Clinical intervention of pain is often accompanied by changes in affective behaviors, so both assays of affective and sensorial aspects of nociception play an important role in the development of novel analgesics. Although positive allosteric modulation (PAM) of α7 nicotinic acetylcholine receptors (nAChRs) has been recognized as a novel approach for the relief of sensorial aspects of pain, their effects on affective components of pain remain unclear. Therefore, we investigated whether PAM-4, a highly selective α7-nAChR PAM, attenuates inflammatory and neuropathic pain, as well as the concomitant depressive/anxiety comorbidities. The anti-nociceptive activity of PAM-4 was assessed in mice using the formalin test and chronic constriction injury (CCI)-induced neuropathic pain model. The anxiolytic- and antidepressant-like activity of PAM-4 was evaluated using the marble burying test and forced swimming test. Acute systemic administration of PAM-4 dose-dependently reversed formalin-induced paw licking behavior and CCI-induced mechanical allodynia without development of any motor impairment. PAM-4 reversed the decreased swimming time and number of buried marbles in CCI-treated mice, suggesting that this ligand attenuates chronic pain-induced depression-like behavior and anxiogenic-like effects. The effects of PAM-4 were inhibited by the α7-selective antagonist methyllycaconitine, indicating molecular mechanism mediated by α7-nAChRs. Indeed, electrophysiological recordings showed the PAM-4 enhances human α7 nAChRs with higher potency and efficacy compared to rat α7 nAChRs. These findings suggest that PAM-4 reduces both sensorial and affective behaviors induced by chronic pain in mice by α7-nAChR potentiation. PAM-4 deserves further investigations for the management of chronic painful conditions with comorbidities.

Background and Objectives: The effects of nicotine on wound healing and flap survival remain controversial. While smoking is associated with increased flap complications, emerging evidence suggests that nicotine may exert dose- and duration-dependent effects. This study aimed to investigate how short-term, low-dose nicotine affects flap survival and to evaluate its potential role in oxidative stress and ferroptosis. Materials and Methods: Twelve adult male BALB/c mice were randomly assigned to either a control group or a nicotine-treated group, with six mice in each group. Nicotine, at a dose of 2 mg/kg, was given subcutaneously for fourteen days before flap surgery. This treatment continued for seven days after the surgery. A dorsal random-pattern skin flap model was established in all animals. The flap necrosis area was assessed on postoperative day 7 using planimetric analysis. Serum and tissue glutathione peroxidase 4 (GPX4) levels and serum malondialdehyde (MDA) levels were measured. Histopathological evaluation included epithelialization, microvascular density, neovascularization, fibroblast density, and inflammatory cell infiltration. Results: Nicotine treatment significantly reduced flap necrosis compared with the control group. Histopathological analysis demonstrated significantly increased epithelialization and microvascular density in the nicotine-treated group, whereas no significant differences were observed in neovascularization, fibroblast density, or inflammatory cell infiltration. Biochemical analyses revealed no significant differences in serum or tissue GPX4 levels or serum MDA levels between the groups. Conclusions: Short-term nicotine administration enhanced flap survival, correlating with increased epithelialization and microvascular density, while not significantly affecting markers of oxidative stress or ferroptosis. These results imply that the positive impact of nicotine on flap viability might be largely attributable to vascular processes rather than pathways involving oxidative stress.