Biomedical subjects

S M Carlton

Publications and source records attributed to S M Carlton.

At least 19 recordsLinked to original sources

PubMed2006

Analgesic activity of a non-peptide imidazolidinedione somatostatin agonist: in vitro and in vivo studies in rat.

Several lines of evidence support an important role for somatostatin receptors (SSTRs) in pain modulation. The therapeutic use of established SSTR peptide agonists for this indication is limited by their broad range of effects, need for intrathecal delivery, and short half-life. Therefore, the goal of the present study was to investigate the analgesic effect of SCR007, a new, highly selective SSTR2 non-peptide agonist. Behavioral studies demonstrated that paw withdrawal latencies to heat were significantly increased following intraplantar SCR007. Furthermore, both intraperitoneal and intraplantar injection of SCR007 significantly reduced formalin- and capsaicin-induced flinching and lifting/licking nociceptive behaviors. Recordings from nociceptors using an in vitro glabrous skin-nerve preparation showed that SCR007 reduced heat responses in a dose-dependent fashion, bradykinin-induced excitation, heat sensitization and capsaicin-induced excitation. In both the behavioral and single fiber studies, the SCR007 effects were reversed by the SSTR antagonist cyclo-somatostatin, demonstrating receptor specificity. In the single fiber studies, the opioid antagonist naloxone did not reverse SCR007-induced anti-nociception suggesting that SCR007 did not exert its effects through activation of opioid receptors. Analysis of cAMP/protein kinase A (PKA) involvement demonstrated that SCR007 prevented forskolin- and Sp-8-Br-cAMPS (a PKA activator)-induced heat sensitization, supporting the hypothesis that SCR007-induced inhibition could involve a down-regulation of the cAMP/PKA pathway. These data provide several lines of evidence that the non-peptide imidazolidinedione SSTR2 agonist SCR007 is a promising anti-nociceptive and analgesic agent for the treatment of pain of peripheral and/or central origin.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2005

Kainate-induced excitation and sensitization of nociceptors in normal and inflamed rat glabrous skin.

This study investigates contributions of peripheral kainate receptors to acute nociception and persistent inflammatory pain in rat. Immunohistochemical analysis of kainate receptor expression using antibodies recognizing glutamate receptor subunits 5, 6, and 7 demonstrates that 28% of unmyelinated axons in normal digital nerve are positively labeled. Following intraplantar injection of complete Freund's adjuvant, a significant increase in glutamate receptor subunits 5, 6, and 7-labeled axons occurs at 2 days (40%), but not 7 (31%) or 14 days (28%) post-complete Freund's adjuvant. In behavioral studies, we confirm an increased mechanical sensitivity in complete Freund's adjuvant-injected hind paws. Furthermore, activation of kainate receptors following intraplantar injection of 1.0 mM kainate in normal animals results in a mechanical sensitivity similar to that observed in inflamed animals. A 1.0 mM kainate injection into inflamed hind paws further enhances the mechanical sensitivity. Injection of the non-N-methyl-D-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (0.1 mM) reverses complete Freund's adjuvant-induced mechanical sensitivity through a local effect. In single unit recordings from nociceptors in a glabrous skin-nerve preparation, mechanical sensitization is present in inflamed skin evidenced by a decrease in mechanical threshold and an increase in discharge rate during a suprathreshold, constant force stimulus. Thermal sensitization is also present evidenced by a decrease in heat threshold. There is a dose-dependent increase in kainate-induced nociceptor activity in both normal and inflamed skin but the kainate required to induce activation is reduced in inflamed skin. Although proportions of kainate-activated nociceptors are the same in normal and inflamed skin, the kainate-induced mean discharge rate is significantly enhanced in inflamed skin. Exposure of normal and inflamed nociceptors to 0.3 mM kainate sensitizes fibers to re-application of kainate and heat. This sensitization is blocked in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione or the glutamate receptor subunit 5 selective antagonist 3S,4aR,6S,8aR-6-[4-carboxy-phenyl] methyl-1,2,3,4,4a,5,6,7,8,8a-deca-hydroisoquinoline-3-carboxylic acid. The data indicate that peripheral kainate receptors not only play an important role in normal nociception but also contribute to mechanical sensitivity and heat sensitization accompanying inflammatory pain.

Animals↗

PubMed2004

The effect of a kainate GluR5 receptor antagonist on responses of spinothalamic tract neurons in a model of peripheral neuropathy in primates.

