Duloxetine, a serotonin and noradrenaline reuptake inhibitor, and celecoxib, a non-steroidal anti-inflammatory drug, are commonly used analgesics for persistent pain, however with moderate gastrointestinal side effects or analgesia tolerance. statistical difference between the theoretical and experimental ED50 87153-04-6 for the second phase pain responses was observed, which indicated synergistic conversation of the two drugs. Concerning the emotional pain responses revealed with USVs, we assumed that this antinociceptive effects were almost completely derived from duloxetine, since celecoxib was ineffective when administered alone or reduced the dosage of duloxetine when given in combination. Based on the above findings, acute concomitant administration of duloxetine and celecoxib showed synergism around the somatic pain behavior but not emotional pain behaviors. Introduction Synergistic, additive or antagonistic interactions can be observed when two analgesics are given at the same time. Under the situation of synergistic 87153-04-6 conversation, the lower doses for each drug can be used to reach an equal or better analgesia with fewer overall side-effects derived from individual compounds . To evaluate the preclinical analgesic effect, two animal models are commonly used, i.e. subcutaneous (s.c.) injection of formalin into the orofacial or hind paw to induce pain of face  or foot [3,4]. The two-phase pain responses are the shared features for both orofacial and hindpaw formalin assessments and are considered to be associated with two at least partially distinct mechanisms for nociception: the first phase is associated with direct activation of nociceptors, whereas the second phase displays integration between peripheral (nociceptors) and central (spinal/supraspinal) signaling . In the orofacial formalin test, face grooming behavior is used as the indication for pain responses  and the combination analgesia of different medications have been investigated with this model [7-9]. However, there still remains debate whether face grooming is really a pain  or hypoalgesic response . On the other hand, the spontaneous finching and licking of the injected hindpaw seem to be a reliable parameter for evaluating the biphasic pain responses induced by s.c. formalin injection and this model has been used in our previous study as well . Antidepressants and non-steroidal anti-inflammatory drugs (NSAIDs) are two commonly used medications targeting different components of pain. Duloxetine, one of the new generation serotonin (5-HT)-norepinephrine reuptake inhibitor (SNRI) antidepressants, is used to treat depressive disorder and also alleviate allodynia in inflammatory [11-13] and neuropathic pain [14,15]. Duloxetine inhibits the reuptake of 5-HT and norepinephrine that are two important neurotransmitters released from your terminals of descending pain control pathways, thereby increasing their local concentrations [16,17] and promoting persistence of their analgesic effects. Although usually mild, the typical side effects for the SNRI class including nausea, dizziness, somnolence are generally observed in the patients with duloxetine treatment 87153-04-6 . Celecoxib, one of the selective cyclooxygenase (COX)-2 inhibitors, Rabbit Polyclonal to CK-1alpha (phospho-Tyr294) has been extensively used in the treatment of osteoarthritis and rheumatoid arthritis [19,20]. This compound exhibits 3 featured biological activities -antipyretic, anti-inflammatory and analgesic  activities attributed to their inhibition of prostaglandin biosynthesis . Moreover, other mechanisms such as activating the endogenous opioid/cannabinoid systems , inhibiting protein kinase C epsilon translocation to modulate TRPV1 function and inhibiting material P synthesis and release  were recently suggested to be the possible contributors 87153-04-6 to celecoxib analgesia. However, the celecoxib analgesia also faces the gastrointestinal side effects  and tolerance as observed in a rat model of inflammatory pain . Because both duloxetine and celecoxib are associated with increased risk of side effects, the synergistic effect at a lower dosage might be a better analgesic strategy. We hypothesized that there exists potential synergism between duloxetine and celecoxib. Since the analgesic mechanisms for duloxetine and celecoxib are different, the combinational using of each agent at lower doses may yield improved analgesia. Such a synergistic analgesia is not associated with some central nervous system (CNS) alteration reflected by locomotion and motor coordination impairments nor the consequence of anti-depression. Thus, in the current study, we observed the potential combination analgesic effect between duloxetine and celecoxib around the inflammatory pain induced by s.c. injection of formalin into one hindpaw of mice with isobolographic analysis. Materials and Methods Animals and drugs Male C57BL/6 mice (about 10 weeks aged) were housed in a temperature-controlled environment on a 12-h light/dark cycle.