Parturition in the rat: a physiological pain model.

BACKGROUND: Pain during labor is a common and severe phenomenon, but its clinical management remains haphazard because its neurophysiology is poorly understood. In the current study, the authors evaluate the parturient rat as a relevant model to study the pharmacology of labor pain. METHODS: Control of birth timing in term pregnant rats was achieved by gavage with RU 486 (5 mg/kg) the day before the expected day of parturition. The behavioral events preceding the expulsion of the first pup were analyzed, and immunodetection of the c-Fos protein was used to evaluate the spinal neuronal activity at the lumbosacral level where genital and perineal inputs terminate. RESULTS: Hind limb and abdominal stretches occurred during labor (mean number, 57 +/- 10), arbitrarily defined as the time elapsed between the first stretch and the expulsion of the first pup (mean duration, 62 +/- 5 min). Subcutaneous oxytocin increased the frequency of stretches, accounting for the fact that these manifestations are linked to uterine contractions. Finally, epidural morphine (30 microg/10 microl) in oxytocin-treated rats, although resulting in no change of labor duration, significantly decreased the number of stretches (8 +/- 2 vs. 57 +/- 12 for epidural saline) and the number of c-Fos-positive neurons in the lumbosacral spinal segments (80 +/- 25 vs. 165 +/- 17 for epidural saline). CONCLUSIONS: These results indicate that stretches during labor in the rat correspond to a behavioral response to nociception associated with uterine contractions and suggest that parturition in the rat could be a relevant model to investigate nociceptive mechanisms associated with parturition in women.

Phosphorylated MAP1B is induced in central sprouting of primary afferents in response to peripheral injury but not in response to rhizotomy.

A peripheral nerve lesion induces sprouting of primary afferents from dorsal root ganglion (DRG) neurons into lamina II of the dorsal horn. Modifications of the environment in consequence to the axotomy provide an extrinsic stimulus. A potential neuron-intrinsic factor that may permit axonal sprouting is microtubule-associated protein 1B (MAP1B) in a specific phosphorylated form (MAP1B-P), restricted to growing or regenerating axons. We show here that both in rat and mouse, a sciatic nerve cut is rapidly followed by the appearance of MAP1B-P expression in lamina II, increasing to a maximum between 8 and 15 days, and diminishing after three months. Evidence is provided that sprouting and induction of MAP1B-P expression after peripheral injury are phenomena concerning essentially myelinated axons. This is in accordance with in situ hybridization data showing especially high MAP1B-mRNA levels in large size DRG neurons that give rise to myelinated fibers. We then employed a second lesion model, multiple rhizotomy with one spared root. In this case, unmyelinated CGRP expressing fibers do indeed sprout, but coexpression of MAP1B-P and CGRP is never observed in lamina II. Finally, because a characteristic of myelinated fibers is their high content in neurofilament protein heavy subunit (NF-H), we used NF-H-LacZ transgenic mice to verify that MAP1B-P induction and central sprouting were not affected by perturbing the axonal organization of neurofilaments. We conclude that MAP1B-P is well suited as a rapidly expressed, axon-intrinsic marker associated with plasticity of myelinated fibers.

Mu and delta opioid receptor-like immunoreactivity in the cervical spinal cord of the rat after dorsal rhizotomy or neonatal capsaicin: an analysis of pre- and postsynaptic receptor distributions.

