Stimulation of small-diameter afferents supplying deep tissues has been shown to increase the excitability of spinal cord neurones responding to cutaneous afferent inputs. This facilitation has been implicated as integral central mechanisms of deep pain that may contribute to the tenderness and spread and/or referral of pain following injury of deep tissues. In view of the recent documentation of deep craniofacial afferent inputs, as well as cutaneous afferent inputs to the trigeminal (V) spinal tract nucleus, we wished to determine the effects of deep inputs excited by the small-fibre irritant mustard oil on trigeminal nociceptive neurones. The extracellular activity of single brain-stem neurones was recorded in subnuclei caudalis and oralis of the V spinal tract nucleus of anaesthetized rats. The neurones were classified as low-threshold mechanosensitive (LTM), wide dynamic range (WDR) and nociceptive specific (NS) on the basis of their cutaneous mechanoreceptive field properties and their responses evoked by electrical stimulation of their cutaneous afferent inputs. Injection of 5% mustard oil (2-5 microliters) into the deep masseter muscle produced a facilitatory effect in 12 of 27 nociceptive neurones tested in caudalis and in 5 of 12 nociceptive neurones in oralis. This effect was reflected in an expansion of the cutaneous mechanoreceptive field, an increase in spontaneous activity or an increase in responsivity to electrical stimulation of cutaneous afferent inputs to the neurones. The facilitation was reversible and typically became apparent within 3-5 min of the injection, reached its peak at 5-10 min, and lasted for 20-30 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. During tactile allodynia, activation of the sensory fibers which normally detect touch elicits pain. Here we provide a new behavioral investigation into the dynamic component of tactile allodynia that developed in rats after segmental removal of glycine inhibition. Using in vivo electrophysiological recordings, we show that in this condition innocuous mechanical stimuli could activate superficial dorsal horn nociceptive specific neurons. These neurons do not normally respond to touch. We anatomically show that the activation was mediated through a local circuit involving neurons expressing the gamma isoform of protein kinase C (PKCγ). Selective inhibition of PKCγ as well as selective blockade of glutamate NMDA receptors in the superficial dorsal horn prevented both activation of the circuit and allodynia. Thus, our data demonstrates that a normally inactive circuit in the dorsal horn can be recruited to convert touch into pain. It also provides evidence that glycine inhibitory dysfunction gates tactile input to nociceptive specific neurons through PKCγ-dependent activation of a local, excitatory, NMDA receptor-dependent, circuit. As a consequence of these findings, we suggest that pharmacological inhibition of PKCγ might provide a new tool for alleviating allodynia in the clinical setting.

Migraine is a chronic disease with episodic manifestations. In a subgroup, attack frequency increases over time, leading to chronic migraine. One of the most important risk factors for migraine progression is frequency of headache attacks at baseline. Unfortunately, the actual effects of repeated activation of dural nociceptors are poorly known. We investigated the behavioral, anatomical, and electrophysiological changes induced by repeated low- and high-intensity stimulation of meningeal nociceptor by injecting an inflammatory soup in rats. Single high-intensity, but not low-intensity, stimulation produces a reversible cephalic allodynia. Upon repetition, however, low-intensity stimulation, too, induces a reversible cephalic allodynia, and high-intensity, reversible cephalic and extracephalic allodynia. Moreover, cephalic allodynia becomes, in part, persistent upon repeated high-intensity stimulation. Fos expression reveals that a single high-intensity stimulation already leads to widespread, trigeminal, and spinal central sensitization, and that such general central sensitization potentiates upon repetition. Trigeminovascular nociceptive neurons become persistently sensitized and their diffuse noxious inhibitory controls (DNIC) concomitantly impaired. Thus, compared with single stimulation, repeated dural nociceptor activation specifically leads to: 1) a gradual worsening of cutaneous hypersensitivity and general neuronal hyperexcitability and 2) spreading of cutaneous hypersensitivity superimposed on 3) persistent cephalic cutaneous hypersensitivity and trigeminal central sensitization. Such repetition-induced development of central sensitization and its consequence, cutaneous allodynia, may arise from both the general neuronal hyperexcitability that results from DNIC impairment and hyperexcitability that likely develops in trigeminal nociceptive neurons in response to their repetitive activation. These neuronal changes may in turn elevate the risk for developing chronic migraine.