| Mammalian tachykinins (TKs) including substance P (SP), neurokinin A (NKA) and neurokinin B are part of a family of neuropeptides that are widely distributed in the central and peripheral nervous system. Their structural similarities are characterized by a common C-terminal pentapeptide. There are three subtypes of TK receptors (neurokinin-1,2,3 receptors). The three TKs are capable of binding each receptor subtype although with different affinities. Two of the TKs: SP and NKA, are colocalized with excitatory neurotransmitter glutamate in primary afferent neurons that respond to painful stimulation. Previous studies have indicated the contribution of SP to neurogenic inflammation and the hyperexcitability of dorsal horn neurons after tissue injury. However, the functional study of TKs have been hampered by the fact that they are often colocalized and coreleased with other neurotransmitters. Using a pharmacological approach to concurrently block the action of SP and NKA, which almost certainly function in unison, is not practical.; In this study, I target-disrupted the mouse preprotachykinin A (PPTA) gene, which encodes both SP and NKA, and tested the responses of wild type and PPTA mutant mice to various noxious stimuli. I found that although the behavioral response to mildly painful stimuli was intact in these mice, the response to moderate to intense pain was significantly reduced; and SP/NKA contributes to acute nociception in all modalities of both cutaneous and visceral origin. Neurogenic inflammation, which results from peripheral release of SP and NKA, is almost absent in the mutant mice. Yet in several mouse models of chronic inflammation or nerve injury I did not detect any difference in the behavior between wild type and mutant mice.; I also examined the response of neurokinin-1 receptor (NK-1R) mutant mice under the same conditions as I tested PPTA mutant mice. NK-1R mutant mice showed a less profound phenotype than did the PPTA mutant mice, indicating that SP/NKA might contribute to nociception through other neurokinin receptors.; I also found that the delta opioid receptor immunoreactivity (DOR-ir) was severely disrupted in the dorsal horn of the spinal cord and several other brain areas in PPTA mutant mice. We propose that it is due to the missorting of DOR protein from regulatory secretory pathway to constitutive secretory pathway in the mutant mice. We also found an attenuated analgesic effect of intrathecal δ1 agonist DPDPE but not δ2 agonist deltorphin, indicating the existence of presynaptic δ1 receptors and postsynaptic δ2 receptors. Nevertheless, the loss of DOR-ir in PPTA mutant mice seems unlikely to contribute to the deficit observed in the mutant mice. |