Opioid compounds have powerful analgesic properties when administered to the spinal cord. These effects are exerted through mu and delta opioid receptors, and both pre- and postsynaptic mechanisms have been implicated. To specifically address the relative pre- and postsynaptic contribution to spinal opioid analgesia, we have quantitatively assessed the pre- vs. postsynaptic distribution of the mu-opioid (MOR-1, MOP(1)) and delta-opioid receptors (DOR-1, DOP(1)). We also examined the rostro-caudal arborization of MOR-1 and DOR-1 immunoreactive primary sensory neurons, using an isolated dorsal root preparation. These results were compared to those obtained by labeling for calcitonin gene-related peptide (CGRP), a neuropeptide whose expression in the spinal cord is restricted to the terminals of small diameter primary sensory neurons. We estimate that approximately one half of MOR-1 and two thirds of DOR-1 immunoreactivity in the cervical spinal cord is located on primary afferent fibers. These fibers have a broad rostro-caudal distribution, extending at least three segments rostral and caudal to their segment of entry. Regardless of marker used, the rostral projection was greatest, however, the distribution of CGRP-immunoreactive fibers differed somewhat in that they had a much smaller projection to the most caudal segments examined. Our results suggest that presynaptic delta opioid actions predominate, but that there are mixed pre- and postsynaptic inhibitory effects exerted by opioid analgesics that act at the spinal cord mu opioid receptor.

Benzodiazepines and pain: effects of midazolam on the activities of nociceptive non-specific dorsal horn neurons in the rat spinal cord.

The high density of GABA-benzodiazepine receptors in the superficial dorsal horn suggests a possible involvement of benzodiazepines (BZs) in the modulation of spinal pain processes. In this electrophysiological study we have examined the effects of midazolam (MZ), a water-soluble short-acting BZ, on the activities of 57 nociceptive non-specific dorsal horn cells, one in each animal. Recordings were performed at lumbar level in unanesthetized decerebrate spinal rats before and following intravenous injection of MZ (1, 2 or 5 mg/kg). The spontaneous activity was weakly and significantly but not dose dependently reduced by MZ. For the total neuronal population MZ induced no significant effect on C-fiber evoked responses, whatever the dose used. More precise analysis shows that for 45/55 neurons the responses were slightly depressed, but this effect was not dose dependent. In contrast, A delta-fiber evoked responses were markedly and dose dependently depressed. These effects of MZ were reversed by intravenous administration of the antagonist flumazenil (FZ). Despite the fact that MZ displays a very weak effect on responses due to C-fiber stimulation, the possible involvement of BZs in the modulation of nociceptive transmission at the level of the dorsal horn is discussed on the basis of clinical and experimental findings, taking into account the role of GABAergic mechanisms in sensory events.

Attempts to gauge the relative importance of pre- and postsynaptic effects of morphine on the transmission of noxious messages in the dorsal horn of the rat spinal cord.

Both pre- and postsynaptic mechanisms have been proposed as an explanation of the depressive effects of opioids on the activity of nociceptive dorsal horn neurons. In order to gauge the importance of the two mechanisms, we studied the effect of morphine on the spontaneous hyperactivity of nociceptive dorsal horn neurons in the spinalized decerebrated deafferented rat (C5-Th1). In this preparation, intravenous morphine was shown to depress spontaneous firing rate in a dose-dependent fashion. A comparative analysis of the effect of the same dose of morphine (2 mg/kg i.v.) in the intact spinalized decerebrated arthritic rat, in which dorsal horn convergent neurons also display high spontaneous activity, revealed that systemic morphine is twice as potent when primary afferent fibers are left intact. These results can explain why the analgesic effect of morphine is more marked against pains due to an excess of nociception than against pains arising from deafferentation.

Deafferentation hypersensitivity in the rat after dorsal rhizotomy: a possible animal model of chronic pain.

Unilateral dorsal rhizotomies were done at the cervicothoracic and lumbosacral spinal cord levels in rats. In preliminary experiments dermatome maps were determined for the roots to be sectioned. The behavior of 37 rats was observed for many months after the rhizotomies. The rats with the dorsal roots sectioned in the cervicothoracic spinal cord exhibited the following behavior: at the border of the skin adjacent to the zone of deafferentation, the rat scratched vigorously and progressively denuded the skin; self-mutilation of varying degrees occurred in the deafferented limb. In some animals scratching occurred in the contralateral skin dermatome opposite to the partially deafferented zone. The rats with the dorsal roots sectioned at the lumbosacral level exhibited hypersensitivity to cutaneous stimulation but there was no scratching or self-mutilation. These results are discussed in the light of previous similar research.