Gelsemine is the principal alkaloid in Gelsemium sempervirens Ait. A single intrathecal injection of gelsemine produced potent and specific antinociception in formalin-induced tonic pain, bone cancer-induced mechanical allodynia, and spinal nerve ligation-induced painful neuropathy. Gelsemine exhibits potent and specific antinociception in chronic pain by acting at spinal α3 glycine receptors. Gelsemine is an effective agent for treatment of both neuropathic pain and sleep disturbance in PSNL mice; anterior cingulate cortex might play a role in the hypnotic effects of gelsemine.

AZ11645373 is a potent and selective antagonist of human P2X7, that was developed by Astra Pharmaceuticals Ltd for treatment pain. AZ11645373 Inhibits BzATP-mediated calcium influx and inhibits ATP-mediated IL-1β release in vitro. AZ11645373 in addition to its well-characterized ability to inhibit the pro-inflammatory action of ATP demonstrates a broad P2X7 receptor-independent anti-inflammatory activity against chemically different types of inflammatory agonists. This type of polypharmacology may be especially effective for treatment of inflammatory disorders due to a combination of P2X7-dependent and P2X7-independent anti-inflammatory mechanisms. In other words, AZ11645373 has a potential to induce several beneficial effects including inhibition of inflammasome-mediated generation of IL-1β and IL-18, inhibition of inflammatory pain.

Beta-erythroidine is an organic heterotetracyclic indole alkaloid isolated from the seeds and other parts of Erythrina species. A drug used to produce muscle relaxation (excepting neuromuscular blocking agents). Its primary clinical and therapeutic use is the treatment of muscle spasm and immobility associated with strains, sprains, and injuries of the back and, to a lesser degree, injuries to the neck. Also used for the treatment of a variety of clinical conditions that have in common only the presence of skeletal muscle hyperactivity, for example, the muscle spasms that can occur in multiple sclerosis. Beta-erythroidine is a neuronal nicotinic acetylcholine receptor antagonist. The beta-erythroidine and its more potent derivative (2,7-dihydro) have been used as muscular relaxants in numerous clinical applications. This activity is attributed to a antagonistic action of the dihydro-beta-erythroidine with the nicotinic receptors of acetyl choline.

CCG-50014 is the potent small molecule RGS inhibitor. It is several hundred-fold selective for RGS4 over other RGS proteins. CCG-50014 binds covalently to the RGS, forming an adduct on two cysteine residues located in an allosteric regulatory site. CCG50014, is likely to enhance the [D-Ala²,N-MePhe⁴,Gly-ol]-enkephalin-mediated analgesic effect by removing RGS4-mediated inhibition of opioid receptors (ORs) and by preventing OR internalization in the spinal cord. The inhibition of RGS4 activity can enhance OR agonist-induced analgesia.

R-Duloxetine is an enantiomer of the antidepressant S-duloxetine. R-Duloxetine was shown was highly effective against postoperative pain, which could be potential new analgesics. R-Duloxetine could show its effect via the blocking of the neuronal Na⁺ channels.

Pamoic acid, also called embonic acid, is a naphthoic acid derivative, used as a counter ion of a drug compound to increase the solubility of the drug in water. Pamoic acid has agonist activity for the orphan G protein-coupled receptor GPR35 by which it activates ERK and beta-arrestin2, and causes antinociceptive activity. Although (like other drug salts) it has been considered an inactive compound by the FDA.

AG-3-5 (also known as icilin) was first identified as a super-cooling agent in the early 1980s and bears little resemblance to menthol structurally. Icilin is able to activate both TRPM8 and TRPA1 channel activity. Icilin alleviates pain sensation in animal models.

Saikosaponin A is a triterpene saponin found in Bupleurum that exhibits anti-inflammatory, analgesic, neuromodulatory, anticancer, and immunosuppressive activities. Saikosaponin A decreases production of TNF-α, IL-1β, and IL-2 and increases mechanical withdrawal thresholds and thermal withdrawal thresholds in animal models of chronic constructive injury. Saikosaponin A also decreases self-administration of cocaine and morphine. In colon carcinoma cells, saikosaponin A causes activation of caspases 2, 3, 8, and 9 and PARP, induces apoptosis, and decreases expression of Bcl-2 and XIAP. Additionally, this compound inhibits the proliferation and activation of ConA-treated T cells, inducing G0/G1 phase cell cycle arrest and decreasing expression of TNF-α, IL-2, and IFN-γ.

Mesaconitine is a diterpene alkaloid, from the plants of the Aconitum genus, Ranunculaceae. Mesaconitine is a centrally acting analgesic without affinity to opioid receptors. It has been reported that the antinociception is due to an interaction with the noradrenergic system. As a neurotoxic, it opens the TTX-sensitive Na+ channels in the heart and other tissues and induces arrhythmia. The activity of Mesaconitine, which is a chemical analog of Aconitine, on TTX sensitive Na+ channels in the heart and other tissues is stronger than that of Aconitine. The duration of its neurotoxic effect is shorter. It possesses an hypotensive activity. The hypotensive action is not inhibited by an adrenergic b-blocker but abolished with muscarinic blocker. It may be partially mediated by a muscarinic mechanism. Mesaconitine binds with high affinity to the open state of the voltage-sensitive sodium channels at site 2, thereby causing a persistent activation of the sodium channels, which become refractory to excitation.

Benzoylmesaconine (BMA) is the main Aconitum alkaloid in Radix Aconiti Lateralis Preparata. Notably, the high levels of toxicity of Radix Aconiti are derived from diester aconitum alkaloids, including aconitine, mesaconitine and hypaconitine, which can be hydrolyzed to benzoylaconine, benzoylmesaconine and benzoylhypaconine, respectively. Benzoylmesaconine exhibits biological effects, including analgesic, antiviral and antifungal activities.