Noxious, but not innocuous, thermal stimuli evoke pERK expression in dorsal horn neurons after spared nerve injury in adult rats.

Noxious stimulation of sensory afferents evokes phosphorylated extracellular signal regulated kinase (pERK) expression in spinal cord neurons. This study investigated the expression of pERK in the dorsal horn neurons in response to innocuous and noxious cold stimuli in naïve versus spared nerve injury (SNI) rats. Noxious cold or hot stimuli (0 or 45°C) elicited pERK expression in laminae I-II whereas cooling stimuli from 32°C to 25, 15 or 5°C produced no or little pERK expression in dorsal horn neurons. Five days after SNI, a time when these animals showed heat hyperalgesia, cold and mechanical hypersensitivity, only noxious heat stimuli produced a significant increase in pERK expression compared to naïve rats in spinal cord neurons. Thus, pERK cannot be used as an activity marker for neurons responding to cooling stimuli or cold allodynia; however, these results confirm the role of pERK as an activity marker for heat hyperalgesia.

Cav3.2-expressing low-threshold C fibres in human hairy skin contribute to cold allodynia--a non-TRPV1- and non-TRPM8-dependent phenomenon.

It is generally agreed that cold allodynia is a consequence of impaired (Aδ-fibre-mediated) central inhibition of C-nociceptive inputs. However, it is also known that C polymodal nociceptors are not activated at innocuous low temperatures. Recently, we demonstrated the contribution of C-tactile fibres to tactile allodynia. In this study, we investigated whether this, or a related, C-fibre class contributes to cold allodynia. In 30 healthy and 3 chronic pain subjects, a series of normally innocuous localised thermal stimuli were applied to the skin overlying a painful tibialis anterior muscle (induced by infusion of hypertonic saline). The effects of thermal stimulation on muscle pain were observed before and after compression blockade of myelinated fibres. Furthermore, intradermal capsaicin, menthol and TTA-A2 were used for desensitisation of TRPV1, TRPM8, and T-type calcium (Cav3.2) channels, respectively. Before muscle pain, all thermal stimuli were reported as nonpainful regardless of whether myelinated fibres were conducting or not. During muscle pain, dynamic skin cooling (32°C → 20°C) evoked significant and reproducible increases in the overall pain intensity (allodynia). This increase was short lived and locked to the dynamic phase of cooling with pain levels returning to baseline during sustained cooling. Dynamic warming (32°C → 39°C) had no effect on pain levels. Cold allodynia persisted after nerve compression and TRPV1 and TRPM8 desensitisation but was abolished by localised Cav3.2 blockade. In clinical subjects, C-fibre-mediated allodynia was observed without the need for experimental pain-producing manipulations. In conclusion, cold allodynia represents a non-TRPV1- and non-TRPM8-dependent phenomenon, which is mediated by low-threshold Cav3.2-expressing C fibres.