Anesth Analg 2004;98:414-419
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000094334.12027.06
PAIN MEDICINE
Differential Opioid Inhibition of C- and A
- Fiber Mediated Thermonociception After Stimulation of the Nucleus Raphe Magnus
Ying Lu, MD*,
Sarah M. Sweitzer, PhD
,
Charles E. Laurito, MD*, and
David C. Yeomans, PhD
*Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois, and the
Department of Anesthesia, Stanford University School of Medicine, Stanford, California
Address correspondence and reprint requests to David C. Yeomans, PhD, Department of Anesthesia, Stanford University, 300 Pasteur Drive, S268, Stanford, CA 94305–5117. Address email to dcyeomans{at}stanford.edu
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Abstract
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Although the importance of the nucleus raphe magnus in descending inhibitory control of nociception is clear, it is not known whether these effects are equivalent for different types of nociception. Thus, we examined the differential inhibition of behavioral responses evoked by A
or C fiber thermonociceptor activation by electrical stimulation of nucleus raphe magnus neurons as well as the involvement of different classes of opiate receptors in this inhibition. In general, it was necessary to apply twice as much current to the nucleus raphe magnus to produce criterion antinociception for A mediated versus C fiber mediated nociceptive responses. Intrathecal administration of the nonselective opioid receptor antagonist, naltrexone, or the 1 opioid receptor antagonist, naltrindole, attenuated both A and C fiber antinociception induced by nucleus raphe magnus stimulation with similar efficacy. In contrast, intrathecal administration of naloxonazine, a µ specific opioid receptor antagonist, or naltriben, a 2 specific opioid receptor antagonist, preferentially attenuated nucleus raphe magnus induced antinociception for C fiber responses when compared with A mediated responses. These findings suggest that nociception evoked by the activation of A or C fiber nociceptors is under pharmacologically distinguishable descending control from the nucleus raphe magnus.
IMPLICATIONS: Opiates differentially inhibit pain produced by the activation of myelinated or unmyelinated pain sensing neurons, a distinction that is clinically important. This article demonstrates that the brain’s own pain control system operates with similar selectivity, and that this selectivity is partly mediated by different opiate receptor subtypes.
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Introduction
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Over 30 yr ago, it was demonstrated that electrical stimulation of the periaqueductal gray (PAG) allowed rats to undergo abdominal incisions without the use of anesthetics (1). Since that time, this endogenous analgesic pathway has been defined anatomically. Cells in the PAG project primarily to neurons in the medullary raphe magnus, which in turn project to the dorsal horn of the spinal cord as well as to other spinally-projecting brainstem nuclei (2–4). Consequently, electrical stimulation of neurons in the nucleus raphe magnus (NRM) inhibits transmission of nociceptive information in spinal cord dorsal horn (5). This antinociception is mediated by release of serotonin, norepinephrine, acetylcholine, and opioid peptides (6). Evidence for spinal antinociceptive activity by endogenous opioids in descending inhibitory pathways from the NRM includes the following: 1) enkephalin-containing neurons located in the ventromedial medulla and dorsolateral pontine tegmentum neurons that receive input from the NRM project to the spinal cord dorsal horn (7,8); 2) interneurons in the superficial lamina of the dorsal horn express opioid receptors and synapse with enkephalin-containing projection neuron terminals (9); 3) dorsal horn interneurons synapse with primary afferents expressing opioid receptors; and 4) naloxone-reversible inhibition of behavioral nociceptive responses by electrical stimulation of brainstem nuclei that receive input from the NRM (8).
