Repetitive Noxious Stimulation with Formalin, Capsaicin, and Freund’s Adjuvant Facilitates Monitoring of the Peripheral and Central Pain Effects

Pain is one of the most frequent symptoms accompanying diseases. Every type of pain invokes various molecular mechanisms leading to the central effects, and hence the pain response. The plasticity of the nervous system is a unique property enabling it to change the number and quality of neural connections in order to adapt to the environment. This property is the basis of memory, particularly “pain memory”. The formalin test is widely used as an experimental model of biphasic pain in laboratory animals. We supposed that adding the second injection of a noxious agent to the classical test will enhance the pain response and let us observe plastic changes in the central nervous system and in the periphery. The contralateral repetitive injection of formalin and capsaicin to the rat hind paw revealed an increase in pain score in Phase 1 and a decrease in Phase 2. In Freund’s adjuvant injected group the pain score in both phases was increased. Different patterns of spinal cord neuronal activity were observed in formalin, capsaicin, and Freund’s adjuvant injections. Contralateral repetitive administration of formalin and capsaicin, but not Freund’s adjuvant revealed a “pain memory”, a pain response in previously injected but unaffected in the second injection paw. Analysis of the “pain memory” based on our previous studies revealed its overall central character and lack of association with inflammation. Investigations of mechanisms underlying each type of pain and deep analysis of pain memory may open new perspectives to prevent and treat pain.