Antinociceptive effect of the hydroethanolic leaf extract of Calotropis procera (Ait) R. Br. (Apocynaceae): Possible involvement of glutamatergic, cytokines, opioidergic and adenosinergic pathways

A cardinal feature of inflammation is heightened pain sensitivity at the site of the inflamed tissue. This results from the local release by immune and injured cells of nociceptor sensitizers, including prostaglandin E(2), bradykinin, and nerve growth factor, that reduce the threshold and increase the excitability of the peripheral terminals of nociceptors so that they now respond to innocuous stimuli: the phenomenon of peripheral sensitization. We show here that the proinflammatory cytokine interleukin-1beta (IL-1beta), in addition to producing inflammation and inducing synthesis of several nociceptor sensitizers, also rapidly and directly activates nociceptors to generate action potentials and induce pain hypersensitivity. IL-1beta acts in a p38 mitogen-activated protein kinase (p38 MAP kinase)-dependent manner, to increase the excitability of nociceptors by relieving resting slow inactivation of tetrodotoxin-resistant voltage-gated sodium channels and also enhances persistent TTX-resistant current near threshold. By acting as an IL-1beta sensor, nociceptors can directly signal the presence of ongoing tissue inflammation.

A method for assessing pain and analgesia in rats and cats is described. The procedure involves subcutaneous injection of dilute formalin into the forepaw, after which the animal's responses are rated according to objective behavioral criteria. The formalin test is a statistically valid technique which has two advantages over other pain tests: (1) little or no restraint is necessary, permitting unhindered observation of the complete range of behavioral responses; and (2) the pain stimulus is continuous rather than transient, thus bearing greater resemblance to most clinical pain. The analgesic effects of morphine, meperidine, and stimulation of the periaqueductal grey matter are evaluated using this test.