Pain Modulation by Lignans (Phyllanthin and Hypophyllanthin) and Tannin (Corilagin) Rich Extracts of Phyllanthus amarus in Carrageenan‐induced Thermal and Mechanical Chronic Muscle Hyperalgesia

Abstract

The current study was aimed at evaluating the antihyperalgesic effects of lignans (phyllanthin and hypophyllanthin) and tannin (corilagin) rich three standardized extracts of Phyllanthus amarus in a model of chronic musculoskeletal inflammatory pain. Three percent carrageenan injected in the gastrocnemius muscle produced hyperalgesia to mechanical and heat stimuli ipsilaterally, which spreads to the contralateral side within 7 to 9 days. To investigate the effects on chronic thermal and mechanical hypersensitivity, three extracts of P. amarus in three doses (100, 200, and 400 mg/kg) were administered to animals intraperitoneally from 14th day to 22nd day after intramuscular injection of carrageenan. It was observed that intraperitoneal administrations of Phyllanthus extracts showed antihyperalgesic activity, as they elevated thermal and mechanical threshold, which was supported by histopathological observations along with reduction in prostaglandin E2 (PGE2) concentration. In conclusion, we strongly suggest that the observed antihyperalgesic and antiinflammatory effects of P. amarus in current pain model are mediated via spinal or supraspinal neuronal mechanisms, mainly by inhibition of PGE2. Modulation of chronic muscular inflammation may be due to presence of phytoconstituents like phyllanthin, hypophyllanthin, and corilagin, which offers a promising means for treatment of chronic muscle pain.

Characterization of the nociceptive effect of carrageenan: Masseter versus gastrocnemius

“…When comparing both results, mechanical hyperalgesia lasts longer in the orofacial muscle than in the limb muscle; the highest concentration of carrageenan‐induced mechanical hyperalgesia lasted for 2 days in the masseter, but only 4 hours in the gastrocnemius. Conversely, we did not observe the long‐lasting nociceptive effect of carrageenan described by other researchers . Those authors found that intramuscular carrageenan administration results in decreased mechanical withdrawal thresholds of muscle and paw, enhanced avoidance to noxious stimuli, and decreased voluntary activity.…”

“…The differences in the methodology may also be the reason we did not observe a reduction in heat pain thresholds. In previous studies, these thresholds were assessed with the plantar test or a water bath at 47°C in the paw, yet we used a device applied on the skin over the muscle at a constant temperature of 45°C, which is the temperature at the limit of being considered painful …”

“…described an animal model of chronic hyperalgesia induced by muscle inflammation, administering 3% carrageenan once in the gastrocnemius muscle. This chronic muscle pain is maintained by spinal or supraspinal neuronal mechanisms and has been suggested to have greater translational validity . Other researchers have also used this model and showed long‐lasting hyperalgesia and inflammation …”

“…These models include those of muscle or joint inflammation, noninflammatory centrally maintained pain, exercise‐induced pain, or long‐lasting muscle pain induced by stress . Of the experimental strategies used to study muscle pain, the intramuscular injection of algesic substances produces quantifiable and clinically relevant pain, hyperalgesia, and altered motor function …”

Polymethoxyflavones from Nicotiana plumbaginifolia (Solanaceae) Exert Antinociceptive and Neuropharmacological Effects in Mice

“…Upon cooling, the mixture was supplemented with MeOH up to 5 mL volume and thoroughly mixed. Five minutes later the absorbance of the mixture was read at 278 nm by UV spectrophotometer (Chopade and Sayyad, 2015 ). The PGE2 content was represented by optical density (OD) value of the mixture.…”