Most of the studies that have investigated descending inhibition of nociception in rodents have used the latency of tail withdrawal from noxious heat. One of the drawbacks of using tail withdrawal as the primary or sole measure of nociceptive response is the assumption that nociception is a single modality. The multi-modality of pain is best illustrated by the sharp stabbing pain associated with A fiber activation termed "first pain" and the dull, aching pain associated with C fiber activation termed "second pain" (10). In addition to the existence of multiple nociceptive modalities, it is likely that these two pain types are differentially modulated by opiate receptor activation (11). In fact, differential antinociceptive effects of spinal opioids on foot withdrawal responses evoked by C or A nociceptor activation have been reported (12). It has been shown that the behavioral responses mediated by the activation of unmyelinated C fibers or the activation of myelinated A fibers can be dissociated experimentally by the application of a slow heating rate (0.9 °C/s) or rapid heating rate (6.5 °C/s) to the rodent hindpaw, respectively (13,14). The aim of the present study was to determine if NRM-induced inhibitory opiate pathways differentially modulate A and C fiber-mediated nociception.
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Methods
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Female Sprague-Dawley rats (weight, 250–350 g) (Sasco, Wilmington, MA) were housed in a 12:12 h light:dark cycle with food and water ad libitum. All experiments were approved by the University of Illinois at Chicago Animal Care Committee. Efforts were made to minimize animal discomfort and to reduce the number of animals used.
Rats were lightly anesthetized with urethane (750 mg/kg IP). Thirty minutes later, the rats were given ether to obtain surgical anesthesia, immobilized in a stereotaxic head-holder, and an intrathecal catheter was introduced. Briefly, an incision was made in the atlanto-occipital membrane and a PE-10 catheter was inserted through the incision and advanced to the lumbar enlargement.
For electrical stimulation of the raphe magnus, an incision was made along the midline of the skull and a burr hole was drilled over the NRM. A metal plate, 10 mm in diameter, was placed under the skin adjacent to the incision to act as an indifferent electrode.
Paw withdrawal latencies evoked by thermal activation of A or C thermonociceptors were assessed as previously described (13,14). Briefly, both hindpaws were blackened with India ink to ensure uniform skin heating. Foot withdrawal latencies were elicited by a focused light source at a rapid (6.5 °C/s) or slow (0.9 °C/s) rate to activate A or C fibers, respectively. The foot withdrawal latency was calculated as the average time to paw withdrawal after exposure of the dorsolateral and dorsomedial surfaces of each hindpaw. Trials were terminated at withdrawal times of 6 s and 20 s for rapid and slow heating rate, respectively, to prevent tissue damage.
After determination of baseline response latencies, a stainless steel monopolar stimulating electrode was lowered into the NRM (coordinates: L = 0, V = 0.8 mm, AP = -2.5 mm). Response latencies were measured again, followed by electrical stimulation of the NRM (250 ms pulses, 100 Hz, 25 uA) for 3 min. Beginning 15 s after initiation of electrical stimulation, response latencies were measured. The amplitude (current) of stimulation was increased in 12.5-uA increments for successive trials separated by 5-min intervals until foot withdrawal latencies for both heating rates were increased to predetermined criterion antinociception (20 s for slow heating rate, 6 s for rapid heating rate). In this way, current thresholds for antinociceptive effects were established for both heating rates. Differences in current thresholds indicated differences in the efficacy of NRM stimulation for attenuating responses evoked by rapid or slow heating rates. Differences in brainstem stimulation thresholds have previously been shown to provide reliable quantification of evoked changes in antinociceptive efficacy of that stimulation (15).
The following drugs were purchased from Sigma Chemical (St. Louis, MO): naltrexone, naloxonazine (bis-[5–4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)-morphinan-6-ylidene]hydrazine), naltrindole hydrochloride, and naltriben methaneslfonate. All antagonists were dissolved in 0.9% saline at a concentration of 100 nM. This dose was chosen based on previous behavioral experiments in which these drugs were used to block the antinociceptive effects of opiate agonists (12). Antagonists or vehicle were injected intrathecally in a volume of 10 µL followed by 10 µL saline to ensure drug delivery into the subarachnoid space at the level of lumbar enlargement. Solutions were injected at a rate of 10 µL/min.
