Modulation of mechanosensory vibrissal responses in the trigeminocervical complex by stimulation of the greater occipital nerve in a rat model of trigeminal neuropathic pain

Abstract

Background: Stimulation of the occipital or trigeminal nerves has been successfully used to treat chronic refractory neurovascular headaches such as migraine or cluster headache, and painful neuropathies. Convergence of trigeminal and occipital sensory afferents in the 'trigeminocervical complex' (TCC) from cutaneous, muscular, dural, and visceral sources is a key mechanism for the input-induced central sensitization that may underlie the altered nociception. Both excitatory (glutamatergic) and inhibitory (GABAergic and glycinergic) mechanisms are involved in modulating nociception in the spinal and medullary dorsal horn neurons, but the mechanisms by which nerve stimulation effects occur are unclear. This study was aimed at investigating the acute effects of electrical stimulation of the greater occipital nerve (GON) on the responses of neurons in the TCC to the mechanical stimulation of the vibrissal pad. Methods: Adult male Wistar rats were used. Neuronal recordings were obtained in laminae II-IV in the TCC in control, sham and infraorbital chronic constriction injury (CCI-IoN) animals. The GON was isolated and electrically stimulated. Responses to the stimulation of vibrissae by brief air pulses were analyzed before and after GON stimulation. In order to understand the role of the neurotransmitters involved, specific receptor blockers of NMDA (AP-5), GABA A (bicuculline, Bic) and Glycine (strychnine, Str) were applied locally. Results: GON stimulation produced a facilitation of the response to light facial mechanical stimuli in controls, and an inhibition in CCI-IoN cases. AP-5 reduced responses to GON and vibrissal stimulation and blocked the facilitation of GON on vibrissal responses found in controls. The application of Bic or Str significantly reduced the facilitatory effect of GON stimulation on the response to vibrissal stimulation in controls. However, the opposite effect was found when GABAergic or Glycinergic transmission was prevented in CCI-IoN cases.

Microglia and Inhibitory Circuitry in the Medullary Dorsal Horn: Laminar and Time-Dependent Changes in a Trigeminal Model of Neuropathic Pain

“…Key players in this inhibition are the local GABAergic and Glycinergic interneurons, which constitute one-third of all neurons in laminae I-IV of the Sp5C [37]. Peripheral nerve injury drives a loss of GABA and Glycinergic inhibition in both the spinal [1,4,5,31,35,[38][39][40][41] and the medullary [2,42,43] dorsal horn. for the GlyT2-strong 'patches' and the more moderately immunoreactive 'non-patch' zones.…”

“…After recovery from surgery the operated animals' motor, grooming or eating behavior did not differ from the controls. Because our previous experience in rats [2,43] and mice [29,96] showed no differences in mechanical responses to facial stimulation and microglial phenotype in the Sp5C between controls and sham-operated animals with simple facial skin incisions, no sham group was included.…”

Microglia and Inhibitory Circuitry in the Medullary Dorsal Horn: Laminar and Time-Dependent Changes in a Trigeminal Model of Neuropathic Pain

“…Key players in this inhibition are the local GABAergic and Glycinergic interneurons, which constitute one-third of all neurons in laminae I-IV of the Sp5C [37]. Peripheral nerve injury drives a loss of GABA and Glycinergic inhibition in both the spinal [1,4,5,31,35,[38][39][40][41] and the medullary [2,42,43] dorsal horn.…”

“…A strong association between reactive microglia and the GABA and Glycine inhibitory mechanisms is now established beyond doubt. CCI, as any other peripheral nerve injury, induces a rapid activation of microglia in the spinal or brain stem territories that received the affected primary afferents [43,[57][58][59][60][61]. Although some authors proposed that neuropathic pain was primarily due to the downregulation of inhibitory transmission, with microglia activation being just a secondary phenomenon [40], other studies hold that nerve injury initiates a cascade of events involved in the development and maintenance of neuropathic pain [12,62,63].…”

“…After recovery from surgery the operated animals' motor, grooming or eating behavior did not differ from the controls. Because our previous experience in rats [2,43] and mice [29,94] showed no differences in mechanical responses to facial stimulation and microglial phenotype in the Sp5C between controls and sham-operated animals with simple facial skin incisions, no sham group was included.…”