Proanthocyanidins Inhibit the Transmission of Spinal Pain Information Through a Presynaptic Mechanism in a Mouse Inflammatory Pain Model

Abstract

Inflammatory pain is one of the most common symptoms of clinical pain that seriously affects patient quality of life, but it currently has limited therapeutic options. Proanthocyanidins, a group of polyphenols enriched in plants and foods, have been reported to exert anti-inflammatory pain-alleviating effects. However, the mechanism by which proanthocyanidins relieve inflammatory pain in the central nervous system is unclear. In the present study, we observed that intrathecal injection of proanthocyanidins inhibited mechanical and thermal pain sensitivity in mice with inflammatory pain induced by Complete Freund’s Adjuvant (CFA) injection. Electrophysiological results further showed that proanthocyanidins inhibited the frequency of spontaneous excitatory postsynaptic currents without affecting the spontaneous inhibitory postsynaptic currents or the intrinsic properties of parabrachial nucleus-projecting neurons in the spinal cord. The effect of proanthocyanidins may be mediated by their inhibition of phosphorylated activation of the PI3K/Akt/mTOR pathway molecules in dorsal root ganglia neurons. In summary, intrathecal injection of procyanidin induces an obvious anti-inflammatory pain effect in mice by inhibiting peripheral excitatory inputs to spinal neurons that send nociceptive information to supraspinal areas.

Proanthocyanidins induce analgesic and anxiolytic effects in spared nerve injured mice by decreasing in vivo firing rate of pyramidal cells in the insular cortex

“…A previous study showed that oral gavage of 90 mg/kg PACs in mice is the optimal does for the attenuation of neuropathic pain via suppressing matrix metalloproteinase-9/2 (Pan et al, 2018). Our previous study pointed out intrathecal injection of 20 μg PACs induced obvious anti-inflammatory pain effect at the spinal cord level by inhibiting phosphorylated activation of the PI3K pathway (Fan et al, 2021). Our present study aimed to observe the PACs' effects at cortical level.…”

“…PACs administration showed obvious alleviation of mechanical allodynia and spontaneous pain, but not of heat hyperalgesia. However, in our previous works, we have shown that intrathecal injection of PACs inhibits both mechanical and heat pain responses (Fan et al, 2021). These different analgesic effects on heat hyperalgesia suggest that PACs may induce different analgesic effect in spinal and cortical level.…”

“…Besides, several studies report that intragastrical administration and intraperitoneal injection of PACs has analgesic effect underlying molecular mechanisms in suppressing matrix metalloproteinase-9/2 and preserving AKT and ERK activations (Pan et al, 2018;Gao et al, 2020). Recently, our group shows that intrathecal injection of PACs relieves inflammatory pain in the central nervous system at the spinal cord level, and also reveals the synaptic mechanisms and molecular mechanisms of PACs' analgesic effect (Fan et al, 2021). However, whether PACs relive neuropathic pain and pain-related anxiety has not been investigated at cortical level.…”

“…Proanthocyanidins (natural extracts, CAS number: 4852-22-6, Molecular formula: C30H26O13, Molecular weight: 594.52) were purchased from Shanghai Yuanye Biotechnology (Shanghai Yuanye Biological Technology Co., Ltd.). The solution was dissolved in artificial cerebrospinal fluid (ACSF) to produce the original solution at a concentration of 8.41 mM, that is, 5 mg/mL (Fan et al, 2021). The final concentration was diluted in ACSF for behavioral and electrophysiological experiments.…”

Polygonum Cuspidatum Alcohol Extract Exerts Analgesic Effects via the MAPK/ERK Signaling Pathway

“…This leads to hyperexcitability of spinal nociceptive neurons and the induction of abnormal pain and hyperalgesia. 36 Our research focuses on the crucial step of pain transmission in the spinal cord, combining HPLC, bioinformatics, and molecular biology methods to preliminarily reveal the active substances and their mechanisms of action in the pain-relieving properties of PC. Using a network pharmacology approach in this study, we provided evident that the five main active components of PC exert analgesic effects via p38 and JNK.…”