Haemorrhage-evoked decompensation and recompensation mediated by distinct projections from rostral and caudal midline medulla in the rat.

The haemodynamic response to blood loss consists of three phases: (i) an initial compensatory phase during which resting arterial pressure is maintained; (ii) a decompensatory phase characterized by a sudden, life-threatening hypotension and bradycardia; and (iii) if blood loss ceases, a recompensatory phase during which arterial pressure returns to normal. Previous research indicates that topographically distinct, rostral and caudal parts of the caudal midline medulla (CMM) contain neurons that differentially regulate the timing and magnitude of each of the three phases. Specifically, decompensation depends critically on the integrity of the rostral CMM; whereas compensation and recompensation depend upon the integrity of the caudal CMM. This study aimed to determine, using retrograde and anterograde tracing techniques, if the rostral and caudal CMM gave rise to different sets of projections to the major cardiovascular region of the ventrolateral medulla (VLM) and spinal cord. It was found that rostral and caudal CMM each have projections of varying density to the region containing bulbospinal (presympathetic) motor neurons in the rostral VLM and preganglionic sympathetic motor neurons in the intermediolateral cell column of the spinal cord. Via these projections vasomotor tone and hence arterial pressure can be regulated. More strikingly: (i) consistent with a role in mediating bradycardia during decompensation, the rostral CMM projects uniquely to VLM regions containing vagal cardiac motor neurons; and (ii) consistent with its role in mediating recompensation, the caudal CMM projects uniquely onto tyrosine hydroxylase-containing, caudal VLM (A1) neurons whose activity mediates vasopressin release, on which recompensation depends.

Peripheral nerve injury evokes disabilities and sensory dysfunction in a subpopulation of rats: a closer model to human chronic neuropathic pain?

Chronic pain conditions for which treatment is sought are characterized usually by complex behavioural disturbances as well as pain. We review here evidence that although chronic constriction injury (CCI) of the sciatic nerve evokes allodynia and hyperalgesia in all rats, persistent social behavioural and sleep disruption occurs only in a subpopulation of animals. The finding that the 'degree of pain', as defined by allodynia and hyperalgesia, is the same in all animals suggests that the complex behavioural disabilities are independent of the level of sensory dysfunction. An absence of correlation between disability and sensory dysfunction is characteristic also of human neuropathic pain. These findings indicate that: (i). in a subpopulation of rats sciatic injury evokes disabilities characteristic of human neuropathic pain conditions; and (ii). testing for sensory dysfunction alone cannot detect this subpopulation.

A subpopulation of rats show social and sleep-waking changes typical of chronic neuropathic pain following peripheral nerve injury.

Neuropathic conditions for which treatment is sought, the so-called chronic pain syndrome, are characterized usually by complex behavioural disturbances as well as pain. In this study we evaluated whether social behavioural and sleep disruptions occurred after nerve injury. Before and after chronic constriction of the sciatic nerve, resident-intruder and sleep-wake cycles, as well as mechanical and thermal allodynia/hyperalgesia, were quantified. Sciatic nerve injury in all animals reduced withdrawal thresholds to tactile and thermal (cold) stimuli. Resident-intruder and sleep-waking behaviours were altered in some but not all animals. One group (30%, 'persistent change') had enduring reductions in dominant behaviour to an intruder and decreased slow-wave sleep and increased wakefulness during both light and dark cycles. Another group (25%, 'recovery') had a transient reduction in dominant behaviours and decreased slow-wave sleep and increased wakefulness during only the light cycle. In a third group (45%, 'no effect') resident-intruder and sleep-waking behaviours remained normal. Our finding that the degree of 'pain' as inferred from the allodynia/hyperalgesia was identical in all animals suggests that the alterations to resident-intruder and sleep-wake cycles were independent of the level of sensory disturbance. An absence of correlation between intensity of sensory disturbances and measures of disability (loss of sleep, familial/social problems) is also characteristic of human neuropathic pain. These data indicate that: (i) in a subpopulation of animals sciatic injury results in two of the major complex behavioural changes which are characteristic of neuropathic pain in humans; (ii) testing only for allodynia and hyperalgesia is not sufficient to detect this subpopulation.

Somatic and visceral afferents to the 'vasodepressor region' of the caudal midline medulla in the rat.

