic pain. Trait segregation developed rapidly, replicating earlier observations using this methodology. The resulting novel selection lines, designated nHA and nLA, share a common genetic background but have dramatically contrasting neuropathic pain behavior.

Key role of the dorsal root ganglion in neuropathic tactile hypersensibility.

Cutting spinal nerves just distal to the dorsal root ganglion (DRG) triggers, with rapid onset, massive spontaneous ectopic discharge in axotomized afferent A-neurons, and at the same time induces tactile allodynia in the partially denervated hindlimb. We show that secondary transection of the dorsal root (rhizotomy) of the axotomized DRG, or suppression of the ectopia with topically applied local anesthetics, eliminates or attenuates the allodynia. Dorsal rhizotomy alone does not trigger allodynia.

Social variables affect phenotype in the neuroma model of neuropathic pain.

When the degree of genetic determination of a trait (i.e. its heritability) is high, one tends to presume that environmental factors will not modify its expression by much.

Corticosteroids suppress ectopic neural discharge originating in experimental neuromas.

Some injured sensory fibers ending in an experimental neuroma in the rat sciatic nerve discharge spontaneously. Furthermore, many become sensitive to a range of physical and chemical stimuli. The resulting afferent barrage is thought to contribute to paresthesias and pain associated with peripheral nerve injury.