Effects of Opioids on Mechanosensitive Pelvic Nerve Afferent Fibers Innervating the Urinary Bladder of the Rat

Su, X., J. N. Sengupta, and G. F. Gebhart. Effects of opioids on mechanosensitive pelvic nerve afferent fibers innervating the urinary bladder of the rat. J. Neurophysiol. 77: 1566–1580, 1997. A total of 443 pelvic nerve afferent fibers in the L6 dorsal root of the rat were identified by electrical stimulation of the pelvic nerve; 319 (72%) were myelinated Aδ fibers with a mean conduction velocity (CV) of 11.8 m/s and 124 (28%) were unmyelinated C fibers with mean CV of 1.9 m/s. Two hundred fifty-two fibers (57%) responded to noxious urinary bladder distension (UBD; 80 mmHg); 108 were C fibers (mean CV: 1.9 m/s) and 144 were Aδ fibers (mean CV: 8.2 m/s). Forty-nine UBD-sensitive fibers were further characterized; all gave monotonic increases in firing to increasing distending pressures. Thirty-six fibers (73%) had a low-threshold (LT) for response (mean: 6 mmHg) and 13 fibers (27%) had high-thresholds (HT) for response (mean: 32 mmHg). Responses of 15 fibers to graded UBD (11 LT and 4 HT) were tested before and after instillation of 0.5 ml of 30% xylenes ( n = 11) or 5% mustard oil ( n = 4) into the bladder. The mean resting activity of 13 fibers significantly increased, and 7 fibers exhibited sensitization of responses to graded UBD 30 min after xylenes or mustard oil instillation. All 4 HT fibers were sensitized; 3 of the 11 LT fibers were sensitized (i.e., gave increased responses to UBD). The effects of opioid receptor agonists were tested on responses to noxious UBD (80 mmHg). Cumulative intraaterial doses of μ-opioid receptor agonists (morphine, 8 mg/kg, and fentanyl, 300 μg/kg) and of δ-opioid receptor agonists (DPDPE, 300 μg/kg, and SNC-80, 300 μg/kg) did not affect responses to noxious UBD. In contrast, cumulative 16 mg/kg intraarterial doses of the κ-opioid receptor agonists U50,488H, U69,593 and U62,066 dose-dependently attenuated responses to noxious UBD. There were no differences in the dose-response relationships of these drugs on afferent fibers from untreated and xylenes- or mustard oil-treated urinary bladder. These results reveal that there is a greater proportion of UBD-sensitive fibers in the L6 dorsal root (57%) than in the S1 dorsal root of the rat (38%; a previous study). The attenuation of responses to UBD by κ, but not μ or δ opioid receptor agonists suggests a potential use for peripherally acting κ opioid receptor agonists in the control of urinary bladder pain.

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Differential Effects of μ-, δ-, and κ-Opioid Receptor Agonists on Mechanosensitive Gastric Vagal Afferent Fibers in the Rat

Journal of Neurophysiology ◽

10.1152/jn.2000.83.4.2209 ◽

2000 ◽

Vol 83 (4) ◽

pp. 2209-2216 ◽

Cited By ~ 48

Author(s):

Noriyuki Ozaki ◽

J. N. Sengupta ◽

G. F. Gebhart

Keyword(s):

Opioid Receptor ◽

Receptor Agonist ◽

Dose Range ◽

Receptor Agonists ◽

Afferent Fibers ◽

Opioid Receptor Agonist ◽

Resting Activity ◽

Vagal Afferent ◽

Δ Opioid Receptor ◽

Opioid Receptor Agonists

Single-fiber recordings were made from the decentralized right cervical vagus nerve (hyponodosal) of the rat. A total of 56 afferent fibers that responded to gastric distension (GD) were studied: 6 fibers were stimulated by phasic balloon GD, 50 by fluid GD. All fibers gave increasing responses to increasing pressures of GD (5–60 mmHg). The effects of μ-opioid (morphine), δ-opioid (SNC80), and κ-opioid (EMD61,753, U62,066) receptor agonists were tested on responses of afferent fibers to GD. Morphine, administered systemically over a broad dose range (10 μg to 31 mg/kg, cumulative), had no effect on either resting activity or responses of vagal afferent fibers to GD. Similarly, the δ-opioid receptor agonist SNC80 (0.05–3.2 mg/kg) did not affect resting activity or responses to GD. In contrast, cumulative intra-arterial doses of the κ-opioid receptor agonist EMD61,753 or U62,066 dose dependently attenuated afferent fiber responses to GD. Doses producing inhibition to 50% of the control response to GD of EMD61,753 (8.0 mg/kg) and U62,066 (8.8 mg/kg) did not differ. The effect of U62,066 was moderately attenuated by a nonselective dose (4 mg/kg) of naloxone hydrochloride; the κ-opioid receptor-selective antagonist nor-BNI (20 mg/kg) was ineffective. These results demonstrate that κ-, but not μ- or δ-opioid receptor agonists modulate visceral sensation conveyed by vagal afferent fibers innervating the stomach. Given that κ-opioid receptor agonists effects were only modestly antagonized by naloxone and not at all by nor-BNI, the results point to a novel site of action.

