Several lines of evidence suggest that the pain experienced during the first stage of labor is transduced by afferents with peripheral terminals in the cervix and lower uterine segment rather than the uterine body, as is often depicted ( Fig. 21.5 ). Uterine body afferents fire in response to distention, but in the absence of inflammation, uterine body distention has no or minimal effect on the behavior of laboratory animals. These observations suggest that uterine body afferents may be an important site of chronic inflammatory disease and chronic pelvic pain but are much less relevant to acute obstetric and uterine cervical pain. In addition, afferents to the uterine body regress during normal pregnancy, whereas those to the cervix and lower uterine segment do not. This denervation of the myometrium may protect against preterm labor by limiting α ₁ -adrenergic receptor stimulation by locally released norepinephrine (noradrenaline). Javert and Hardy reproduced the pain of uterine contractions in women during labor by manual distention of the cervix. Bonica and Chadwick later confirmed that women undergoing cesarean delivery under a local anesthetic field block experience pain from cervical distention, which mimics that of labor pain, but do not experience pain from uterine distention.

Uterocervical Afferents Activated During the First Stage of Labor .

Uterine body afferents (A) partially regress during pregnancy and may contribute to the pain of the first stage of labor. However, the major input is from afferents in the lower uterine segment and endocervix (B). By contrast, at least in animals, the activation of afferents that innervate the vaginal surface of the cervix (C) results in analgesia, not pain, and they enter the spinal cord in sacral areas rather than at the site of referred pain in labor.

The uterine cervix has dual innervation; afferents innervating the endocervix and lower uterine segment have cell bodies in thoracolumbar dorsal root ganglia (DRG), whereas afferents innervating the vaginal surface of the cervix and upper vagina have cell bodies in sacral DRG. These two innervations result in different sensory input and referral of pain. Pelvic afferents innervating the vaginal surface of the cervix are almost exclusively C fibers, with the majority containing the peptides substance P and calcitonin gene-related peptide (CGRP). These afferents express alpha and beta estrogen receptors and have an innervation pattern that is not affected by pregnancy. Stimulation of the vaginal surface of the cervix in rats results in antinociception, lordosis, ovulation, and a hormonal state of pseudopregnancy, all of which are related to mating behaviors in this species. In rats, these vaginal afferent terminals are activated only during delivery and not during labor, which suggests that they are not relevant to the pain of the first stage of labor. By contrast, dilation of the endocervix in rats results in the activation of afferents entering the lower thoracic spinal cord and nociception rather than antinociception. These afferents, which are mostly or exclusively C fibers, are activated during the first stage of labor, suggesting that they are relevant to pain during this period.

More than 90 years ago, experiments in dogs allowed Cleland to identify T11–T12 as the segmental level of entry into the spinal cord of afferents that transmit the pain of the first stage of labor. Because dysmenorrhea could be treated through the destruction of the superior or inferior hypogastric plexus, Cleland reasoned that the sensory afferents and sympathetic efferents were likely intermingled; he subsequently demonstrated that the bilateral blockade of the lumbar paravertebral sympathetic chain could produce analgesia during the first stage of labor. First-stage labor pain is transmitted by afferents that have cell bodies in T10–L1 DRG and pass through the paracervical region, the hypogastric nerve and plexus, and the lumbar sympathetic chain.

Classical teaching states that pain-transmitting C and A-delta nerve fibers enter the spinal cord through the dorsal roots and terminate in a dense network of synapses in the ipsilateral superficial laminae (I and II) of the dorsal horn, with minimal rostrocaudal extension of fibers. Whereas this characterization is true for somatic afferents, visceral C fiber afferents enter the cord primarily—but not exclusively—through the dorsal roots and terminate in a loose network of synapses in the superficial and deep dorsal horn and the ventral horn. These afferents also cross to the contralateral dorsal horn, with extensive rostrocaudal extension of fibers. This anatomic distinction underlies the precise localization of somatic pain and the diffuse localization of visceral pain, which may cross the midline; it may also determine the potency or efficacy of drugs that must reach afferent terminals, such as intrathecal opioids.

