1. Parabrachiohypothalamic (PB-H) neurons (n = 71) were recorded with extracellular micropipettes in the parabrachial (PB) area and were antidromically driven from the ventromedial nucleus (VMH) or the retrochiasmatic area (RCh) of the hypothalamus, in the anesthetized rat. The spontaneous activity of these neurons was very low, (10th percentile < median frequency < 90th percentile were 0.01 < 0.2 < 7 Hz). The axons of these neurons exhibited a very slow conduction velocity in the range of 0.2-1.4 m/s, i.e., corresponding to thin unmyelinated fibers. 2. Most PB-H neurons (89%) were located in the mesencephalic division of the PB area (mPB) mainly in the superior lateral (mPBsl) and external lateral (mPBel) subnuclei. 3. These units were separated in three groups: 1) a group of nociceptive-specific (NS) neurons (49%) activated by mechanical and/or thermal (heat) cutaneous stimuli only in noxious range; 2) a group of inhibited neurons (7%), not activated by any of the mechanical or thermal cutaneous stimuli but inhibited, by at least one of these stimuli, which had to be in noxious range; and 3) a group of nonresponsive neurons (44%). 4. The NS neurons responded exclusively to mechanical (pinch or squeeze) and/or thermal (waterbath or waterjet > 44 degrees C) noxious stimuli with a rapid onset, a marked and sustained activation, and generally no afterdischarge. The magnitude of the responses was between 2 and 30 Hz with a mean value of 14.8 +/- 1.4 Hz (mean +/- SE, n = 49). These neurons exhibited a clear capacity to encode thermal stimuli in the noxious range: 1) the stimulus-response function was always positive and monotonic; 2) the slope of the mean curve increased up to a maximum (between 46 and 50 degrees C) then beyond the slope decreased; and 3) the mean threshold was 44.3 +/- 2.2 degrees C. 5. The excitatory receptive fields of the NS neurons were often large including all (22% of the population) or several (67% of the population) parts of the body. In the few remaining cases (11%) they were restricted to one part of the body. In addition, in several cases, noxious stimuli applied outside the excitatory receptive field were found to strongly inhibit the discharge of NS neurons. 6. Most NS neurons responded to intense transcutaneous electrical stimulation with two peaks of activation.(ABSTRACT TRUNCATED AT 400 WORDS)

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Peripheral interactions between nociceptive fibers and mast cells contribute to inflammatory pain, but little is known about mechanisms mediating neuro-immune communication. Here we show that metalloproteinase MT5-MMP (MMP-24) is an essential mediator of peripheral thermal nociception and inflammatory hyperalgesia. We report that MT5-MMP is expressed by CGRP-containing peptidergic nociceptors in dorsal root ganglia and that Mmp24-deficient mice display enhanced sensitivity to noxious thermal stimuli under basal conditions. Consistently, mutant peptidergic sensory neurons hyperinnervate the skin, a phenotype that correlates with changes in the regulated cleavage of the cell-cell adhesion molecule N-cadherin. In contrast to basal nociception, Mmp24 ؊/؊ mice do not develop thermal hyperalgesia during inflammation, a phenotype that appears associated with alterations in N-cadherin-mediated cell-cell interactions between mast cells and sensory fibers. Collectively, our findings demonstrate an essential role of MT5-MMP in the development of dermal neuro-immune synapses and suggest that this metalloproteinase may be a target for pain control.inflammation ͉ mast cell ͉ N-cadherin

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