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.

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Peripheral nerve stimulation has been used in the treatment of several chronic pain conditions including pain due to peripheral nerve dysfunctions, complex regional pain syndrome, and cranial neuralgias. It has been shown to be effective for chronic, intractable pain that is refractory to conventional therapies such as physical therapy, medications, transcutaneous electrical stimulations, and nerve blocks. Recently, a new generation of peripheral nerve stimulation devices has been developed; these allow external pulse generators to transmit impulses wirelessly to the implanted electrode, and their implantation is significantly less invasive. In this review, we discuss the history, pathophysiology, indications, implantation process, and outcomes of employing peripheral nerve stimulation to treat chronic pain conditions.

In this study we recorded activity from afferent fibers innervating the mouse plantar skin, the same region evaluated in pain behavior experiments. We compared responses of afferents from incised and unincised hind paw skin. The plantar skin together with attached medial and lateral plantar nerves were dissected until they could be completely removed intact and placed in an organ bath chamber continuously perfused with oxygenated Kreb's solution and temperature maintained at 32°C. Afferent nerve activities to feedback controlled mechanical and heat stimuli and cooling were recorded. Eighty-five single A and C-fiber afferents were recorded, 42 from control and the remainder from incised animals. A greater proportion of C-fibers (11/34) from incised skin had spontaneous activity than the unincised preparation (2/32). The mechanical thresholds of both A and C-fiber units were not different between control and incised groups but the responses to suprathreshold mechanical stimulation were increased in low threshold A and C-fibers. The greatest change in heat sensitivity was apparent when multi-fiber total activity was measured; threshold was reduced, total spikes were greater and the peak discharge frequency was increased. In summary, feedback-controlled stimulation identified mechanical sensitization after incision in an in vitro preparation. Few fibers were excited by cooling. Heat sensitization of primary afferents was more prominent when activities of unclassified afferents are included. The preparation allows us to study afferent function of the same tissue that is examined for in vivo pain behavior assays in mice.

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