Pain-transmitting neurons in the spinal cord dorsal horn send axons to the contralateral ventral spinothalamic tract (stimulating thalamic neurons) with further projections to the somatosensory cortex, where pain is perceived. These spinal neurons also send axons through the spinoreticular and spinomesencephalic tracts to provide signals to the areas of vigilance (locus coeruleus, reticular formation), cardiorespiratory regulation (nucleus tractus solitarius, caudal medulla), and reflex descending inhibition (periaqueductal gray, locus coeruleus and subcoeruleus, nucleus raphe magnus, rostral medial medulla, cerebellum). Thalamic activation from painful stimuli results in the activation not only of the somatosensory cortex but also areas of memory (prefrontal cortex), motor response (M1 motor cortex), and emotional response (insular cortex, anterior cingulate cortex). Supraspinal pain pathways activated by pain of the first stage of labor can be briefly described sequentially, starting with the ascending pathways projecting to the pons and the medulla, thereby activating centers of cardiorespiratory control and descending pathways as well as the thalamus, which in turn sends projections to the anterior cingulate, motor, somatosensory, and limbic regions.

The anatomic basis for pain of the first stage of labor implies that amelioration of pain requires blockade of peripheral afferents (by paracervical, paravertebral, lumbar sympathetic, or epidural [T10–L1 dermatome] block) or of spinal cord transmission (by intrathecal injection of local anesthetic and/or opioid) ( Fig. 21.6 ). Given the widespread distribution of visceral synapses in the spinal cord, intrathecally administered drugs must have physicochemical properties that facilitate deep penetration into the spinal cord to effectively reach and block the terminals responsible for pain transmission. In particular, the lipophilicity of opioids and the ionization state of local anesthetics affect the rate of uptake across cellular membranes, thereby influencing the onset and clinical efficacy of the drug when administered in the epidural or intrathecal space.

Transmission and Blockade of Labor Pain .

Labor pain has a visceral component (e.g., release of potassium, bradykinin, histamine, and serotonin) and a somatic component (e.g., mechanoreceptors). Noxious stimuli invoke nociceptive responses in the paracervical region and the pelvic and hypogastric plexus, as well as the lumbar sympathetic chain. Through the white rami communicantes of the T10, T11, T12, and L1 spinal nerves, nociceptive signals enter the dorsal horn of the spinal cord. Blockade at different levels along this path (sacral nerve root block of S2–S4, pudendal block, paracervical block, low caudal or true saddle block, lumbar sympathetic block, segmental epidural block of T10–L1, and paravertebral block T10–L1) can alleviate the visceral and somatic components of labor pain.

Illustration by Naveen Nathan, MD, NorthShore University HealthSystem, University of Chicago Pritzker School of Medicine.

Pain during the second stage of labor is transmitted by the same afferents activated during the first stage of labor but with additional afferents that innervate the cervix (vaginal surface), vagina, and perineum. These additional afferents are somatic, coursing through the pudendal nerve DRG at S2 to S4. Thus, the pain specific to the second stage of labor is precisely localized to the vagina and perineum and reflects distention, ischemia, and frank injury, either by stretching to the point of disruption or by surgical incision. Studies in nonpregnant women indicate a minor analgesic effect of mechanical self-stimulation of the vaginal surface of the cervix ; this effect may result from the stimulation of C fibers, because in women with a high oral intake of capsaicin, the activity of such fibers is reduced. The relevance of this minor effect in reducing the pain of the second stage of labor has not been examined; however, it does suggest that noxious input during labor may activate endogenous analgesia (see later discussion).

The anatomic basis for pain of the second stage of labor implies that analgesia for this stage can be obtained by augmenting the methods used to treat the pain of the first stage of labor with caudad extension of the epidural blockade from T10 to S4, or alternatively with a bilateral pudendal nerve block for sacral analgesia (see Fig. 21.6 ).

Visceral nociceptors, such as those that transduce the pain of the first stage of labor, are activated by stretching and distention. However, unlike somatic afferents, they are not activated by cutting. With each uterine contraction, pressure is transmitted to stretch the uterine cervix, leading to the activation of these visceral afferent nerve terminals. How mechanical distention results in the depolarization of the nerve terminal and the generation of an action potential is not entirely known, but the following mechanisms are likely:

• 1.

