Studies on the effects of mechanical pressure on nerves have employed different force levels (from several grams to hundreds of grams), for various time periods (from tens of minutes to several weeks), and have demonstrated that pressure duration has a profound effect on nerve function and viability
]. For example, Fern and colleagues studied changes in nerve conduction caused by the deformation and ischemia induced by compression of the cat sciatic nerve
]. These researchers recorded unitary action potentials from a dorsal root filament during stimulation of the flexor digitorum longus nerve when the sciatic nerve was subjected to 70 mmHg of pressure. Little change was found in conduction of action potentials over the first 19 min of pressure. However, the second, third and fifth fastest action potentials disappeared when the duration of pressure was extended to 28 min, and even the fastest action potential was blocked by 48 min of pressure
]. These data are in accordance with clinical observations showing that prolonged pressure (even at very low levels) applied to nerves can cause severe neural dysfunction
In our previous clinical studies, we showed that manual pressure applied through the skin, soft tissue and muscle on the back of the leg to the sciatic nerve provides significantly more relief from pain than placebo pressure on the front of the leg. We also examined pressure on different parts of the leg, and demonstrated that effective pressure on any accessible area along the sciatic nerve will give rapid pain relief; and the effectiveness is reduced if the same manual pressure is applied at a distance from the sciatic nerve tract
]. These previous clinical results may suggest that, in addition to activating mechanosensitive receptors in the skin and muscle afferent neurons, pressure on the sciatic nerve itself may provide significant analgesic effect. In the present study, we demonstrate that a short duration of pressure (2 min), directly on the sciatic nerve, causes rapid inhibition of WDR responses to both innocuous and noxious mechanical stimuli, and that the inhibitory responses recover within tens of minutes after pressure release. Thus, this animal data may partially explain the rapid analgesia in the clinical setting.
The Diffuse Noxious Inhibitory Control (DNIC) model has been frequently used for quantifying central sensitization in several pain conditions. DNIC relies on painful conditioning stimulation of one part of the body to inhibit pain in another part; the inhibition of pain is rapid and short lasting
]. In our model, pressure on the sciatic nerve is stimulation from another part of the body, and the consequent inhibition induced by the stimulation is rapid and short lasting. Thus, the DNIC mechanism may explain the early inhibition caused by acute pressure on the sciatic nerve in our model.
Sensory transduction in nerves is accomplished by proteins in the membrane called ion channels, which are gated pores that allow the exchange of ions across the cell membrane. Acid-sensitive ion channels (ASIC) have been found expressed in neurons of the mammalian central and peripheral nervous systems, and proposed to constitute mechanoreceptors, and play an important role in responses to mechanical stimuli
]. After a comparison study between ASIC1 knockout mice and wild-type mice for visceral mechanosensation, Page at al
found ASIC1 contributed to visceral but not cutaneous mechanoreceptor function, and suggested that mechanosensory function in different tissues may involve different mechanisms (33). In a recent report, mice with simultaneous disruptions of ASIC1a, ASIC2, and ASIC3 genes showed increased paw withdrawal frequencies when mechanically stimulated with von Frey filaments. Moreover, in single-fiber nerve recordings of cutaneous afferents, mechanical stimulation generated enhanced activity in ASIC triple-knockouts mice compared to wild-type mice (32). Mogil et al.
reported ASIC3 mice with a dominant-negative mutation were more sensitive to a number of modalities including mechanical pain, mechanical hypersensitivity after zymosan inflammation, and mechanical hypersensitivity after intramuscular injection of hypotonic saline (36). Four ASIC proteins (ASIC1, ASIC2, ASIC3, and ASIC4) have been found expressed in the sciatic nerve
]. Thus, rapid inhibition of WDR responses to mechanical stimuli in our model may involve ASICs.
Reports on WDR responses to mechanical stimuli after application of pressure to nerves have been inconsistent. This may be attributable to differences in experimental conditions. The surfaces of the clips that compressed the sciatic nerve were covered with a soft layer of rubber in our studies, which not only absorb a considerable proportion of the pressure, but also protect the nerves from direct damage that might be caused by the clip. The actual pressure on the sciatic nerves estimated varied between 30 and 70 g. This pressure may be several times higher than that employed in clinical studies. Hanai et al.
used a clip similar to ours to compress the dorsal root or the dorsal root ganglion; the WDR responses to mechanical stimuli increased after release of the pressure
]. These data differ from ours. The clip force in their study was 40 g; thus, the pressure on the sciatic nerve was similar to ours; but the pressing surfaces of their clips did not have a soft rubber layer. Using clips similar to ours, Kawasaki and et al.
applied much longer time pressure (30 min), higher pressure (120 g), and without any soft layer on the surface of clips
The WDR responses to pinch and pressure stimuli gradually recovered in both our and Kawasaki’s studies after the release of the pressure on the sciatic nerve. However, in Kawasaki’s study, the WDR response to an innocuous stimulus (brushing) did not show any recovery for 30 minutes after the release of the pressure on the sciatic nerve. In contrast, in our study, the WDR response to brushing, gradually recovered from 7.5 spikes/s to 11 spikes/s within 20 minutes after release of the pressure. Innocuous sensations are mainly mediated by large myelinated afferent fibers (Aβ fibers), which are sensitive to pressure. Whereas, noxious sensations are mediated by fine afferent fibers (Aδ and C fibers) which are sensitive to oxygen deprivation
]. Thus, the lack of recovery of WDR neurons to the brushing stimulus after the release of pressure on the sciatic nerve in Kawasaki’s study may be attributed to damage to large myelinated afferent fibers. Gradual recovery of WDR neurons after the release of pressure in our model, which is similar to but slower than the recovery after release of pinch and pressure, may indicate that nerves were only partially injured, if at all. This is consistent with the histological data: when the injury of sciatic nerves was observed, it occurred when pressure was applied to the sciatic nerve for 20 minutes, but not when the pressure was applied for 2 minutes.