Pain is the fifth vital signs besides body temperature, respiration, heart rate, blood pressure, which can serve as a warning when the body is hurt and cause a series of defensive responses of the body. However, excessive pain will cause damage to the body, and become one kind of unbearable torture to the body. Therefore, analgesia is an important task for healthcare practitioners. Chronic pain threatens the survival and quality of human life, and also causes a great burden on families and society. According to American Pain Society, it was reported that the prevalence of chronic pain in United States was estimated as 35.5%, including 105 million people. It costs over $ 100 billion, directly resulting in the consumption of healthcare spending and the loss of working hours.
The most commonly used analgesics include acetaminophen, non-steroidal anti-inflammatory drugs and opioid receptor agonists, such as tramadol and morphine. Non-steroidal anti-inflammatory drugs (NSAIDs) have weak analgesic efficacy, and may lead to gastrointestinal bleeding, renal failure and liver dysfunction as well as other side effects; and overdose of opioids will cause respiratory depression, and long-term use thereof will lead to side effects, such as constipation, abuse, dependence and addiction. In recent years, there are some other analgesics which are also marketed, for example antidepressants (such as Duloxetine, Lilly), anticonvulsants (such as Puri Galindo, Lyrica™, Pfizer) and selective cyclooxygenase-2 (COX-2) inhibitors (such as Parecoxib, Pfizer).
A new mode for developing analgesic drugs is the mechanism-mediated development of new drug targets. For such mode, the mechanism of pain is mainly studied to find an important factor or target for regulating occurrence and development of pain, thereby developing a new medicament to intervene with the factor or target and achieve analgesia. Many clinical applications based on the results of such basic research are currently tested, however, few of them are successful.
One typical example is the development of anti-nerve growth factor (Nerve Growth Factor, NGF) antibodies. NGF is a member from neurotrophic factor family, and plays an important role in the survival and apoptosis of neuron during development. Basic research shows that NGF may promote pain, therefore blocking NGF may be an important method for treating pain. Therefore many anti-NGF antibodies were developed, including Tanezumab (Pfizer), SAR164877/REGN475 (Sanofi/Regeneron) and NJ-42160443/AMG403 (Johnson & Johnson/Amgen). These drugs show analgesic effects in animal models and clinical trials of phase I/II also show safety and analgesic effects, however, in the clinical trial of phase III in rheumatoid arthritis and ankylosing spondylitis patients for evaluating clinical efficacy and safety of analgesia of anti-NGF antibodies in combination with NSAID drugs, painless ischemic necrosis of caput femoris can be found in a small number of patients (Garber K Painkiller Novel Fate of the mAbs Hangs in Balance. Nat Biotechnol 2011, 173-174; Seidel M, Lane N, Control of Arthritis Pain with Anti-Nerve-Growth Factor, Risk and Benefit, Curr Rheumatol Rep, 2012, 583-585).
Therefore, there is a huge market demand in the development of analgesics with new mechanism. Brain-derived neurotrophic factor BDNF is a neurotrophic factor discovered after nerve growth factor was discovered, molecular weight of which is 12.4 kDa. BNDF mainly distributes in central nervous system, and is also synthesized in peripheral nervous system and plays an important role in the regulation of survival, differentiation of neuron and synaptic plasticity and damage repair. Currently, there is an evidence to show that BDNF is not only an important factor in regulating development of nervous system and emotional disorders, but also an important mediator of pain.
Precursor for brain-derived neurotrophic factor (proBDNF) is synthesized in endoplasmic reticulum from BDNF gene through transcription and translation. The peptide chain is of 247 amino acids in length, and the theoretical molecular weight of the amino acid sequence is 27.8 KD. However, the molecular weight may be varied in a range of 32-36 kD due to different degree of glycosylation for the protein. In ProBDNF, the amino acid sequence at 1-18 positions is signal peptide sequence, and two fragments are produced during secretion process, wherein one fragment is a polypeptide fragment containing amino acids at 19-129 positions (that is, precursor domain), which is called precursor domain (proBDNF pro-domain), and another fragment is a fragment of amino acids at 130-247 positions (that is, mature domain), which will form BDNF with bioactivities upon processing.
At present, a lot of evidence shows that proBDNF is not only an intermediate of mature BDNF, but also can be used as a ligand to bind high-affinity receptor, p75 neurotrophin receptor (p75NTR) for exerting biological effects. Currently, the function of proB DNF-p75NTR signaling pathway in pain is unclear, however, there is a point-of-view that spinal sensitization mechanism of pain is similar to forming mechanism of Long-term potentiation (LTP)/long term depression (LTD) of hippocampus, while BDNF-TrkB and proBDNF-p75NTR signaling pathway are important signaling molecules for regulating LTP/LTD.
In 2012, experiments from Zhang, Yanling (Central South University) demonstrated that the expression of proBDNF in dorsal root ganglion was up-regulated after hind legs of a rat were cut; after an adenoviral vector of proBDNF was injected into hind legs of a rat, a great deal of proBDNF was expressed on nerve fibers by the adenovirus vector, and over-expression of proBDNF caused a significant decrease in withdrawal threshold of hind legs to mechanical stimulation and inflammation in plantar tissue; and withdrawal threshold of hind legs after the hind legs of a rat were cut can be increased by intraperitoneal administration of anti-proBDNF polyclonal antibody.
Cutting pain belongs to acute pain. For acute and chronic pain, both of outer peripheral sensitization and central sensitization can occur, and the difference between which is that: for outer peripheral sensitization, transmitters released by nerve fibers or axons in local tissue and intracellular signaling pathways are different, and pain transmitter and signaling pathways associated with dorsal root ganglion are also different, the latter of which lasts longer; in addition, for central sensitization, sustained activation of glial cells in spinal cord may also be the most important difference between the mechanisms of acute and chronic pain.