  Several ion channels respond to the distortion of the cell membrane. One of them, brain sodium channel-1 or acid-sensing ion channel-2 (ASIC-2), is exclusively expressed in sensory afferents and might directly depolarize the nerve terminal by opening its channel when the membrane is distorted ( Fig. 21.7 ).

  

  Afferent nerve endings contain multiple excitatory ligand-gated ion channels, including those that respond to mechanical distortion: BNC-1 , Brain sodium channel-1; ATP , adenosine triphosphate; P2X3 , purinergic receptor; H ⁺ , hydrogen ion; ASIC , acid-sensing ion channel; VR-1 , vanilloid receptor type 1.

• 2.

  Mechanical distortion may result in the acute release of a short-acting neurotransmitter that directly stimulates ion channel receptors on nerve terminals. Although this process has not yet been examined in the uterine cervix, studies have observed that stretching the bladder urothelium releases adenosine triphosphate, which directly stimulates a type of ligand-gated ion channel, P2X3, on sensory afferents in the bladder wall. Because P2X3 receptors are widely expressed in C fibers, this mechanism might be responsible for the pain resulting from the acute distention of the uterine cervix.

• 3.

  Local ischemia during contractions may result in gated or spontaneous activity of other ion channels. Some of these ion channels—the ASIC family—respond directly to the low pH that occurs during ischemia, whereas other classes of ion channels may be activated to open spontaneously. For example, the vanilloid receptor type 1 (VR-1) is a receptor-gated ion channel that responds to noxious heat and capsaicin-like ligands. VR-1 receptor-gated ion channels are not normally open in the absence of high temperature or capsaicin-like ligands; however, in the presence of low pH, these channels open at room temperature. It is likely that VR-1 receptors are expressed on visceral afferent terminals, given that the application of capsaicin or heat to the distal esophagus in humans results in pain. VR-1 receptors in the visceral afferent fibers implicated in the first stage of labor pain are presumed to demonstrate similar activation in response to the low pH produced by contraction-induced ischemia.

Uterine cervical afferents (including the C fibers innervating the vaginal surface of the cervix) contain substance P, CGRP, and the enzyme nitric oxide synthase. C fibers can be divided into two groups: (1) those that contain substance P and CGRP and respond to nerve growth factor through actions on tyrosine kinase A receptors, and (2) those that contain somatostatin and respond to glially derived growth factor through actions on a c-ret complex. Other compounds commonly contained in C fiber terminals include glutamate, vasoactive intestinal peptide, and neuropeptide Y. The variable role of C fiber subtypes in the transmission of pain is also unclear. Given that somatostatin typically inhibits substance P release and pain transmission, the net transmission of nociception at the spinal cord level may reflect a complex interaction between excitatory and inhibitory C fiber subtypes.

The numerous ion channels involved in the neurophysiology of pain during the first stage of labor may represent important new targets for local or systemic analgesic drug delivery. As an understanding of the classification, function, and relevance of different C fiber subtypes remains in its infancy, research involving these endocervical subtypes may ultimately benefit the treatment of labor pain.

Role of Sensitization

Nociceptors typically respond to high-threshold stimuli. Peripheral afferent terminals, which can change their properties in response to various conditions, can be directly stimulated by the low pH associated with inflammation and ischemia ( Fig. 21.8 ); selective ligand-gated ion channels on these terminals can also be stimulated by the release of bradykinin. In addition, peripheral inflammation can sensitize afferent terminals within minutes to hours, thereby altering their gene expression and leading to a large amplification of pain signaling.

Effects of Inflammation From Cervical Ripening on Afferent Terminals .

A variety of factors, including bradykinin, heat and hydrogen ions, prostaglandins (including PGE ₂ ), tumor necrosis factor-α (TNFα), interleukin-1 beta (IL-1β), and nerve growth factor (NGF), act on their cognate receptors to sensitize nerve endings and amplify the perception and severity of pain from nerve stimulation. B2 , Bradykinin-2 receptor; EP , prostaglandin E receptor; ILr , interleukin-1 receptor; p75 , p75 tumor necrosis factor-α receptor; trkA , tyrosine kinase A; VR-1 , vanilloid receptor type 1.

