An easily induced preclinical trigeminal neuropathic nerve injury model is described here for the study of chronic pain, the model acronym FRICTION (Foramen Rotundum Inflammatory Constriction Trigeminal InfraOrbital Nerve). In patients, neuropathic pain is thought to be related to vascular alignment or multiple sclerosis along this small trigeminal nerve branch (V2) innervating the maxillary teeth and middle third of the face. With no detectable outward physical signs, the FRICTION model is ideal for blinded studies. The acronym FRICTION applied relates to the persistence of the trigeminal neuropathic pain model likely due to sliding irritation with normal chewing in the mice. A stepby-step method to induce the mild chronic rodent neuropathic pain model is described here. The surgery is performed orally through a tiny surgical slit inside the cheek crease to align a chromic gut suture irritant along the nerve as it passes into the skull. The model allows testing of non-evoked subjective measures and evoked quantitative mechanical hypersensitivity (allodynia) testing with von Frey filaments through at least 10-14 weeks (100 days). Anxiety and depression behaviors develop within 3-6 weeks relevant to the affective component of chronic pain. While many pain drugs have failed based on testing performed in the acute animal models available, the more stable and easily replicated trigeminal inflammatory compression model is the better suited for understanding both mechanistic and affective components of nerve injury-induced chronic neuropathic pain states as well as the more ideal for preclinical trials of novel non-opioid pain relief therapies.

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The blood–brain barrier (BBB) and blood–nerve barrier ensure protection of the nervous system but pose a challenge for the treatment of pain since it restricts passage of many therapeutic drugs. Although it is unknown which blood–neural barrier is more relevant, or whether permeabilities are the same for different barriers, we proposed that the inefficiency of thiazolidinedione-type agonists for peroxisome proliferator-activated receptor gamma (PPARɣ) is due to their difficulty in passage through the BBB. We developed a new highly BBB penetrable PPARɣ agonist for the treatment of neuropathic pain, assuming BBB permeability is a rule of thumb to estimate the overall permeability of relevant blood–neural barriers.  As an index of brain penetration, the brain–plasma ratio (Kp) of ELB00824 is 5.13, suggesting very high brain bioavailability, which is 58-fold that of pioglitazone. The series of studies presented here indicate that ELB00824 may be the most potent PPARɣ agonist currently known for acute reduction of neuropathic pain in trigeminal nerve in rat and mouse models. Low-dose PPARɣ agonist, ELB00824 (10 mg/kg), effectively decreased neuropathic hypersensitivity in mice and rats at both acute and chronic time points, a dose 100-fold lower than the effective dose (1000 mg/kg, i.p.) of pioglitazone. Comparisons of ELB00824 alone or in combination with gabapentin or carbamazepine are provided. While PPARɣ agonists used to treat Type 2 diabetes produce several adverse side effects, sub-chronic oral toxicity study provided promising results that ELB00824 does not produce any significant short-term toxicity. The study animals of either sex remained alive and healthy with no significant alteration of body weight long term. Toxicity study results obtained were satisfactory, with no significant alterations in any serum biochemistry parameters.

Highlights Ribosome display used for recombinant antibody selection and scFv generation targeting CCK-BR. Engineered scFv have stronger affinity and increased tissue penetrability due to smaller size. Single dose scFv reduces hypersensitivity, anxiety- and depression-like behavior in two models. Reduced neuronal firing frequency in TG primary neuronal cultures treated in vitro . CCK-BR scFv is ideal for neuropathic pain with both nociceptive and emotional components.

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