Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice

Abstract

Overline: PainOne Sentence Summary: Silencing key neurons with botulinum toxin conjugates exerts long-lasting pain relief in mouse models of chronic pain. 2 AbstractChronic pain is a widespread debilitating condition affecting millions of people worldwide. Although several pharmacological treatments for relieving chronic pain have been developed, they require frequent chronic administration and are often associated with severe adverse events, including overdose and addiction. Persistent increased sensitization of neuronal subpopulations of the peripheral and central nervous system has been recognized as a central mechanism mediating chronic pain, suggesting that inhibition of specific neuronal subpopulations might produce antinociceptive effects. We leveraged the neurotoxic properties of the botulinum toxin to specifically silence key pain processing neurons in the spinal cords of mice.We show that a single intrathecal injection of botulinum toxin conjugates produced long-lasting pain relief in mouse models of inflammatory and neuropathic pain without toxic side effects. Our results suggest that this strategy might be a safe and effective approach for relieving chronic pain while avoiding the adverse events associated with repeated chronic drug administration.

Pachyonychia congenita and botulinum toxin

“…Btx has been in clinical use for over 15 years in the treatment of muscle spasms, glabellar lines and axillary hyperhidrosis, where its effects are due to the blockade of acetylcholine exocytosis at the neuromuscular junction resulting in muscle paralysis or blocking eccrine gland sweat production. In addition, Btx can reduce inflammatory and neuropathic pain by acting on neurokinin‐1 receptor‐expressing neurons in the central nervous system or by blocking pain‐related neurotransmitters such as substance P, glutamate and even reducing levels of the inflammatory pain‐related protein transient receptor potential vanilloid 1 in the peripheral nervous system . Our understanding of these additional mechanisms of action of Btx has led to many off‐label disease treatments in dermatology, with some success …”

Developing Modern Pain Therapies

“…Whilst exceptionally promising these approaches have limited efficacy at present and do not seem able to restore pain to near baseline levels. However, the injection of dermorphin targeted botulinum toxin had an effect even when administered 2 weeks after nerve injury suggesting that silencing dorsal horn neurons is a therapeutic possibility for inhibiting pain that is already established (Maiarù et al, 2018). Together, these protein-based therapies have substantial potential for the future treatment of pain.…”

Analgesia without opioids

“…When you inject it, it quickly binds to nerves, " says Davletov. Injecting nanograms of the engineered toxin into a mouse with neuropathic pain proved effective in relieveing pain 10 . Davletov hopes to move the treatment into clinical trials in the next two years.…”