Peripheral inflammation is commonly associated with pain resulting from acute postoperative and chronic arthritic conditions, but it may also play an essential role in labor pain. Both the cervical ripening process and labor itself result from local synthesis and release of various inflammatory products including macrophages and leukocytes in the term cervix, inducible nitric oxide synthetase, and proinflammatory cytokines and metalloproteinases that degrade the cervical extracellular matrix. The clinical utility of these inflammatory mediators includes agents (e.g., prostaglandin E ₂ [PGE ₂ ]) that prepare the cervix for labor induction and inhibitors (e.g., indomethacin) that slow preterm labor.

PGE ₂ is an especially important sensitizing agent for uterine cervical afferents. In most species, the onset of labor is triggered by a sudden decline in circulating estrogen concentration. This decrease removes a tonic block on the expression of cyclooxygenase, leading to an increase in local production of prostaglandins, especially PGE ₂ . PGE ₂ is central to a variety of processes that allow ripening and dilation of the uterine cervix. During the 24 to 72 hours preceding the onset of labor, collagen in the cervix becomes disorganized owing to the activation of prostaglandin receptors and the activity of inflammatory cytokines (mostly interleukin-1-beta [IL-1β] and tumor necrosis factor-alpha [TNF-α]) and matrix metalloproteinases (especially types 2 and 9). A series of studies in the rat paw have demonstrated that PGE ₂ induces peripheral sensitization in a sex-independent manner by activation of protein kinase A and nitric oxide synthase.

Cytokines and growth factors are released into the uterine cervix immediately before and during labor. Cytokine IL-1β enhances cyclooxygenase activity and substance P release in the DRG and spinal cord. TNF-α increases the spontaneous activity of afferent fibers and enhances CGRP release and VR-1 receptor expression in DRG cells in culture. Nerve growth factor also induces mechanical hypersensitivity. These sensitizing substances (prostaglandins, cytokines, and growth factors) signal peripheral nerves in a manner that results in changes in DRG cell number, peptide expression and release, receptor and ion channel expression, and biophysical properties. For example, inflammatory mediators alter the expression of sodium (Na ⁺ ) channel subtypes, thereby resulting in more rapid, repetitive firing capability and spontaneous afferent activity. Thus, sensitized peripheral afferents may fire at a lower stimulus threshold and more frequently, though the intensity and nature of the stimulus may be objectively unchanged.

Estrogen receptor signaling can dramatically affect the structure of the uterine cervix and possibly modulate pain responses. Long-term estrogen exposure sensitizes a subset of mechanosensitive afferents innervating the uterine cervix. The hypogastric afferents that innervate the uterine cervix are polymodal and contain high-threshold (HT) and low-threshold (LT) fibers. Long-term estrogen exposure increases the spontaneous activities of both HT and LT fibers, but only HT fibers show greater responses to uterine cervical distention. Long-term estrogen exposure also increases the proportion of hypogastric afferents innervating the uterine cervix, which express transient receptor potential vanilloid type 1 (TRPV-1). Capsazepine, a TRPV-1 channel antagonist, reduces the hypogastric afferent responses to cervical distention in estrogen-treated animals but not in ovariectomized animals without estrogen replacement. These data suggest that the TRPV-1 receptor is important for estrogen-induced sensitization and amplification of pain responses to uterine cervical distention and thus represents a potential new target for preventing or treating such pain.

Implications of peripheral sensitization of cervical afferents during labor include:

• 1.

  Braxton-Hicks contractions, prior to the onset of this inflammatory process, may be as powerful as labor contractions but with significantly less pain.

• 2.

  Pain may increase with the progress of labor as a result of sensitization.

• 3.

  Inflammatory mediators may provide new targets to treat labor pain.

Inhibitory Receptors

Given the multiplicity of direct excitatory and sensitizing mechanisms on peripheral terminals, more plausible peripheral targets are the endogenous inhibitory receptors expressed on the afferent terminals ( Fig. 21.9 ). Although μ-opioid receptors have achieved the widest attention and are expressed in some afferents in the setting of inflammation, the efficacy of local instillation of morphine has proved disappointing, with the exception of an intraarticular injection. Moreover, antinociception by μ-opioid receptor agonists to uterine cervical distention occurs in the central, but not peripheral, nervous system.