The responses of antidromically identified spinothalamic tract (STT) neurons to mechanical and thermal stimuli were compared in anesthetized normal and neuropathic monkeys before and after administration of a GluR5 kainate receptor antagonist (LY382884) into the spinal cord dorsal horn through a microdialysis fiber. Peripheral neuropathy was induced by tight ligation of the L7 spinal nerve 13-15 days prior to the experiment. STT neurons recorded in the animals with neuropathy showed increased responsiveness to weak mechanical stimuli and to heating and cooling of the skin compared to STT cells in normal animals. In both normal and the neuropathic monkeys the responses of the STT neurons to mechanical and thermal stimuli were attenuated by LY382884 application in a concentration-dependent manner. Intraspinal application of LY382884 in the neuropathic animals led to a potent reduction of those responses of the STT neurons that were aggravated by the peripheral neuropathy (weak mechanical, heat and innocuous cooling stimuli). These results suggest that kainate receptors are involved in synaptic activation of STT cells in the normal state and may also play an important role in pathological pain states such as peripheral neuropathy in primates. Kainate receptor antagonists could thus be useful for the treatment of certain forms of allodynia and hyperalgesia.

Animals↗

PubMed2003

N-methyl-D-aspartate-induced excitation and sensitization of normal and inflamed nociceptors.

The present study investigates the contribution of peripheral N-methyl-D-aspartate (NMDA) receptors to acute nociception and persistent inflammatory pain in the rat. Immunohistochemical localization of the NMDA receptor one (NMDAR1) subunit demonstrates that 47% of unmyelinated axons in the normal digital nerve are positively labeled. In concert with the overall progression of inflammation following injection of complete Freund's adjuvant (CFA) in the hind paw, a significant increase in the proportion of NMDAR1-labeled unmyelinated digital axons occurs at 2 and 7, but not 14 days following hind-paw inflammation. In behavioral studies, we confirm an increased mechanical sensitivity in CFA-injected hind paws. Furthermore, activation of NMDA receptors following intraplantar NMDA (1.0 mM) in normal animals results in a mechanical sensitivity similar to that observed in inflamed animals. Conversely, a low concentration of NMDA (0.5 mM) that has little affect on mechanical thresholds in normal animals produces a significant increase in mechanical sensitivity in the inflamed state. CFA-induced mechanical sensitivity involves NMDA-receptor activation demonstrated by the observation that injection of MK-801 alone into the inflamed hind paw returns mechanical sensitivity to normal (pre-inflammation) levels. In single-unit studies, there is a dose-dependent increase in NMDA-induced nociceptor activity in both normal and inflamed skin, but the amount of NMDA required to induce activation is reduced in inflamed skin. In addition, NMDA-induced discharge rates and percentage of NMDA-activated nociceptors are significantly increased in inflamed compared with normal skin, and this activation can be blocked by co-administration of MK-801. Exposure of nociceptors in normal skin to 1 mM NMDA sensitizes the units to reapplication of NMDA and to heat. Nociceptors that demonstrate sensitization to heat in persistent inflammation show an enhanced sensitization when exposed to exogenous NMDA. Thus, peripheral NMDA receptors not only play an important role in modulating the responses of nociceptors in normal skin, but their upregulation and activation on peripheral nociceptors contributes significantly to the mechanical sensitivity and heat sensitization that accompanies persistent inflammation.

Action Potentials↗

PubMed2003

A role for peripheral somatostatin receptors in counter-irritation-induced analgesia.

Our hypothesis is that peripheral somatostatin (SRIF) has a role in counter-irritation-induced analgesia. Our paradigm involves the reduction of nociceptive behaviors produced by primary noxious stimuli (formalin or complete Freund's adjuvant [CFA] in the rat hind paw) by a counter-irritating stimulus (capsaicin [CAP] in the tail or muzzle). Activation of peripheral SRIF receptors is key since an SRIF receptor antagonist cyclo-somatostatin (c-SOM) and SRIF antibodies in the hind paw attenuate the counter-irritation-induced analgesia of both formalin and more persistent CFA nociception. Specificity of c-SOM is shown by reversal of its effects with octreotide, a SRIF analog. Injection of formalin in one hind paw and c-SOM in the other does not reduce the counter-irritation analgesia demonstrating local action of the c-SOM. Approximately 33% of peripheral sensory axons contain SRIF, which could release the peptide to activate SRIF receptors on cutaneous axons. Intraplantar naloxone has no effect on the counter-irritation analgesia indicating that SRIF is not activating opioid receptors. These results indicate that in addition to the classic central descending noxious inhibitory control systems that underlie counter-irritation-induced analgesia, there is a peripheral contribution arising from activation of SRIF receptors. Identifying a peripheral contribution of SRIF to mechanisms of counter-irritation analgesia offers opportunities for peripheral therapy.

