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

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.

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.