κ-Opioid receptor agonists act primarily at visceral afferent terminals in the periphery and in the supraspinal central nervous system to provide analgesia during the first stage of labor, whereas µ-opioid receptor agonists act in the spinal cord and the supraspinal central nervous system. Estrogens block the effect of µ-opioid receptor agonists at supraspinal sites.

κ-Opioid receptor agonists may effectively treat visceral pain owing to the presence of these receptors in visceral (but not somatic) afferents, at least in the gastrointestinal tract. κ-Opioid receptor agonists can also produce antinociception in response to uterine cervical distention through actions in the peripheral nervous system. Pharmaceutical firms are developing drugs of this class that are restricted to the periphery, have few central side effects, and presumably express little potential for placental transfer; potentially, such agents could be useful for labor analgesia.

Estrogen and progesterone can alter the analgesic response to opioids. In most cases involving somatic stimulation, tonic estrogen treatment reduces the efficacy of μ-opioid but not κ-opioid receptor agonists. Further, κ-opioid receptor agonists have greater analgesic efficacy in women than in men. In animals, tonic estrogen exposure reduces the inhibitory responses to uterine cervical distention by morphine but not to the κ-opioid receptor agonist U-50488. In contrast, the inhibitory action of intrathecal morphine against responses to uterine cervical distention is unaffected by tonic estrogen exposure, which is consistent with the observation that intrathecal opioids relieve the pain of the first (visceral), but not second (mostly somatic), stage of labor.

Implications of inhibitory receptors on afferent terminals are that κ- but not μ-opioid receptor agonists may produce pain relief through their actions in the periphery. Selective, peripherally restricted drugs are under development for the systemic treatment of visceral pain. In addition, estrogen-dependent inhibition of the supraspinal (but not the spinal) analgesic action of μ-opioid receptor agonists may underlie the limited analgesic effect produced by systemic opioids, a finding that is in contrast to the efficacy of intrathecal opioids in relieving the pain of the first stage of labor.

The current approach to labor analgesia relies primarily on an understanding of the afferent axons and their level of entry into the spinal cord and on the central administration of local anesthetics to block afferent traffic conduction. Axons are considered conduits that allow for the propagation of action potentials by the transitory opening of sodium and other ion channels.

Although a number of voltage-gated sodium channel subtypes exist, most studies have focused on three specific subtypes that are expressed in sensory but not motor afferents. Two of these, NaV1.8 and NaV1.9, are relatively resistant to blockade by tetrodotoxin (TTX-R); NaV1.9 is often referred to as “persistent,” owing to its very slow inactivation kinetics. Inflammation and injury to nerves decrease the TTX-R current density in afferent cell bodies. Some investigators have suggested that NaV1.8 is selectively trafficked to the periphery after injury and inflammation and that a reduction of its expression reduces hypersensitivity. Other investigators, using sucrose gap measurements of compound action potentials, have demonstrated a shortened refractory period and a decrease in delayed depolarization after nerve injury that are consistent with the greater expression of rapidly repriming tetrodotoxin-sensitive (TTX-S) channels and the decreased expression of kinetically slow TTX-R channels. To date, these studies have focused primarily on peripheral nerve injury models of chronic pain, and neither the subtypes nor their change during the cervical inflammation of labor has been studied. In one animal study, dexmedetomidine was shown to reduce NaV1.8 currents in DRG neurons and decrease excitability of small sensory neurons via increased activation threshold and decreased rate of firing.

Selective subtype-specific sodium channel blockers could improve both the safety and efficacy of the treatment of labor pain, because such agents would potentially not interact with sodium channels in the brain, heart, or motor nerve fibers. Some investigators have observed that injection of the antidepressant amitriptyline, an agent known to block the NaV1.8 sodium channel, around the peripheral nerves provides a neural blockade two- to fivefold longer than that provided by injection of long-acting local anesthetics.