Analgesia↗

PubMed2001

Metabotropic glutamate 1alpha receptors on peripheral primary afferent fibers: their role in nociception.

Several lines of evidence indicate that Group I metabotropic glutamate (mGlu) 1alpha receptors are involved in the processing of nociceptive information in the spinal cord. The goals of the present study are to document the role of mGlu1alpha receptors in peripheral nociception. To accomplish this we investigate the presence of mGlu1alpha receptors on peripheral primary afferent fibers and determine the behavioral effects of (S)-3,5-dihydroxyphenylglycine (S-DHPG), which is an mGlu1/5 receptor agonist and (RS)-1-aminoindan-1, 5-dicarboxylic acid (AIDA), a selective mGluR1alpha antagonist, on mechanical and thermal sensitivity and formalin-induced nociceptive behaviors. The anatomical studies at the electron microscopic level demonstrate that 32.4+/-2.9% of the unmyelinated axons and 21.6+/-4.7% of the myelinated axons are positively immunostained for mGlu1alpha receptors. Intraplantar injection of 0.1 or 1 mM S-DHPG results in a significant increase in mechanical sensitivity that persists for more than 60 min and this effect is blocked by co-injection of S-DHPG with 1 mM AIDA. Intraplantar injection of 40 microM AIDA+2% formalin significantly attenuates phase 2 lifting/licking and flinching behavior and this AIDA-induced effect is blocked with co-injection of 1 microM S-DHPG. In behavioral tests, intraplantar S-DHPG (0.1, 1.0, 10 mM) does not change tail flick latencies or paw withdrawal latencies to heat stimulation. These data indicate that mGlu1alpha receptors are present on peripheral cutaneous axons and activation of peripheral mGlu1alpha receptors contributes to mechanical allodynia and inflammatory pain but not thermal hyperalgesia.

Animals↗

PubMed2001

Peripheral capsaicin receptors increase in the inflamed rat hindpaw: a possible mechanism for peripheral sensitization.

The vanilloid receptor-1 (VR1) is activated by capsaicin, heat and protons and is localized on primary sensory neurons. The present study investigates whether VR1 increases in the inflamed hindpaw thereby contributing to the peripheral sensitization and heat hyperalgesia that characterizes the inflamed state. Forty-eight hours after intraplantar injection of Complete Freund's Adjuvant into one hindpaw, there is a significant increase in the proportion of VR1-labeled unmyelinated axons in digital nerves in the inflamed (32.8 +/- 5.9%) compared to normal (17.1 +/- 2.6%) hindpaws (t-test, P<0.01). A few, small diameter myelinated axons are labeled in normal and inflamed rats with no change in percentages following inflammation. The data suggest that an increase in number of unmyelinated sensory axons expressing VR1 may be one mechanism underlying peripheral sensitization of nociceptors in inflammation.

Animals↗

PubMed2001

Tonic control of peripheral cutaneous nociceptors by somatostatin receptors.

The peptide somatostatin [somatotropin release-inhibiting factor (SRIF)] is widely distributed in the body and exerts a variety of hormonal and neural actions. Several lines of evidence indicate that SRIF is important in nociceptive processing: (1) it is localized in a subset of small-diameter dorsal root ganglion cells; (2) activation of SRIF receptors results in inhibition of both nociceptive behaviors in animals and acute and chronic pain in humans; (3) SRIF inhibits dorsal horn neuronal activity; and (4) SRIF reduces responses of joint mechanoreceptors to noxious rotation of the knee joint. The goal of the present study is to show that cutaneous nociceptors are under the tonic inhibitory control of SRIF. This is accomplished using behavioral and electrophysiological paradigms. In a dose-dependent manner, intraplantar injection of the SRIF receptor antagonist cyclo-somatostatin (c-SOM) results in nociceptive behaviors in normal animals and enhancement of nociceptive behaviors in formalin-injected animals, and these actions can be blocked when c-SOM is coapplied with three different SRIF agonists. Furthermore, intraplantar injection of SRIF antiserum also results in nociceptive behaviors. Electrophysiological recordings using an in vitro glabrous skin-nerve preparation show increased nociceptor activity in response to c-SOM, and this increase is blocked by the same three SRIF agonists. Parallel behavioral and electrophysiological studies using the opioid antagonist naloxone demonstrate that endogenous opioids do not maintain a tonic inhibitory control over peripheral nociceptors, nor does opioid receptor antagonism influence peripheral SRIF effects on nociceptors. These findings demonstrate that SRIF receptors maintain a tonic inhibitory control over peripheral nociceptors, and this may contribute to mechanisms that control the excitability of these terminals.

