Pain.

Substance P, the principal neurokinin peptide in the mammalian brain and the natural ligand for the NK(1) tachykinin receptor, plays an integrative role in the regulation of cardiovascular, neuroendocrine and behavioural responses to stress. In rats, stimulation of periventricular NK(1) receptors in the forebrain induces a distinct pattern of cardiovascular responses which is accompanied by intense grooming behaviour. Ligands for NK(3) receptors induce a different pattern of cardiovascular and behavioural responses which comprises an increased release of vasopressin from the posterior pituitary and wet-dog shakes behaviour. To define the brain areas in the rat which respond to stimulation of forebrain NK(1) and NK(3) receptors and participate in the generation of these responses, the induction of c-Fos immunoreactivity was examined in brains following intracerebroventricular injections of substance P and neurokinin B in conscious rats. Stimulation of central NK(1) receptors by substance P (25, 100 and 500 pmol) injected into the lateral ventricle elicited grooming behaviour (face washing and hind limb grooming) and resulted in a marked c-Fos expression in the paraventricular, dorsomedial and parabrachial nuclei and in the medial thalamus. At 25 pmol, substance P did not significantly increase c-Fos expression, at 100 pmol, maximal c-Fos activation was induced in all four brain regions which responded to the peptide. Intracerebroventricular pretreatment of rats with the selective and high-affinity, non-peptide NK(1) receptor antagonist, RP 67580 (500 pmol), but not with its inactive enantiomer, RP 68651, completely abolished the behavioural response to substance P and reduced the substance P-induced c-Fos expression in all brain areas to nearly control levels. Intracerebroventricular injection of the natural ligand for NK(3) receptors, neurokinin B (500 pmol), elicited wet-dog shakes behaviour and activated c-Fos expression in localized regions of the forebrain including the organum vasculosum laminae terminalis, subfornical organ, median preoptic nucleus, paraventricular, supraoptic and anterior hypothalamic nuclei, medial thalamus and in the ventral tegmental area. These results demonstrate that the neurokinins, substance P and neurokinin B, induce specific and different patterns of c-Fos expression in distinct regions of the rat brain. Brain areas which selectively responded to substance P have been traditionally linked to the central regulation of cardiovascular and neuroendocrine reactions to stress or involved in the processing of nociceptive responses. On the other side, brain areas activated by neurokinin B are known to be involved in the central regulation of blood pressure, water and salt homeostasis or control of behaviour.

Analgesics↗

PubMed2001

Parallel nociceptive reflex pathways with negative and positive feedback functions to foot extensors in the cat.

1. Nociceptive reflex pathways to foot extensors were investigated with particular attention given to those not following a flexor reflex (FRA) or withdrawal pattern. 2. In anaemically decapitated, high spinal paralysed cats nociceptive afferents of the foot pad were activated by noxious radiant heat (48-60 degrees C), while for comparison non-nociceptive afferents were activated by weak mechanical stimulation of the skin or graded electrical nerve stimulation. The reflex action of the afferents on hindlimb motoneurones, innervating plantaris and intrinsic foot extensors (tibial nerve), was investigated by intracellular recording, by monosynaptic reflex testing and by recording of neurograms during fictive locomotion. A possible descending control of the nociceptive and non-nociceptive pathways was tested by application of opioidergic and monoaminergic compounds. 3. Beside the typical FRA pattern evoked in the majority of hindlimb motoneurone pools by nociceptive afferents from different skin areas of the foot, the results revealed parallel excitatory and inhibitory nociceptive reflex pathways from the central pad and partly from the toe pads to foot extensors. The excitatory pathways, which did not follow the FRA pattern, were predominantly to plantaris and intrinsic foot extensors. They were distinctly less depressed by opioids and monoaminergic compounds than FRA pathways. 4. While the nociceptive FRA pathways have a general nocifensive withdrawal function, the nociceptive excitatory non-FRA pathway to the foot extensors causes a movement of the affected area towards the stimulus or at least a resistance against the stimulus, i.e. it mediates a positive feedback.

Analgesics↗