After determining current thresholds for antinociception for both heating rates, 100 nmoles of naltrexone, naloxonazine, naltrindole, naltriben methanesulfonate, or saline vehicle was injected intrathecally. Current thresholds for antinociception were re-established 15 min later.
At the end of experiment, 5 µL of methylene blue was injected into the catheter and the rats were killed with ether. The spinal canal was opened and the placement of the intrathecal catheter was confirmed. The brains were removed and stored overnight in a 4% paraformaldehyde/10% sucrose solution. Brains were cut on a Cryo-Cut microtome and stained with cresyl violet, and the location of each stimulation electrode track was determined using camera lucida drawing. All electrode tract tips were found to be within the NRM (data not shown), and so results from all animals were used for analysis.
Analyses of variance were performed to determine whether significant differences exist between the attenuated antinociceptive effect of NRM stimulation on A versus C fiber mediated responses, the current after NRM stimulation versus the current after different antagonists or saline injection for rapid or slow heating rate evoked responses.
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Results
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Baseline response latencies for both rapid (A fiber specific) and slow (C fiber specific) heating rates before NRM stimulation were similar to those previously reported at 2.2 ± 0.2 s for rapid heating rate and 12.5 ± 0.6 s for the slow heating rate (13,14). Electrical stimulation of the NRM increased paw withdrawal latencies to the criterion antinociceptive latency (6 s for rapid heating rate and 20 s for slow heating rate). Significantly more current applied to the NRM was required to produce criterion antinociception for rapid versus slow heating rate responses (Fig. 1). Intrathecal application of saline vehicle did not significantly change the current requirement to produce criterion antinociception for either rapid or slow rate heating (Fig. 1). Intrathecal application of the nonselective opiate receptor antagonist naltrexone (100 nmoles) significantly attenuated NRM stimulation-induced antinociception for both rapid and slow heating rate responses as evidenced by the significant increase in current required to reach pre-drug criterion antinociception for rapid and slow heating rate responses (Fig. 2). Similarly, intrathecal application of µ-opioid receptor antagonist naloxonazine (100 nmoles) attenuated the antinociceptive effects of NRM stimulation for both slow and rapid heating rate responses (Fig. 3). However, the current required to reach pre-drug criterion antinociception after intrathecal naloxonazine was significantly greater for slow heating rate responses than for rapid heating rate responses, implying a greater dependence on µ opiate receptor activation for C fiber antinociception (Fig. 3, Table 1). Intrathecal administration of the opiate receptor antagonist naltrindole (100 nM) was equally effective at inhibiting NRM stimulation induced antinociception after both rapid and slow heating rate responses (Fig. 4). In contrast, intrathecal administration of the 2 opiate receptor antagonist naltriben (100 nM) while attenuating NRM stimulation induced antinociception for both A and C fiber activation preferentially inhibited NRM-induced antinociception for slow heating rate as compared with rapid heating rate (Fig. 5, Table 1).
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Figure 1. Similar current applied to the nucleus raphe magnus produces criterion antinociception at baseline (dark bars) and post-intrathecal saline (light bars) after hindpaw exposure to a rapid heating rate or a slow heating rate that preferentially activate A or C-fiber thermonociceptors, respectively (n = 6).
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Figure 2. Intrathecal administration of the nonspecific opioid receptor antagonist naltrexone (100 nmoles) increases the current requirement to the nucleus raphe magnus to produce criterion antinociception in the hindpaw for both a rapid heating rate that is selective for activation of A-fiber thermonociceptors and a slow heating rate that is selective for activation of C-fiber thermonociceptors (n = 6). *P < 0.05 when compared to baseline.