Previous research has found that the integrity of a restricted region of the caudal midline medulla (including caudal portions of nucleus raphé obscurus and nucleus raphé pallidus) was critical for vasodepression (hypotension, bradycardia, decreased cardiac contractility) evoked either by haemorrhage or deep pain. In this anatomical tracing study we found that the vasodepressor part of the caudal midline medulla (CMM) receives inputs arising from spinal cord, spinal trigeminal nucleus (SpV) and nucleus of the solitary tract (NTS). Specifically: (i) a spinal-CMM projection arises from neurons of the deep dorsal horn, medial ventral horn and lamina X at all spinal segmental levels, with approximately 60% of the projection originating from the upper cervical spinal cord (C1-C4); (ii) a SpV-CMM projection arises primarily from neurons at the transition between subnucleus caudalis and subnucleus interpolaris; (iii) a NTS-CMM projection arises primarily from neurons in ventrolateral and medial subnuclei. In combination, the specific spinal, SpV and NTS regions which project to the CMM receive the complete range of somatic and visceral afferents known to trigger vasodepression. The role(s) of each specific projection is discussed.

Delta- and kappa-opioid receptors in the caudal midline medulla mediate haemorrhage-evoked hypotension.

In mammals blood loss can trigger, shock, an abrupt, life-threatening hypotension and bradycardia. In the halothane-anaesthetised rat this response is blocked by inactivation of a discrete, vasodepressor area in the caudal midline medulla (CMM). Haemorrhagic shock is blocked also by systemic or ventricular injections of the opioid antagonist, naloxone. This study investigated, in the halothane anaesthetised rat, the contribution of delta-, kappa- and mu-opioid receptors in the CMM vasodepressor region to haemorrhage-evoked shock (i.e. hypotension and bradycardia) and its recovery. It was found that microinjections into the CMM of the delta-opioid receptor antagonist, naltrindole delayed and attenuated the hypotension and bradycardia evoked by haemorrhage, but did not promote recompensation. In contrast, CMM microinjections of the kappa-opioid receptor antagonist, nor-binaltorphamine, although it did not alter haemorrhage-evoked hypotension and bradycardia, did lead to a rapid restoration of AP, but not HR. CMM microinjections of the mu-opioid receptor antagonist, CTAP had no effect on haemorrhage-evoked shock or recompensation. These data indicate that delta- and kappa- (but not mu-) opioid receptor-mediated events within the CMM contribute to the hypotension and bradycardia evoked by haemorrhage and the effectiveness of naloxone in reversing shock.

Distinct central representations of inescapable and escapable pain: observations and speculation.

It is well established clinically that the affective response to pain of deep origin (muscles, joints and viscera) is distinct from that evoked by cutaneous pain. Cutaneous pain triggers a fight-flight reaction (active emotional coping), whereas deep pain evokes a reaction of quiescence, decreased vigilance and vasodepression (passive emotional coping). These observations led to suggestions of distinct central representations for deep versus cutaneous pain. Indeed, studies using immediate early gene (c-fos) expression revealed selective activation of ventrolateral versus lateral columns of the midbrain periaqueductal grey region (PAG) by persistent pain of deep origin versus intermittent cutaneous pain. Ventrolateral versus lateral PAG activation had been found earlier to evoke passive versus active emotional coping. However, not all cutaneous pain triggers active coping. Persistent cutaneous pain (e.g. burns) instead, usually evokes passive coping. This raised the question of whether the behavioural significance of pain (i.e. its escapability versus inescapability), rather than its tissue origin, is represented in supraspinal regions such as the PAG. Subsequent study revealed that a persistent (inescapable) noxious cutaneous manipulation (clip of the neck) evoked both selective ventrolateral PAG Fos expression and passive emotional coping. Such data suggest that pain representation in the PAG reflects a quality akin to behavioural significance, rather than tissue origin. In contrast, in the spinal cord predominantly superficial dorsal horn Fos expression was seen after either persistent or intermittent noxious cutaneous stimuli, leaving the question of the pathway(s) via which persistent (inescapable) cutaneous pain activates the vlPAG unanswered. One experimental approach to this question is suggested.

Neural responses to intravenous serotonin revealed by functional magnetic resonance imaging.

We examined the sequence of neural responses to the hypotension, bradycardia, and apnea evoked by intravenous administration of 5-hydroxytryptamine (serotonin). Functional magnetic resonance imaging signal changes were assessed in nine isoflurane-anesthetized cats during baseline and after a bolus intravenous low dose (10 microg/kg) or high dose (20-30 microg/kg) of 5-hydroxytryptamine. In all cats, high-dose challenges elicited rapid-onset, transient signal declines in the intermediate portion of the solitary tract nucleus, caudal midline and caudal and rostral ventrolateral medulla, and fastigial nucleus of the cerebellum. Slightly delayed phasic declines appeared in the dentate and interpositus nuclei and dorsolateral pons. Late-developing responses also emerged in the solitary tract nucleus, parapyramidal region, periaqueductal gray, spinal trigeminal nucleus, inferior olivary nucleus, cerebellar vermis, and fastigial nucleus. Amygdala and hypothalamic sites showed delayed and prolonged signal increases. Intravenous serotonin infusion recruits cerebellar, amygdala, and hypothalamic sites in addition to classic brain stem cardiopulmonary areas and exhibits site-specific temporal patterns.