Another subject of current research is the prolongation of selective antinociception without motor or sympathetic block via manipulation of the TRPV-1 receptor, a nonselective ligand-gated cation channel. TRPV-1 receptors are expressed in peripheral primary afferent neurons, nociceptive C and A-delta fibers, and the DRG, as well as the structures involving the endogenous antinociceptive descending pathway. TRPV-1 receptors can be activated by capsaicin, heat, and endovanilloids, leading to release of substance P and activation of inhibitory neurons in laminae I, III, and IV. Further, activation of the TRPV-1 receptors causes opening of the small TRPV-1 channels on the neurons and allows size-selective entry of coadministered charged molecules. Permanently charged local anesthetic, when applied alone, cannot cross the nerve membrane to exert its effect on sodium channels in small sensory neurons. When applied in the presence of capsaicin or other TRPV-1 agonists, the permanently charged local anesthetic becomes permeant to exert its local anesthetic effect. Binshtok et al. reported the inhibition of nociceptors by TRPV-1-mediated entry of impermeant sodium channel blockers. However, stimulation of TRPV-1 receptors, such as with capsaicin alone, also results in the induction of receptor-mediated acute pain. Rodent studies indicate that the coapplication of lidocaine and its quaternary permanently charged derivative QX-314, which activate and enter TRPV-1 channels, respectively, produces a prolonged, predominantly nociceptor-selective block without the nocifensive behavior associated with capsaicin. The issues of pain elicited with administration of TRPV-1 agonists such as capsaicin and, more importantly, the neurotoxicity of permanently charged Na ⁺ channel blockers remain to be overcome and require further research. Should future research prove the absence of toxicity, it is conceivable that amitriptyline or other agents that interact with Na ⁺ channel subtypes and/or TPRV-1 receptors could be considered for single-injection techniques to produce prolonged and selective analgesia for labor pain and postoperative pain relief.

Interactions among the numerous ion channels expressed on axons can alter neural conduction. An example is the transient refractory period caused by the membrane hyperpolarization following a short burst of nerve firing. This phenomenon results from activation of the Na ⁺ /K ⁺ exchange pump and dampens high-frequency nerve activity. The Na ⁺ /K ⁺ exchange pump activity, in turn, can be reduced by a hyperpolarization-induced current termed I _h . Drugs that block the I _h current enhance the hyperpolarization caused by the Na ⁺ /K ⁺ exchange pump and ultimately serve to reduce nerve traffic and provide prolonged analgesia. A second example is the desensitization of VR-1 receptors present on the axons of C fibers. The perineural injection of drugs that desensitize these receptors without first stimulating them avoids the induction of receptor-mediated acute pain and instead produces prolonged selective sensory analgesia without motor effects. The mechanism by which VR-1 receptor desensitization alters the transmission of action potentials is under investigation.

Implications of the neurophysiology of axonal transmission of labor pain are that sodium channel subtype-selective agents, or those that affect other ion channels expressed on axons, may provide safer and more selective tools for regional analgesic techniques.

When action potentials invade the central terminals of C and A-delta fiber afferents in the spinal cord, voltage-gated calcium channels open. Increased intracellular calcium triggers a multistep process of neurotransmitter docking and fusion with the plasma membrane, which results in neurotransmitter release. Inhibition of these calcium channels, such as by gabapentin, and the consequent neurotransmitter release, produces antinociception to visceral stimulation.

A nociceptive stimulus can result in the release of multiple excitatory neurotransmitters, including amino acids (glutamate, aspartate) and peptides (especially substance P, CGRP, and neurokinin A) that interact with specific receptors on spinal cord neurons. Although the stimulation of neurokinin receptors is necessary for the perception of moderate to severe pain, a complex and poorly understood interplay exists among these released neurotransmitters.

As described, neurotransmitter release at sensory afferent terminals is controlled by presynaptic receptors that act primarily by altering the flux of intracellular calcium when an action potential arrives. Some of these neurotransmitters are excitatory; for example, the action of acetylcholine on nicotinic acetylcholine receptors amplifies further neurotransmitter release. Gamma-aminobutyric acid (GABA) is the key endogenous inhibitory neurotransmitter in the nervous system, and stimulation of GABA receptors significantly reduces the afferent terminal release of other neurotransmitters. Multiple compounds produce analgesia by enhancing the release of GABA at afferent terminals in the spinal cord. The coexistence of excitatory and inhibitory systems can make the response to a neurotransmitter or an exogenously administered agent, such as a local anesthetic drug given intrathecally, difficult to predict. For example, acetylcholine can enhance or reduce the afferent terminal release of neurotransmitters by actions on nicotinic and muscarinic receptors, respectively. The net effect of acetylcholine appears to be inhibitory, which is indicated by the analgesic effect of intrathecal administration of the cholinesterase inhibitor neostigmine.

