Acutely, nerve growth factor (NGF) exerts profound effects on nociceptive transmission and produces pain and hyperalgesia. In the present study, we sought to determine the tissue levels and role of NGF after a plantar incision. A substantial increase in NGF protein expression occurred in skin 4-h, 1-day and 2-days and 5-days after incision comparing contralateral uninjured skin. Plantar incision did not change NGF levels in the tibial nerve and L4-L6 dorsal root ganglia. The therapeutic effect of a monoclonal antibody against endogenous NGF was evaluated by intraperitoneal administration of a single preoperative dose of anti-NGF. Of three different doses of anti-NGF used, the highest dose 2.8 mg/kg anti-NGF attenuated or almost abolished guarding pain scores at 4-h, 1-day (>80% decrease) and 2-days after incision. This effect is dose dependent in that lower doses (1, 0.1 mg/kg) were effective only at 1-day after incision. Anti-NGF also attenuated heat hyperalgesia at 1-day and 2-days after incision when the highest dose was used. However, treatment by anti-NGF did not affect C-fibers sensitized 1-day after incision in a glabrous skin-tibial nerve in vitro preparation. In conclusion, increased NGF was present in skin after plantar incision. NGF contributes to some incision-induced pain behaviors, guarding and heat hyperalgesia. Anti-NGF did not affect the extent of sensitization of C-fibers observed in vitro.

Although several studies postulated that mouse strain influences pain models, the authors' data indicate that such influence on incisional pain is negligible. This suggests that studies using an incision and knockout mice resulting from 129 strain mutation in a C57BL/6 strain background should have modest influence. The lack of sex differences in incisional pain may encourage researchers to use both male and female subjects in their studies.

Postoperative pain is characterized by spontaneous pain at the surgical site and increased pain due to movements. To study postoperative pain mechanisms, we investigated discharge properties of mechano-heat sensitive C-fiber afferents innervating the rat glabrous hindpaw skin 1 day after plantar incision. Behaviors indicating spontaneous pain, heat and mechanical hyperalgesia were present 1 day after incision. Recording of afferents using in vitro glabrous skin-nerve preparation showed that more C-fibers from the incision had spontaneous discharge than control rats. The spontaneously discharging fibers from incised rats had lower heat response threshold compared with fibers without spontaneous activity. In all fibers less than 2 mm from the incision, an increased percentage responded to lower temperatures (35-41 degrees C), the mean heat response threshold was 3.1 degrees C less, the stimulus-response function for heat evoked response was shifted to the left and the total number of impulses in response to a 33-48 degrees C heat stimulus was increased. Heat responses of C-fibers more than 2 mm from the incision, however, were not different from control. The mean mechanical response thresholds, measured by a servo force-controlled stimulator, were not different between groups. The total spikes evoked at supra-threshold mechanical stimulation were not increased in afferents from the incision. In conclusion, 1 day after incision, when behaviors indicating spontaneous pain, heat and mechanical hyperalgesia are present, C-fibers close to incision showed spontaneous discharge and sensitization to heat but not to mechanical stimuli, in vitro.

Bradykinin is an endogenous nonapeptide known to induce pain and hyperalgesia to heat and mechanical stimulation. Correspondingly, it excites nociceptors in various tissues and sensitizes them to heat, whereas sensitizing effect on the mechanical response of nociceptors is not well established. Protein kinase C and TRPV1 contribute to the sensitizing mechanism of bradykinin to heat. In addition, TRPA1 and other ion channels appear to contribute to excitation caused by bradykinin. Finally, prostaglandins sensitize bradykinin-induced excitation in normal tissues by restoring desensitized responses due to the inhibition of protein kinase A.