Preclinical Pharmacological Evaluation Method for Centrally Acting Analgesics in Nociplastic Pain Induced by Inflammation in the Trigeminal Region

The term “nociplastic pain,” a recently proposed novel mechanistic descriptor of chronic pain, is defined as pain that arises from altered nociception without nociceptor activation and nerve injury^1）. Diseases with the nociplastic pain include fibromyalgia, complex regional pain syndrome, irritable bowel syndrome, chronic primary temporomandibular disorder pains, and burning mouth syndrome. Since there is no established pharmacotherapy for these diseases, developing drugs that effectively mitigate aberrant nociception in conditions characterized by nociplastic pain becomes an urgent issue. However, the limited availability of preclinical murine models hampers the evaluation of nociplastic pain without nociceptor activation or injury^2）. <br>In this context, we present our recently developed model for nociplastic pain. Through a single subcutaneous injection of formalin into the upper lip, sustained sensitization lasting over 13 days at the bilateral hind paws occurs despite the absence of injury or neuropathy in rats and mice^3）. Using this nociplastic pain model, we demonstrated that repeated daily injections of pregabalin （PGB）, a drug conventionally employed to treat neuropathic pain, transiently attenuated sensitization in bilateral hind paws for the first 6 days following the initial inflammation^4）. By the 10th day of formalin injection, hindlimb sensitization was significantly reduced, even without PGB, implying its action site within the brain’s pain network^4）. This review encompasses the presentation of our obtained results, along with a discussion of potential future strategies for nociplastic pain treatment.