Animals↗

PubMed2001

Glutamate-induced excitation and sensitization of nociceptors in rat glabrous skin.

Anatomical studies demonstrate the presence of glutamate receptors on unmyelinated axons in peripheral cutaneous nerves. Pharmacological studies show that intraplantar injection of glutamate or glutamate agonists in the glabrous skin results in nociceptive behaviors. The present study describes a novel in vitro skin-nerve preparation using the glabrous skin from the rat hindpaw. In the first series of experiments, recordings were obtained from 141 fibers that responded to a strong mechanical search stimulus. Based on their conduction velocity they were classified as C (27%), A delta (28%) and A beta (45%) fibers. The C and A delta fibers typically exhibited sustained firing during suprathreshold mechanical stimuli whereas both rapidly (66%) and slowly (34%) adapting responses were obtained from A beta fibers. Noxious heat excited 46% of the C fibers but only 12% of the A delta units. In another series of experiments application of an ascending series of glutamate concentrations (10, 100, 300, and 1000 microM) to A delta (n=14) and C (n=19) nociceptors resulted in a significant excitation of 43% (6/14) A delta fibers and 68% (13/19) C fibers. At these concentrations, there was no excitation of A beta units (n=13). Superfusion of the receptive fields of either mechanoheat-sensitive A (AMH, n=10) or C fibers (CMH, n=12) for 2 min with 300 microM glutamate resulted in sensitization of 90% (9/10) AMH and 92% (11/12) CMH fibers to subsequent thermal stimulation. This was evidenced by a significant (1) decrease in thermal threshold for activation, (2) increase in discharge rate, and (3) increase in peak instantaneous frequencies during the second heat trial. Glutamate-induced sensitization to heat occurred in the absence of either a glutamate-induced excitation or an initial heat response. Exposure of A delta or C fibers to glutamate did not result in a decrease in von Frey thresholds. These data provide a physiological basis for the nociceptive behaviors that arise following intraplantar injection of glutamate or glutamate agonists. Furthermore, demonstration of glutamate-induced excitation and heat sensitization of nociceptors indicates that local or topical administration of glutamate receptor antagonists may have therapeutic potential for the treatment of pain.

Animals↗

PubMed2001

Localization of metabotropic glutamate receptors 2/3 on primary afferent axons in the rat.

The goal of the present study is to determine the relationship of metabotropic glutamate receptors 2/3 (mGluR2/3) to dorsal root ganglion cells, peripheral primary afferent fibers in digital nerves and central primary afferent fibers in the spinal cord. We demonstrate that approximately 40% of L4 and L5 dorsal root ganglion cells contain mGluR2/3-like immunoreactivity. These mGluR2/3-positive cells are small in diameter (23 microm) and 76% stain for the isolectin Griffonia simplicifolia (I-B4), while 67% of I-B4 cells have mGluR2/3-like immunoreactivity. Electron microscopic analyses of mGluR2/3-like immunoreactivity in axons in digital nerves indicate that 32% of unmyelinated and 28% of myelinated axons are labeled. In the lumbar dorsal horn, mGluR2/3-like immunoreactivity is localized preferentially in lamina IIi with lighter staining in laminae III and IV. The dense mGluR2/3-like immunoreactivity in lamina IIi is consistent with the localization of these receptors in I-B4-labeled dorsal root ganglion cells. Elimination of primary afferent input following unilateral dorsal rhizotomies significantly decreases the mGluR2/3-like immunoreactivity density in the dorsal horn although some residual staining does remain, suggesting that many but not all of these receptors are located on primary afferent processes. The finding that mGluR2/3s are located on peripheral sensory axons suggests that they are involved in peripheral sensory transduction and can modulate transmission of sensory input before it reaches the spinal cord. This offers the possibility of altering sensory input, particularly noxious input, at a site that would avoid CNS side effects. Since many but not all of these receptors are located on primary afferent terminals, these receptors may also influence primary afferent transmission in the dorsal horn through presynaptic mechanisms and glutamatergic transmission in general through both presynaptic and postsynaptic mechanisms. Since these receptors are concentrated in lamina IIi and also largely co-localized with I-B4, they may have considerable influence on nociceptive processing by what are considered to be non-peptidergic primary afferent neurons.