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Figure 3. Administration of the µ opioid receptor antagonist naloxonazine (intrathecal, 100 nmoles) increases the nucleus raphe magnus stimulation current necessary to produce criterion antinociception after hindpaw exposure to a rapid heating rate or a slow heating rate that preferentially activate A or C-fiber thermonociceptors, respectively (n = 6, *P < 0.05 when compared to baseline). A significantly larger increase in current applied to the nucleus raphe magnus, compared with pre-antagonist baselines, is required to produce criterion antinociception after exposure of the hindpaw to the slow heating rate versus the rapid heating rate (#P < 0.05).
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Table 1. Electrical Stimulation of the Nucleus Raphe Magnus Inhibits A- and C-Fiber Thermonociception Through Pharmacologically Distinguishable Mechanisms
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Discussion
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This study was performed to determine if descending inhibitory circuits originating from the NRM preferentially modulate pain of different modalities. The presence of opioid peptide-containing neurons in the NRM and pontine cells that receive input from the NRM and that project to the dorsal horn of the spinal cord suggests that NRM neurons are critical to opioid-mediated descending inhibition. Using heating rates selective for A fiber activation or C fiber activation, this study provides evidence that activation of NRM descending inhibitory pathways preferentially attenuates C fiber activity more than A fiber mediated activity. Thus, to inhibit A fiber mediated activity it took twice as much current applied to the NRM as it took to inhibit C fiber mediated activity. This is evidenced by the necessity of applying double the current to the NRM to produce criterion antinociception for A mediated rapid heating rate responses when compared with C fiber-mediated slow heating rate responses. Additionally, stimulation of the NRM preferentially attenuates C fiber activity through µ and 2 opioid receptors, whereas nonselective opiate antagonists inhibit the antinociceptive effect on C and A responses with approximately the same potency. These findings indicate that A and C fiber-mediated nociception are under pharmacologically distinct descending opiate control.
The present work builds on a previous report (12) that demonstrated differential antinociceptive effects of spinal opioids on foot withdrawal responses evoked by C or A nociceptor activation. In that study, intrathecal administration of a µ or 2 opioid receptor agonist produced more potent antinociception for C fiber activation as compared with A fiber activation. Perhaps the preferential inhibition of C fibers over A fibers by µ and 2 opioid receptor agonists represents dissimilar sites/mechanisms of action of opioids on primary afferents, which transmit diverse nociceptive modalities. µ opioid receptors are located both on neurons within the spinal cord dorsal horn as well as on primary afferents that terminate within the dorsal horn of the spinal cord (16). Depending on the method used, 50%–75% of µ opioid receptors have been reported to be located presynaptically on primary afferents. These µ-opioid receptor positive primary afferents do not co-localize with a marker for myelinated afferents (17). In addition, these µ-opioid receptor positive primary afferents also exhibit sensitivity to capsaicin (18). At small doses, µ agonists inhibit spontaneous and evoked EPSP/Cs (Excitatory Post-Synaptic Potentials/Currents) in lamina II neurons, suggesting presynaptic modulation of lamina II neurons, whereas larger concentrations can directly hyperpolarize lamina II neurons, suggesting a postsynaptic site of action (19).
Although the aforementioned studies did not look specifically at A or C fibers, they likely represent C fiber effects, as 1) lamina II are predominantly innervated by C as opposed to A nociceptive afferents in the absence of prolonged injury (20), 2) C fibers lack myelin, and 3) C fibers are capsaicin sensitive (13,14). Electrophysiological studies of lumbar dorsal horn neurons further support the postulate that A and C fibers are modulated through distinct mechanisms. For example, dose-dependent inhibition of C fiber-evoked neuronal activity was obtained with µ or opioid receptor agonists at doses that had little effect on A fiber evoked neuronal activity (21). Similarly, activation of µ opioid receptors inhibits calcium channels in C but not A tooth pulp afferent cell bodies (22).