The primary mechanism of action of the neurotransmitter enkephalin, which is released by spinal cord interneurons, and of norepinephrine, which is released by axons descending from pontine centers, is the inhibition of neurotransmitter release from primary afferent terminals. These substances act on μ-opioid and α ₂ -adrenergic receptors, respectively, and may produce some of the similar effects observed after the intrathecal administration of opioids and α ₂ -adrenergic agonists for the treatment of labor pain.

Amino acids and peptides released from sensory afferents stimulate a heterogeneous group of spinal cord neurons, including neurons that project to supraspinal structures, interneurons that modulate transmission at the afferent terminal itself (the “gate” of the control theory), and interneurons that stimulate motor and sympathetic nervous system reflexes. Large and sustained glutamate release from an intensely noxious stimulus can activate N -methyl- d -aspartate (NMDA) receptors, resulting in sustained depolarization and enhanced excitability of projection neurons ( Fig. 21.10 ). Although the intrathecal injection of NMDA receptor antagonists (e.g., ketamine) has been restricted because of neurotoxicity concerns, systemic infusion of magnesium sulfate has been observed to produce postoperative analgesia. Magnesium is an endogenous inhibitory modulator of NMDA receptors, and it is conceivable that magnesium sulfate administered systemically for obstetric indications may have a minor effect on labor pain.

Pain Transmission in the Spinal Cord .

Excitatory transmission occurs directly by release of amino acids such as glutamate (Glu) and peptides (sP [substance P], CGRP [calcitonin gene–related peptide]) and indirectly via activation of enzymes such as cyclooxygenase (COX) in nearby glia, which synthesize prostaglandins, including prostaglandin E ₂ (PGE ₂ ). Inhibitory mechanisms are primarily presynaptic, with µ-opioid and α ₂ -adrenergic receptors being the most common (or at least the most studied).

Prolonged and intense nociceptive stimuli can produce sensitization and amplification of pain signaling at the spinal cord level that mirrors the peripheral sensitization resulting from inflammation. Some of these processes are a direct consequence of receptors (e.g., NMDA receptors) that are activated only with highly intense and prolonged stimulation or by the long-term release of neurotransmitters that simultaneously activate the glutamate and substance P receptors on the same cell. Others reflect the synthesis and release of classic “inflammatory” substances by the spinal cord glial cells in response to prolonged afferent stimulation from nitric oxide and prostaglandins, especially PGE ₂ . Some nonopioid analgesic drugs produce analgesia by actions exclusively (e.g., acetaminophen [paracetamol]) or primarily (e.g., aspirin) in the central nervous system, especially the spinal cord.

Spinal sensitization processes represent a novel target for the treatment of labor pain. More than 90 years ago, Cleland noted the presence of hypersensitivity to light touch on the skin of dermatomes T11 and T12 in laboring women, which likely represents the enhanced sensitivity of spinal cord neurons receiving both visceral input from the cervix and skin input at those levels. When the visceral stimulation to these dermatomes was blocked by a paravertebral local anesthetic injection, Cleland observed that the hypersensitivity was ablated; this observation is consistent with the later finding that ongoing C fiber input is required for hypersensitivity to occur.

Uterine cervical distention results in a pattern of spinal cord neuronal activation similar to that witnessed during labor and delivery. In a study in rats reported by Tong et al., uterine cervical distention significantly increased c-fos immunoreactivity in the spinal cord from T12 to L2, with most of the c-fos expression occurring in the deep dorsal horn and central canal regions. Uterine cervical distention–evoked c-fos expression was prevented by prior infiltration of lidocaine into the cervix or by intrathecal administration of ketorolac (a cyclooxygenase [COX] inhibitor) in a dose-dependent manner. Intrathecal administration of indomethacin (a nonspecific COX inhibitor) and the selective COX-2 inhibitor SC-58238 effectively ablated uterine cervical distention–induced electromyographic activity without altering the hemodynamic response,. By contrast, the selective COX-1 inhibitor SC-58360 was ineffective in ablating uterine cervical distention–induced electromyographic activity, as was ketorolac, an agent with higher affinity for COX-1 than COX-2. Together, these data suggest that targeting COX-2 is necessary to treat the acute visceral pain often associated with brief infrequent contractions in late pregnancy; therefore, intrathecal ketorolac would be predicted to be ineffective. However, in the setting of sustained, frequent, and repetitive contractions for a prolonged period (as occurs during active labor), intrathecal ketorolac might be effective. The intrathecal injection of ketorolac has been introduced into experimental human trials and warrants examination as a potential modality for selective treatment of labor pain.

