Altered tachykinin expression by dorsal root ganglion neurons in a rat model of neuropathic pain

Abstract

The experiments described in the present study approached nerve injury from both a biochemical and anatomical perspective by monitoring changes in expression of preprotachykinin (PPT) mRNA encoding the prototypic tachykinin substance P and related peptide species in neurons of the rat dorsal root ganglia (DRG) following unilateral chronic constriction injury of the sciatic nerve. In situ hybridization histochemistry (ISHH) analyses in conjunction with computer-assisted image processing were employed to quantify levels of PPT mRNA distributed in DRG neurons. Injury-induced changes in PPT mRNA expression by affected DRG neurons included: (1) at early postoperative times, generally increased levels of PPT mRNA associated with small and intermediate-size B cells exhibiting normal morphology, (2) at late postoperative times, markedly decreased levels of PPT mRNA associated with degenerating B cells, and (3) induction of PPT gene expression by large A cells which is highly correlated with degenerative morphological changes. The significant aspects of these changes are discussed with special emphasis on the contribution of altered transmitter expression by DRG neurons to the pathophysiology of causalgia. In particular, the induction of PPT gene expression by many of the large neurons undergoing degenerative changes may represent an important biochemical parameter which is associated with the development and persistence of experimental allodynia.

Attenuation of hyperalgesia in a rat model of neuropathic pain after intrathecal pre- or post-treatment with a neurokinin-1 antagonist

“…CCI has been found to produce decreases in substance P-like immunoreactivity in the ipsilateral spinal cord dorsal horn (Cameron et al, 1991;Garrison et al, 1993;Xu et al, 1996) and DRG (Munglani et al, 1995) for up to 60 days following the nerve injury, although this effect is dependent on the type of ligatures used . Nerve injury can also lead to increases in substance P mRNA in the ipsilateral spinal cord dorsal horn (Delander et al, 1997), as well as increases in the level of pre-protackykinin A mRNA, a precursor of substance P, in the DRG (Marchand et al, 1994;Noguchi et al, 1994). This latter increase may reflect alterations in neuronal phenotypes, since the increase in pre-protackykinin A mRNA is dependent on the initiation of expression in large diameter A-fibers in the DRG which normally do not express substance P (Marchand et al, 1994;Noguchi et al, 1994).…”

“…Nerve injury can also lead to increases in substance P mRNA in the ipsilateral spinal cord dorsal horn (Delander et al, 1997), as well as increases in the level of pre-protackykinin A mRNA, a precursor of substance P, in the DRG (Marchand et al, 1994;Noguchi et al, 1994). This latter increase may reflect alterations in neuronal phenotypes, since the increase in pre-protackykinin A mRNA is dependent on the initiation of expression in large diameter A-fibers in the DRG which normally do not express substance P (Marchand et al, 1994;Noguchi et al, 1994). The reported reductions in SP-like immunoreactivity and increases in substance P and pre-protackykinin A mRNA in DRG and spinal cord following nerve injury suggest that there may be an increase in substance P utilization and turnover associated with neuropathic pain.…”

“…Furthermore, substance P expression is initially enhanced in DRG cells following sciatic nerve injury (Marchand et al, 1994). Evidence that NK-1 receptors may play a vital role in nerve injury-induced pain behaviors has been provided by experiments demonstrating that i.t.…”

Increased substance P responses in dorsal root ganglia and intestinal macrophages duringClostridium difficiletoxin A enteritis in rats

“…In the intestine, SP has been found in capsaicin-sensitive sensory neurons (2), enteric neurons (3), as well as intestinal enteroendocrine cells (4). SP is also synthesized in the cell bodies of the dorsal root ganglia (DRG) (5), and evidence indicates that release of SP from DRG to spinal cord mediates nociceptive and inflammatory stimuli (6)(7)(8). Recently, Reinshagen et al (9) reported decreased levels of SP in the DRG of rabbits 48 hr after induction of colitis, suggesting that SP may be released from sensory neurons during the acute phase of inflammation.…”

Antinociceptive activity of the tachykinin NK1 receptor antagonist, CP‐99,994, in conscious gerbils

“…A recent study examining rats with a sciatic nerve constriction injury, which caused guarding behaviours and persistent thermal hyperalgesia, showed an induction of preprotachykinin gene expression by large A cells in the dorsal root ganglion which normally transmit non-noxious sensory stimuli (Marchand et al, 1994). However, preliminary studies have failed to demonstrate an anti-algesic effect of acute administration of either CP-96,345 (400 pg intrathecally) in rats with sciatic nerve ligation (Yamamoto & Yaksh, 1992), or CP-99,994 (up to 100 pg kg-', i.v.)…”