In order to determine the regions within the parabrachial nucleus that receive synaptic input from nociceptive regions of the spinal cord and medulla in the rat, we analyzed the "Golgi-like" labeling produced by anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L) from discrete iontophoretic injections confined to either the superficial dorsal horn of the lumbar spinal cord or to the superficial dorsal horn of the trigeminal nucleus at the level of the obex. Labeled fibers from both the spinal cord and the medulla ascended through the ventral lateral pons and coursed with the ventral spinocerebellar tract toward the parabrachial nuclei. Spinal cord injections led to labeling of fine caliber fibers and en passant and terminal enlargements in the rostral part of the contralateral lateral parabrachial nucleus (PBL), mostly in the central lateral and dorsal lateral subnuclei. Medullary injections revealed fiber and enlargement labeling primarily in the ipsilateral caudal PBL, mostly in the central lateral, external lateral, and medial subnuclei. Injections in both regions resulted in labeled terminations in the Kölliker-Fuse nucleus. These results indicate that the nociceptive regions of the spinal cord and medulla terminate in regions of the parabrachial nucleus that have been associated with autonomic functions because of their interconnections with the hypothalamus, brainstem cardiovascular and respiratory control centers, and the amygdala.

The goal of this study was to determine the capacity of primary afferent nociceptive fibers (nociceptors) to encode information about noxious mechanical stimuli in primates. Teased-fiber techniques were used to record from 14 A-fiber nociceptors and 18 C-fiber nociceptors that innervated the hairy skin. Stimulus-response functions were examined with an ascending series of force-controlled stimuli. Stimulus-interaction effects were examined with use of a series of paired stimuli in which the interval between the stimulus pairs was varied systematically. Both A-fiber and C-fiber nociceptors exhibited a slowly adapting response to the stepped force stimuli. The response of the A fibers increased monotonically with increasing force, whereas the response of the C fibers reached a plateau at low force levels. The slope of the stimulus-response function for the A fibers was significantly steeper than that for the C fibers, and the total response was greater. The A fibers also provided more discriminative information regarding stimulus intensity. The C fibers demonstrated a significant fatigue in response when the interstimulus interval between the paired stimuli was

The endogenous opioid neurotransmitter β-endorphin (β-END), a product of the proopiomelanocortin (POMC) gene, is strongly implicated in the control of the female reproductive cycle, stress responses, and antinociception. Using selective gene targeting, we have generated a strain of mice that do not express any β-END. These mice exhibit both normal reproduction and normal basal and stress-induced hypothalamic-pituitary-axis activity, but exhibit a significantly attenuated opioid-mediated stress-induced analgesia. To further understand the cellular bases of these responses, we have studied mediobasal hypothalamic (MBH) neurons, including POMC neurons, using whole-cell patch recording in an in vitro slice preparation. Twenty-seven MBH cells were recorded in wild-type and 25 MBH cells were recorded in β-END knockout mice. Neurons from both genotypes showed a significant positive correlation between DAMGO concentration (from 30 nM to 10 µM) and the induced outward K⁺ current. The genotypes did not differ, however, in either the DAMGO-induced maximum outward current response or EC₅₀, or for the maximal response to the GABA_B agonist baclofen. Furthermore, quantitative receptor autoradiography utilizing ³H-DAMGO did not reveal any differences in total µ-opioid receptor binding between genotypes. Therefore, we conclude that the complete absence of β-END throughout development did not alter either the expression of µ-opioid receptors or their coupling to K⁺ channels in MBH neurons.

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The peripheral neural mechanism of pain to mechanical stimuli remains elusive. C-fiber nociceptors do not appear to play a major role in mechanical pain sensation, because the stimulus-response function of mechanically sensitive C-fiber nociceptors to punctate mechanical stimuli applied to the most sensitive region in the receptive field (the hot spot) reaches a plateau at force levels insufficient to produce pain in humans. However, studies at the hot spot give an incomplete understanding of the inputs of nociceptors to the spinal cord. To estimate how the population of nociceptors responds to a punctate stimulus, it is necessary to know how the response varies with the position within the receptive field. For A-fiber and C-fiber nociceptors, we systemically measured the response to a 100 m wide blade stimulus as a function of position in the receptive field at different force levels. Highly reproducible receptive field response maps that contained multiple peaks and valleys were obtained. Some peaks were only 100 m wide. As force increased, the response and width of the peaks increased, the response in valleys increased, and new peaks appeared. The averaged response across the map provides an estimate of the population response and was found to increase monotonically with force over a large stimulus range for both A-fiber and C-fiber nociceptors. These data provide evidence that both C-fiber and A-fiber nociceptors may encode high-intensity mechanical stimuli.