Biology subjects

Davletov, B.

Publications and source records attributed to Davletov, B..

3 recordsLinked to original sources

bioRxiv2026

Transient silencing of spinal nociceptive neurons leads to a long-term reduction in joint pain mediated by recruitment of opioid activity.

Chronic inflammatory joint pain remains inadequately treated despite current therapies, creating urgent clinical need for non-addictive alternatives in an era of heightened opioid-related concerns. A promising new approach involves conjugates of botulinum toxin and substance P (SP-BOT), which, when infused locally or spinally, have been shown to produce temporary pain relief in neuropathic mouse models, with its effects declining after approximately 100 days as the construct loses activity. However, its long-term efficacy in inflammatory pain models was unknown. Unexpectedly, in a mouse model of ankle inflammatory arthritis, a single intrathecal injection of SP-BOT at the peak of pain sensitivity produced a persistent reduction in mechanical hyperalgesia that lasted for weeks beyond the loss of construct activity. Furthermore, this late-phase pain relief exhibited a striking mechanism in that a single injection of the opioid antagonist naltrexone partially reversed the anti-hyperalgesia generated by SP-BOT. These data indicate that SP-BOT-mediated neuronal silencing initiates two distinct phases of pain relief. An initial, direct phase is followed by a second, sustained phase that maintains pain alleviation and is driven by endogenous opioid mechanisms.

pharmacology and toxicology↗

bioRxiv2024

Novel therapies for cancer-induced bone pain

1.Cancer pain is a growing problem, especially with the substantial increase in cancer survival. Reports indicate that bone metastasis, whose primary symptom is bone pain, occurs in 65-75% of patients with advanced breast or prostate cancer. We optimized a preclinical in vivo model of cancer-induced bone pain (CIBP) involving the injection of Lewis Lung Carcinoma cells into the intramedullary space of the femur of C57BL/6 mice or transgenic mice on a C57BL/6 background. Mice gradually reduce the use of the affected limb, leading to altered weight bearing. Symptoms of secondary cutaneous heat sensitivity also manifest themselves. Following optimization, three potential analgesic treatments were assessed; 1) single ion channel targets (targeting the voltage-gated sodium channels NaV1.7, NaV1.8, or acid-sensing ion channels), 2) silencing {micro}-opioid receptor-expressing neurons by modified botulinum compounds, and 3) targeting two inflammatory mediators simultaneously (nerve growth factor (NGF) and tumor necrosis factor (TNF)). Unlike global NaV1.8 knockout mice which do not show any reduction in CIBP-related behavior, embryonic conditional NaV1.7 knockout mice in sensory neurons exhibit a mild reduction in CIBP-linked behavior. Modified botulinum compounds also failed to cause a detectable analgesic effect. In contrast, inhibition of NGF and/or TNF resulted in a significant reduction in CIBP-driven weight-bearing alterations and prevented the development of secondary cutaneous heat hyperalgesia. Our results support the inhibition of these inflammatory mediators; and more strongly their dual inhibition to treat CIBP, given the superiority of combination therapies in extending the time needed to reach limb use score zero in our CIBP model.

neuroscience↗

bioRxiv2020

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.

There 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.

neuroscience↗