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Introduction Glabrous skin and hairy skin are innervated by different types of noxious fibers. However, the different nociceptive behaviors induced by formalin, a commonly used model of acute inflammatory pain, have not yet been systematically examined in the glabrous and hairy skin. Methods In this study, we compared nociceptive behaviors induced by formalin injections (2%, 4%, and 8%) into either glabrous skin (plantar surface) of the hind paw or hairy skin of the hind limb in adult rats. Results A typical biphasic nociceptive response was seen after formalin injection into the plantar surface of the hind paw. A brief interphase separates the first and second phases where nociceptive behaviors were barely spotted. However, following subcutaneous injection into the hairy skin nociceptive behaviors were only seen after 10 minutes of formalin injection, which correlates in time with the second phase of the formalin response. First phase nociceptive behaviors were never seen with hairy skin injection, even following multiple injections of formalin. Conclusion These data suggest that nociceptive behaviors and spinal responses induced by formalin injections to glabrous and hairy skin areas are different, and that the first and second phases may be mediated through different noxious afferent fibers.

Background: Musculoskeletal pain is a major clinical problem, but researchers lack viable animal models to study this phenomenon. However, formalin injections are widely used to produce tonic and neurogenic nociceptive responses in rodents. Rodents can present a potential animal model for pain. Objectives: To develop a muscle pain model with intramuscular injection of formalin in rats. Materials and Methods: We injected formalin intramuscularly at different concentrations (50 µl; 2%, 4% and 8%) and compared them to its plantar surface subcutaneous injection (50 µl; 2%). Pain responses were scored in the first phase (1-7 minute), interphase (8-14 minute) and the second phases of 2A (15-60 minute) and 2B (61-90 minute). Results: After intramuscular and subcutaneous formalin injection, rats showed nociceptive behaviors for less than 10 minutes, and then nociceptive behaviors decreased significantly or stopped. Subsequently, the second phase showed ongoing peripheral activity. In the first phase subcutaneous injection was more painful and in second phase intramuscular injection with doses of 2% and 4%. Conclusion: We developed a novel muscle pain model based on tonic nociceptive behaviors in rats; following intramuscular formalin injections. This model has great clinical relevance and can facilitate new studies on pain.

Intracerebroventricular injection of orexin-A (hypocretin-1) has been shown to elicit the analgesic responses. However, the locations of central sites that may mediate these effects have not been clearly elucidated. This study was performed using male Sprague Dawley rats to investigate the antinociceptive effects of intra-periaqueductal gray matter (PAG) administration of orexin-A, 5 minutes prior to formalin (50 μL of 2%) injection. Orexin-A had no effect on tail-flick test as thermal and acute model. In the formalin test, intra-PAG injection of orexin-A (10 nM) decreased the formalin-induced nociceptive behaviors in the interphase and phase 2, but not in phase 1, indicating an antinociceptive role of exogenous orexin-A in the PAG. While Orexin-A failed to produce a dose-dependent decrease in formalin-evoked behaviors in phase 1, it may have induced a dose-dependent decrease in formalin-evoked behaviors in early phase 2. Control injections of orexin-A into the sites near the PAG resulted in less or no reduction in pain, indicating that the analgesia observed is probably due to a site of action within the PAG rather than at surrounding neural structures. The antinociceptive effect of orexin-A was compared with intra-PAG administration of morphine (.5 μL of 20 mM, 5 minutes before the formalin injection). Morphine decreased the formalin-induced nociceptive behaviors in all phases. To investigate whether the orexin has a special action on the early part of the second phase, or its delayed effects are related to its pharmacokinetics, the orexin-A was injected into the PAG, 10 minutes before the formalin injection. No difference was observed between 5 and 10 minutes injection of orexin-A prior to formalin injection. The antinociceptive effect of orexin was blocked by intra-PAG injection of SB-334867, a putative type 1 orexin receptor antagonist, suggesting the involvement of orexin receptor type 1 in antinociception produced with intra-PAG injection of orexin-A. The results showed that the orexin-A plays an antinociceptive role in PAG in the interphase and the late phase of formalin test through type 1 orexin receptor dependent mechanism. Perspective Orexin is produced exclusively in the lateral hypothalamus, where it is known to modulate the pain processing through PAG. The antinociceptive effect of orexin in PAG may provide a role for this neurotransmitter in the up-down modulating pain system and further support the development of orexin-1 agonists for pain treatment.