The alleviation of neuropathic pain behaviours by a single injection of a synthetic substance P-botulinum conjugate persists for up to 120d and can be restored with a second injection of conjugate

Abstract

AbstractThere is an urgent need for new pain-relieving therapies. We have previously shown using mouse models of persistent pain that a single intrathecal injection of substance P conjugated to the light chain of botulinum toxin (SP-BOT) silenced neurons in the dorsal horn of the spinal cord and alleviated mechanical hypersensitivity. The SP-BOT construct selectively silenced neurokinin 1 receptor positive (NK1R+) neurons in the superficial dorsal horn of the spinal cord. A subset of these NK1R+ neurons are nociceptive projection neurons and convey injury-related information to the brainstem, initiating and maintaining programmes of escape and recovery essential for healing. Previously, we observed a reduction in mechanical hypersensitivity in a spared nerve injury (SNI) model of neuropathic pain state after intrathecal injection of SP-BOT over the lumbar spinal cord and lasting for up to 40 days. In this latest study, we have extended these observations and now show that thermal and affective measures of pain behaviour were also alleviated by a single intrathecal injection of SP-BOT. By introducing SNI 30 days, 60 days, 90 days or 120 days after injection of SP-BOT we have established that NK1R+ spinal neurons in the superficial lamina of the dorsal horn were silenced for up to 120 days following a single intrathecal injection of the botulinum construct. We also show that behavioural alleviation of neuropathic pain symptoms could be reinstated by a second injection of SP-BOT at 120 days. Taken together this research demonstrates that this recently developed botulinum toxin conjugate provides a powerful new way of providing long term pain relief without toxicity following a single injection and also has a therapeutic potential for repeated dosing when pain begins to return.