Thus, we suggest that the differential modulation of A and C fiber thermal thresholds by descending inhibitory µ opioid pathways is a function of pre- and postsynaptic sites of action for C fibers and only a postsynaptic site of action for A fibers. Furthermore, using a herpes simplex virus delivery system as a novel tool for administering µ opioid receptor antisense to primary afferents to "knock-down" the expression of µ opioid receptors selectively on primary afferents, we have recently observed attenuation of DAMGO (D-Ala, N-Me-Phe, Gly-ol-enkephalin) induced analgesia after C fiber thermal stimulation and not after A fiber thermal stimulation (unpublished findings), supporting the postulate that C-fibers are modulated both pre- and postsynaptically by µ opioids whereas A fibers are modulated only postsynaptically.
Similar to µ opioid receptors, opioid receptors are located on neurons within the spinal cord dorsal horn and also on primary afferents (23,24). Experiments using dorsal rhizotomy have reported that two-thirds of opioid receptors are located presynaptically on primary afferents (16). A parallel loss of Calcitonin Gene related-Peptide immunoreactivity, a peptide expressed by C fibers, in the dorsal horn of the spinal cord is reported after dorsal rhizotomy that results in a dramatic decrease in opioid receptor immunoreactivity (23). A predominantly presynaptic site of action of opioids has been further supported by electrophysiological findings in lamina II neurons whereby both 1 and 2 receptor agonists inhibit evoked EPSP/Cs but without an alteration in resting membrane potential even at larger concentrations (19). Presynaptically, opioids have been reported to inhibit the release of substance P in the lumbar dorsal cord after noxious thermal stimuli (25). Release of substance P has been found to be specific to C fiber activation, and not A fiber activation (26), supporting the postulate that C fibers are modulated presynaptically by endogenous opioid release after activation of the NRM. Similar to findings with the µ opioid receptor antagonists, our findings with the 2 opioid receptor antagonist suggest a differential modulation of C fiber versus A fiber-induced thermal antinociception by NRM opioid-dependent descending inhibitory pathways. Whether the differential modulation of NRM stimulated C or A fiber antinociception by a 2 opioid receptor antagonist in the present study represents a different mode of action of opioids on C versus A fibers (i.e., postsynaptic versus presynaptic) or merely a difference of receptor density on these fibers is unknown. Although the studies above highly support a presynaptic site of action of opioids on C fiber primary afferents, it remains to be determined whether a presynaptic site or postsynaptic site for opioids exists for descending modulation of A fiber activity.
In summary, the present work has shown that the antinociceptive effect of NRM stimulation on A and C fiber evoked responses is mediated, in part, by the spinal release of endogenous opiates. Furthermore, µ and 2 opioid receptor antagonists preferentially block NRM induced antinociception after C fiber, as opposed to A fiber, activation. This study highlights the need to examine multiple nociceptive modalities to begin to understand how descending inhibition modulates primary afferents and spinal neurons to attenuate nociception. Much of the previous work examining descending inhibitory inputs to spinal antinociception has depended on tests of tail withdrawal latency. The drawback of using tail withdrawal as the primary or sole measure of nociceptive response are the assumptions that 1) nociception at all anatomical sites are equal and that 2) all measurement indices for nociception are equal. In fact, the tail flick response may not be representative of simple withdrawal movements and can be pharmacologically dissociated from paw withdrawal responses to noxious heat (27–29). Thus, opioid-induced antinociception incorporates both presynaptic and postsynaptic modulation of thin somatosensory afferent fibers by endogenous and exogenous opioid receptor agonists in a modality specific manner. The current study suggests that although both C and A thermonociception is attenuated by descending opiate modulation, endogenous inhibitory control of C fiber nociception involves pre- and postsynaptic µ opioid receptor activation and presynaptic 2 opioid receptor activation. In contrast, descending inhibitory control of A fiber nociception may involve only postsynaptic µ opioid receptors and a lessened input from 2 opioid receptor activation as compared with C fiber activation.
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Acknowledgments
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Supported, in part, by USPHS grant DA08256 (to DCY).
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Accepted for publication August 19, 2003.
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Abstract
Introduction