Animals↗

PubMed2001

Peripheral excitatory amino acids.

Glutamate receptors (GluRs) are localized in the periphery on nociceptive primary afferent terminals. Studies in animal models of pain demonstrate that peripheral glutamate is involved in nociceptive transmission in the normal and the inflamed state and that modulation of peripheral GluRs reduces pain behaviors and nociceptor activity. These data provide strong motivation to develop new pharmacological agents that will target peripheral GluRs, offering novel approaches to treatment of pain of peripheral origin.

Animals↗

PubMed2001

Peripheral group I metabotropic glutamate receptors modulate nociception in mice.

The metabotropic glutamate receptors (mGluRs) are found throughout the central nervous system, where they modulate neuronal excitability and synaptic transmission. Here we report the presence of phospholipase C-coupled group I mGluRs (mGluR1 and mGluR5) outside the central nervous system on peripheral unmyelinated sensory afferents. Given their localization on predominantly nociceptive afferents, we investigated whether these receptors modulate nociceptive signaling, and found that agonist-induced activation of peripheral group I mGluRs leads to increased sensitivity to noxious heat, a phenomenon termed thermal hyperalgesia. Furthermore, group I mGluR antagonists not only prevent, but also attenuate established formalin-induced pain. Taken together, these results suggest that peripheral mGluRs mediate a component of hyperalgesia and may be therapeutically targeted to prevent and treat inflammatory pain.

Animals↗

PubMed2001

Placenta increta/percreta associated with uterine perforation during therapy for fetal death. A case report.

BACKGROUND: Placenta accreta involves abnormal adherence of the placenta to the myometrium. Placenta increta and percreta are defined by the degree of trophoblastic penetration of the myometrium. These conditions are rarely observed in the first trimester; placenta increta and percreta are exceptionally infrequent. CASE: A woman had a uterine perforation after suction curettage for fetal death at 11 weeks' gestation, requiring hysterectomy for control of a profuse hemorrhage. Histopathologic examination of the uterus revealed placenta increta involving the lower uterine segment and placenta percreta at the site of uterine perforation. CONCLUSION: This is the first report of placenta percreta associated with uterine perforation during therapy for first-trimester fetal death.

Adult↗

PubMed2000

Localization of ionotropic glutamate receptors in peripheral axons of human skin.

Recent observations suggest that glutamate is important in sensory transduction in the periphery, contributing to peripheral sensitization of nociceptors and the hyperalgesia that accompanies inflammation. This study examined the presence of ionotropic glutamate receptors N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazolone-4-propionic acid (AMPA) and kainate (KA) in normal human hairy skin (n=6) using immunohistochemistry at the electron microscopic level. Analysis of labeled axons at the dermal-epidermal junction demonstrated that 26. 9+/-2, 19.5+/-3 and 18.5+/-1% of the axons analyzed were labeled for subunits of the NMDA, AMPA or KA receptors, respectively. An occasional Schwann cell process was labeled for either NMDA or KA receptors. The findings support the hypothesis that glutamate and its ionotropic receptors may play a role in the periphery in sensory processing in humans.

Axons↗

PubMed2000

Peripheral glutamate release in the hindpaw following low and high intensity sciatic stimulation.

The present study demonstrates that following A and/or C fiber stimulation of the sciatic nerve, glutamate levels increase significantly in the hindpaw extracellular space. In hindpaw dialysate, electrical stimulation (5 min) of the sciatic nerve at 2x, 20x, 50x or 200x threshold current required to produce a muscle twitch resulted in peak glutamate increases of 120.8 +/- 9%, 134.3 +/- 5%, 153.9 +/- 10% and 150.5 +/- 5% of basal levels, respectively. Application of 1% capsaicin to the sciatic nerve (10 min) to selectively activate C fibers resulted in a peak glutamate increase of 130.8 +/- 8% of basal levels. Aspartate levels did not change significantly in either paradigm. These data indicate that low and high intensity stimulation can result in peripheral release of glutamate, providing a major source of ligand for the glutamate receptors localized on peripheral primary afferents.