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Effects of Kappa Opioid Receptor-Selective Agonists on Responses of Pelvic Nerve Afferents to Noxious Colorectal Distension

Journal of Neurophysiology ◽

10.1152/jn.1997.78.2.1003 ◽

1997 ◽

Vol 78 (2) ◽

pp. 1003-1012 ◽

Cited By ~ 70

Author(s):

X. Su ◽

J. N. Sengupta ◽

G. F. Gebhart

Keyword(s):

Opioid Receptor ◽

Dorsal Root ◽

Afferent Fiber ◽

Kappa Opioid Receptor ◽

Receptor Subtypes ◽

Pelvic Nerve ◽

Colorectal Distension ◽

Receptor Agonists ◽

Afferent Fibers ◽

Selective Agonists

Su, X., J. N. Sengupta, and G. F. Gebhart. Effects of kappa opiois receptor-selective agonists on responses of pelvic nerve afferents to noxious colorectal distension. J. Neurophysiol. 78: 1003–1012, 1997. The aim of this study was to examine the effects of κ-opioid receptor selective agonists on responses of mechanosensitive afferent fibers in the pelvic nerve. Single-fiber recordings were made from pelvic nerve afferents in the decentralized S1 dorsal root of the rat. A total of 572 afferent fibers in the S1 dorsal root were identified by electrical stimulation of the pelvic nerve; 252 (44%) responded to noxious colorectal distension (CRD; 80 mmHg). Of these 252 fibers that responded to CRD, 100 were studied further. All 100 fibers gave monotonic increases in firing to increasing pressures of CRD. Eighty-eight fibers had low thresholds for response (mean: 3 mmHg) and 12 fibers had high-thresholds for response (mean: 28 mmHg). Responses of 17 fibers also were tested after instillation of 5% mustard oil (MO) into the colon. The resting activity of 16/17 fibers significantly increased after MO instillation; 13 (77%) also exhibited sensitization of responses to graded CRD when tested 30 min after intracolonic MO instillation. The effects of κ1-opioid receptor preferring agonists (U50,488H, U69,593 and U62,066), the κ2-opioid receptor preferring agonist bremazocine, and the κ3-opioid receptor preferring agonist naloxone benzoylhydrazone (nalBzoH) were tested on responses of 64 mechanosensitive afferent fibers to noxious CRD. All five agonists dose-dependently inhibited afferent fiber responses to noxious CRD. Doses producing inhibition to 50% of the control response to CRD did not differ among the five agonists, ranging from ∼4 to 15 mg/kg. The effects of κ1, κ2, and κ3 receptor agonists were attenuated by naloxone; two κ-opioid receptor-selective antagonists were ineffective. There were no differences in the dose-response relationships of these drugs for fibers recorded from untreated and irritant-treated colons. Conduction velocities of the fibers remained unaffected after high doses of all tested agonists. In an in vitro study, U50,488 (10−4 M) did not produce any significant change in the tension of colonic smooth muscle. These results document that responses of mechanosensitive pelvic nerve afferent fibers innervating the colon are inhibited by κ-opioid receptor agonists having varying affinities for putative κ-opioid receptor subtypes. The inhibitory effects of these drugs likely are mediated by an action at receptors associated with the afferent fibers. The receptor at which these effects are produced is κ-opioid-like but clearly different from the κ-opioid receptor characterized in the CNS and is perhaps an orphan receptor.

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Effects of Intracolonic Opioid Receptor Agonists on Polymodal Pelvic Nerve Afferent Fibers in the Rat

Journal of Neurophysiology ◽

10.1152/jn.2000.83.2.963 ◽

2000 ◽

Vol 83 (2) ◽

pp. 963-970 ◽

Cited By ~ 27

Author(s):

X. Su ◽

V. Julia ◽

G. F. Gebhart

Keyword(s):

Opioid Receptor ◽

Thermal Sensitivity ◽

Afferent Fiber ◽

Rat Colon ◽

Krebs Solution ◽

Pelvic Nerve ◽

Receptor Agonists ◽

Afferent Fibers ◽

Opioid Receptor Agonists

We studied the effects of intracolonic administration of opioid receptor agonists (ORAs) on responses of pelvic nerve afferent fibers to colorectal distension (CRD) and heat. Single-fiber recordings were made from the decentralized S1 dorsal rootlet in the rat. An ∼7-cm length of descending colon was isolated in situ to permit intracolonic perfusion with Krebs solution, which, when the outflow was clamped, was used to distend the colon. Responses to noxious CRD (40 mmHg, 30 s) were tested after intracolonic instillation of μ-, δ- or κ-ORAs. Intracolonic administration of the κ-ORAs EMD 61,753 ( n = 5/12) and U62,066 ( n = 8/11), but not either the μ-ORA fentanyl or the δ-ORA SNC-80, concentration-dependently inhibited responses of afferent fibers. For fibers unaffected by intracolonic administration of EMD 61,753 or U62,066, intra-arterial administration of κ-ORAs was effective. Forty-one of 54 mechanosensitive fibers also responded to intracolonic instillation of heated Krebs solution (50°C). Intra-arterial injection of fentanyl or SNC-80 did not attenuate responses to heat. Either intracolonic or intra-arterial administration of EMD 61,753 or U62,066, however, inhibited afferent fiber responses to heat. These results document that mechanical and thermal sensitivity of polymodal pelvic nerve afferent fibers innervating the rat colon can be inhibited peripherally by intracolonic instillation of κ-ORAs.

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