The neurophysiologic basis for labor pain in the spinal cord implies that purely inhibitory mechanisms (e.g., opioid and α ₂ -adrenergic receptors) can be mimicked by the intrathecal injection of agonists to these receptors. However, the administration of other agents (e.g., acetylcholine) in this location has less predictable results. Central sensitization mechanisms in the spinal cord most certainly occur during labor, and future treatments may target these mechanisms.

Spinal cord neurons project to multiple brainstem sites as well as the thalamus. Descending systems, which are activated primarily by stimulation of the nucleus raphe magnus, the periaqueductal gray, and the locus coeruleus, modulate pain transmission as described in the gate control theory. Activation of descending pathways results in the spinal release of endogenous ligands for serotonergic, opioid, and α ₂ -adrenergic receptor-mediated analgesia. Spillover of neurotransmitters into the cerebrospinal fluid has been used as a measure of activation of these systems. Studies measuring these substances in laboring women have shown no increase in enkephalin but an increase in norepinephrine. These descending inhibitory systems can be activated by psychoprophylactic methods, and agents that prolong or intensify the action of these ligands, such as enkephalinase inhibitors and monoamine reuptake inhibitors, might further enhance analgesia.

Brainstem activation by the pain of labor leads to other reflexes, such as increases in sympathetic nervous system activity and respiratory drive and, with prolonged activation, stimulation of descending pathways that amplify rather than reduce pain transmission at the spinal cord. The circuitry and pharmacology of such pain-enhancing systems in the brainstem and their potential applications for treatment are under current investigation.

Our understanding of the areas of the brain activated during labor pain is limited, although studies of other types of experimental nociception in healthy volunteers indicate that visceral pain is considered more unpleasant than somatic pain. This difference reflects, in part, the greater activation of centers for negative emotions, including fear. Although distraction methods do not alter the thalamic activation from noxious stimulation, a reduction in cortical activation and the report of pain have been observed, supporting a suprathalamic mechanism of psychoprophylaxis in the reduction of pain.

The neurophysiologic basis of labor pain and ascending projections suggests the activation of multiple supraspinal sites. Some of these sites stimulate potentially detrimental cardiorespiratory reflexes. Other sites, which send descending projections modulating transmission in the spinal cord, may be targeted for the provision of analgesia. In addition, suprathalamic modulation of pain signals appears to partially account for interindividual differences in pain perception and for the relative efficacy of psychoprophylaxis in reducing the intensity of reported pain.

Several aspects of labor pain can affect the course of labor and delivery ( Fig. 21.11 ). Pain enhances the activity of the sympathetic nervous system, leading to increased plasma concentrations of catecholamines, especially epinephrine (adrenaline). The provision of labor analgesia reduces the plasma concentration of epinephrine and its associated beta-adrenergic tocolytic effects on the myometrium. This process may underlie the observations by some investigators who have noted, either anecdotally or under controlled conditions, a shift from dysfunctional to normal labor patterns in some women when analgesia is achieved with paravertebral or epidural blocks or with systemic meperidine (pethidine) analgesia. The abrupt reduction in plasma epinephrine concentration following the rapid onset of neuraxial analgesia may result in an acute reduction of beta-adrenergic tocolysis and a transient period of uterine hyperstimulation. In some cases, these changes may lead to transient fetal stress and fetal heart rate abnormalities. Therefore, the presence of a dysfunctional labor pattern or fetal monitoring suggestive of fetal compromise are important considerations in the decision to institute neuraxial blockade. Some studies have found that prolonged fetal decelerations are more common following the combined spinal-epidural technique than conventional epidural or dural puncture epidural techniques, while others have found minimal difference; regardless, fetal heart rate alterations can occur following any technique of neuraxial block and thus the maternal and fetal conditions should always be observed.

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