Amino Acids↗

PubMed1999

Inflammation-induced changes in peripheral glutamate receptor populations.

The ionotropic glutamate receptors N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) have been localized on subpopulations of unmyelinated and myelinated sensory axons in normal skin. Behavioral studies indicate that activation of these receptors results in nociceptive behaviors and contributes to inflammatory pain. The goal of the present study was to determine if these glutamate receptors might contribute to the peripheral hypersensitivity observed in inflammation. The major findings were that 48 h following complete Freund's adjuvant (CFA)-induced inflammation, the proportions of unmyelinated axons labeled for NMDA, AMPA or KA receptors were 61%, 43% and 48%, respectively, in cutaneous nerves in the inflamed paw compared to 48%, 22% and 27%, respectively, in the non-inflamed paw. The proportions of myelinated axons labeled for NMDA, AMPA or KA receptors were 61%, 61% and 43%, respectively, compared to 43%, 42% and 28%, respectively, in the non-inflamed hindpaw. These increases were all significant. These data indicate that the number of sensory axons containing ionotropic glutamate receptors increases during inflammation, and this may be a contributing factor to peripheral sensitization in inflammation.

Animals↗

PubMed1999

Evidence for an inflammation-induced change in the local glutamatergic regulation of postganglionic sympathetic efferents.

Sympathetic efferents are involved in the pain of inflammation. Thus the control of these fibers is a matter of considerable importance. In this regard, postganglionic sympathetic fibers in normal rats express ionotropic glutamate receptors. The present study tests the hypothesis that inflammation leads to a significant increase in numbers of sympathetic efferents that express these receptors. In normal rats, the percentage of fibers in the L4 and L5 sympathetic gray rami immunostained with antibodies against subunits of NMDA (NMDAR1), AMPA (GluR1), or kainate (GluR5,6,7) receptors are 29, 5 and 5%, respectively. Forty-eight hours following injection of complete Freund's adjuvant into one hindpaw, the percentages of fibers in the ipsilateral gray rami immunostained for NMDA, AMPA or kainate are 57, 52 and 48%, respectively. Thus, following inflammation there is a two-fold increase in axons expressing NMDA receptors and a ten-fold increase in axons expressing AMPA or kainate receptors. These data suggest that postganglionic activity may be enhanced by glutamate receptor activation during inflammation. Increased activity in postganglionic fibers could lead to an increased release of NE and other substances in postganglionic efferents such as prostaglandins which in turn could enhance nociceptor activity. This change in glutamate receptor organization offers a possible site of pharmacological intervention for the maladaptive symptoms that often arise following peripheral inflammation.

Animals↗

PubMed1999

Peripheral GABA(A) receptors: evidence for peripheral primary afferent depolarization.

We propose that the primary afferent depolarization that follows GABA(A) receptor activation in the spinal cord also occurs in the periphery. As evidence, the present study localizes beta2/beta3 and alpha1 subunits of the GABA(A) receptor on 10-14% of the unmyelinated primary afferents axons in the glabrous skin of the cat paw. Behavioral studies demonstrate that local peripheral injection of the GABA(A) agonist muscimol at a low concentration (2.0 microM) attenuates, and at a high concentration (1 mM) enhances, formalin-induced nociceptive behaviors. Intraplantar injection of muscimol alone at a high dose evokes thermal hyperalgesia. Bicuculline, a GABA(A) antagonist, prevents these muscimol-induced changes in behavior. The muscimol-induced effects are due to local rather than systemic or central activation of GABA(A) receptors, as such effects are not observed in the contralateral paw. We interpret these findings to indicate that activation of GABA(A) receptors by low concentrations of muscimol depolarizes peripheral primary afferent terminals, a phenomenon we call peripheral primary afferent depolarization, in turn reducing the size of the peripheral action potentials and concomitantly reducing the amount of algogenic substances released from the peripheral terminals of these fibers. This sequence of events presumably results in a reduction in nociceptor activation. Higher concentrations of muscimol further depolarize GABA(A) receptor-containing terminals, which then initiates action potentials in nociceptors analogous to the appearance of dorsal root reflexes that arise following activation of GABA(A) receptors on central primary afferent terminals. These latter events reverse the analgesic effects of GABA(A) ligands and lead to potentiation of nociceptive input. Thus, the present study provides anatomical and behavioral evidence supporting a bimodal role for GABA(A) receptors in the modulation of peripheral nociceptive transmission.

Animals↗