The amino-terminal heptapeptide of the algesic substance P provides analgesic effect in relieving chronic neuropathic pain.

Of painful conditions, somatic pain of acute nociceptive origin can be effectively managed clinically, while neuropathic pain of chronic neuropathy origin is difficult to control. For molecules involved in pain sensation, substance P (SP) is algesic, exacerbating painful sensation, while its amino-terminal fragment, heptapeptide SP, confers biological activities different from its full-length parent neuropeptide precursor. We previously demonstrated SP interaction with pain processing to alleviate chronic pain. Here we evaluated SP and its C-terminal amidated analogue SPamide, together with SP and opioid agonist DAMGO. We tested mouse behaviors of both acute somatic pain in tail-flick latency assay, and neuropathic pain in sciatic nerve injury model of chronic constriction injury (CCI). DAMGO produced dose-dependent analgesia for somatic pain as expected, so did both SP and its analogue SPamide, while SP yielded the opposite effect of algesia, in a phenomenon we termed 'contrintus', meaning 'opposite from within' to denote that two peptides of the same origin (SP and its metabolic fragment SP) produced opposite effects. In CCI model, DAMGO showed a general reduction in allodynia sensitivity for both nerve-injured and normal paws, without selective effect for neuropathic pain, consistent with clinical observation that opioids are less effective for chronic neuropathic pain. On the other hand, both SP and SPamide displayed dose-dependent anti-allodynia effect that is selective for neuropathic pain. These findings suggest that SP and its analogue may be useful for developing pharmaceuticals to treat neuropathic pain.