Since the failure of specific substance P antagonists to induce analgesia, the role of tachykinins in the development of neuropathic pain states has been discounted.
In the last decades, the heptapeptide SP1-7, the major bioactive metabolite produced by substance P (SP) cleavage, has been largely investigated as a potential target for the development of novel peptidomimetic molecules to treat NP.
The dipeptide amide H-Phe-Phe-NH<sub>2</sub> (1) that previously was identified as a ligand for the substance P 1-7 (SP<sub>1-7</sub>) binding site exerts intriguing results in animal models of neuropathic pain after central but not after peripheral administration.
Nerve growth factor (NGF) is released after nerve injury by immune and Schwann cells and transported in retrograde fashion to the dorsal root ganglion (DRG), resulting in increased synthesis of Substance P (SP) and the triggering of neuropathic pain.
Importantly, glial cells in the dorsal horn of the spinal cord (L4- L5) of SP-treated CCI mice, expressed the anti-inflammatory cytokine, IL-10, which was not seen in vehicle saline-treated mice.Thus, i.v. administration of substance P may be beneficial for improving the treatment of patients with neuropathic pain, since it decreases the activity of nociceptive factors and increases the expression of anti-nociceptive factors.
The lower efficacy of opioids in neuropathic pain may be due to the increased activity of pronociceptive systems such as substance P. We present evidence to support this hypothesis in this work from the spinal cord in a neuropathic pain model in mice.
However, with the two exceptions of the [MeLys<sup>3</sup>]SP<sub>1-7</sub> amide (3) and the [MeGln<sup>5</sup>]SP<sub>1-7</sub> amide (4), the peptides with a methyl group attached to the backbone are devoid of significant anti-allodynic effects after peripheral administration in the spared nerve injury (SNI) mouse model of neuropathic pain.