C-nociceptors do not normally fire action potentials unless challenged by adequate noxious stimuli. However, in pathological states nociceptors may become hyperexcitable and may generate spontaneous ectopic discharges. The aim of this study was to compare rat neuropathic pain models and to assess their suitability to model the spontaneous C-nociceptor activity found in neuropathic pain patients. Studies were performed in normal rats (n=40), healthy human subjects (n=15), peripheral neuropathic pain patients (n=20), and in five rat neuropathic pain models: nerve crush (n=24), suture (n=14), chronic constriction injury (n=12), STZ-induced diabetic neuropathy (n=56), and ddC-induced neuropathy (n=15). Microneurographic recordings were combined with electrical stimulation to monitor activity in multiple C fibers. Stimulation at 0.25 Hz allowed spontaneous impulses to be identified by fluctuations in baseline latency. Abnormal latency fluctuations could be produced by several mechanisms, and spontaneous activity was most reliably identified by the presence of unexplained latency increases corresponding to two or more additional action potentials. Spontaneous activity was present in a proportion of mechano-insensitive C-nociceptors in the patients and all rat models. The three focal traumatic nerve injury models provided the highest proportion (59.5%), whereas the two polyneuropathy models had fewer (18.6%), and the patients had an intermediate proportion (33.3%). Spontaneously active mechano-sensitive C-nociceptors were not recorded. Microneurographic recordings of spontaneous activity in diseased C-nociceptors may be useful for both short- and long-term drug studies, both in animals and in humans.

Recent findings have shown that muscle contraction evokes an exaggerated pressor response in type 1 diabetes mellitus (T1DM) rats; however, it is not known whether the mechanoreflex, which is commonly stimulated by stretching the Achilles tendon, contributes to this abnormal response. Furthermore, the role of mechano-gated Piezo channels, found on thin-fiber afferent endings, in evoking the mechanoreflex in T1DM is also unknown. Therefore, in male and female streptozotocin (STZ, 50 mg/kg)-induced T1DM and healthy control (CTL) rats, we examined the pressor and cardioaccelerator responses to tendon stretch during the early stage of the disease. To determine the role of Piezo channels, GsMTx-4, a selective Piezo channel inhibitor, was injected into the arterial supply of the hindlimb. At 1 wk after STZ injection in unanesthetized, decerebrate rats, we stretched the Achilles tendon for 30 s and measured pressor and cardioaccelerator responses. We then compared pressor and cardioaccelerator responses to tendon stretch before and after GsMTx-4 injection (10 µg/100 ml). We found that the pressor (change in mean arterial pressure) response [41 ± 5 mmHg ( n = 15) for STZ and 18 ± 3 mmHg ( n = 11) for CTL ( P < 0.01)] and cardioaccelerator (change in heart rate) response [18 ± 4 beats/min for STZ ( n = 15) and 8 ± 2 beats/min ( n = 11) for CTL ( P < 0.05)] to tendon stretch were exaggerated in STZ rats. Local injection of GsMTx-4 attenuated the pressor [55 ± 7 mmHg ( n = 6) before and 27 ± 9 mmHg ( n = 6) after GsMTx-4 ( P < 0.01)], but not the cardioaccelerator, response to tendon stretch in STZ rats and had no effect on either response in CTL rats. These data suggest that T1DM exaggerates the mechanoreflex response to tendon stretch and that Piezo channels play a role in this exaggeration.

Previous studies have shown that diabetic peripheral neuropathy affects both unmyelinated and myelinated afferents, similar to those evoking the exercise pressor reflex. However, the effect of type 1 diabetes (T1DM) on this reflex is not known. We examined, in decerebrate male and female T1DM [streptozotocin (STZ)] and healthy control (CTL) rats, pressor and cardioaccelerator responses to isometric contraction of the hindlimb muscles during the early and late stages of the disease. STZ (50 mg/kg) was injected to induce diabetes, and experiments were conducted at 1, 3, and 6 wk after injection. On the day of the experiment, we statically contracted the hindlimb muscles by stimulating the sciatic nerve and measured changes in mean arterial pressure and heart rate. We found that the pressor but not cardioaccelerator response was exaggerated in STZ rats at 1 wk (STZ: 21 ± 3 mmHg, = 10, and CTL: 14 ± 2 mmHg, = 10, < 0.05) and at 3 wk (STZ: 26 ± 5 mmHg, = 10, and CTL: 17 ± 3 mmHg, = 11, < 0.05) after injection. However, at 6 wk, and only in male rats, both the pressor (STZ: 13 ± 3 mmHg, = 12, and CTL: 17 ± 3 mmHg, = 13, < 0.05) and cardioaccelerator responses (STZ: 7 ± 3 beats/min, = 12, and CTL: 10 ± 3 beats/min, = 13, < 0.05) to contraction were significantly attenuated in STZ rats compared with CTL rats. These data indicate that T1DM exaggerates the exercise pressor reflex during the early stages of the disease in both male and female rats. Conversely, T1DM attenuates this reflex in the late stage of the disease in male but not female rats. This is the first study to provide evidence that the pressor and cardioaccelerator responses to skeletal muscle contraction vary depending on the duration of type 1 diabetes.

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