Formalin injection into knee joints of rats: pharmacologic characterization of a deep somatic nociceptive model.

UNLABELLED: Formalin (0.25, 0.5, 3, and 5%) injected into the knee joint of rats induced a dose-dependent nociception that was featured by 2 phases of intense guarding behavior of the affected limb, interposed by a period of quasinormal gait (quiescent phase). The guarding behavior during a period of forced gait was measured by the total time the paw of the affected limb was not in contact with the surface of a revolving cylinder (paw elevation time [PET]). Pretreatment with morphine (4 mg/kg, subcutaneously) reduced PET in both nocifensive phases, and naloxone (1 mg/kg, subcutaneously) antagonized morphine's effect. The cyclooxygenase inhibitor diclofenac (5 mg/kg, intraperitoneal) reduced only the second phase of nocifensive responses. A low dose of the benzodiazepine midazolam (0.25 mg/kg, intraperitoneal) significantly reduced only the second phase of response, but a higher dose (1 mg/kg, intraperitoneal) had no effect. A subconvulsant, anxiogenic dose of pentylenetetrazol (30 mg/kg, intraperitoneal) also did not affect the PET increase induced by formalin. The antihistamine meclizine (2.5 mg/kg, intraperitoneal) caused an increase of the response in the second phase, but a higher dose (7.5 mg/kg, intraperitoneal) caused inhibition. The peripheral antihistamine loratadine (5 and 10 mg/kg, intraperitoneal) also caused an increase of the second phase. Neither antihistamine altered the first phase of PET. These results reproduced previous findings with classical analgesics in formalin-induced nociception. However, the pronociceptive effect of antihistamines, and the antinociceptive effect of midazolam observed here suggest that formalin-induced incapacitation introduces new characterists of nociceptive system that may complement the study of analgesics. PERSPECTIVES: Anxiety is thought to influence pain experience in an opposing manner depending on nociception originates in cutaneous or deep somatic/visceral tissues. The present formalin-induced nociceptive test may help to predict more reliably the pain-killing effect of new pharmacologic strategies, with classical or nonclassical mechanisms, for the treatment of clinically relevant pains, which are generally originated in deep structures.