7-benzylidenenaltrexone and Pain

Opioid analgesic tolerance remains a considerable drawback to chronic pain management. The finding that concomitant administration of delta opioid receptor (DOR) antagonists attenuates the development of tolerance to mu opioid receptor (MOR) agonists has led to interest in producing bifunctional MOR agonist/DOR antagonist ligands. Herein, we present 7-benzylideneoxymorphone (6, UMB 246) displaying MOR partial agonist/DOR antagonist activity, representing a new lead for designing bifunctional MOR/DOR ligands.

Topics: Analgesics; Animals; Benzylidene Compounds; Ligands; Mice; Oxymorphone; Pain; Receptors, Opioid, delta; Receptors, Opioid, mu

Two highly selective mu-opioid receptor agonists, endomorphin-1 and endomorphin-2, have been identified and postulated to be endogenous ligands for mu-opioid receptors. Intrathecal (i.t.) administration of endomorphin-1 and endomorphin-2 at doses from 0.039 to 5 nmol dose-dependently produced antinociception with the paw-withdrawal test. The paw-withdrawal inhibition rapidly reached its peak at 1 min, rapidly declined and returned to the pre-injection levels in 20 min. The inhibition of the paw-withdrawal responses to endomorphin-1 and endomorphin-2 at a dose of 5 nmol observed at 1 and 5 min after injection was blocked by pretreatment with a non-selective opioid receptor antagonist naloxone (1 mg/kg, s.c.). The antinociceptive effect of endomorphin-2 was more sensitive to the mu (1)-opioid receptor antagonist, naloxonazine than that of endomorphin-1. The endomorphin-2-induced paw-withdrawal inhibition at both 1 and 5 min after injection was blocked by pretreatment with kappa-opioid receptor antagonist nor-binaltorphimine (10 mg/kg, s.c.) or the delta(2)-opioid receptor antagonist naltriben (0.6 mg/kg, s.c.) but not the delta(1)-opioid receptor antagonist 7-benzylidine naltrexone (BNTX) (0.6 mg/kg s.c.). In contrast, the paw-withdrawal inhibition induced by endomorphin-1 observed at both 1 and 5 min after injection was not blocked by naloxonazine (35 mg/kg, s.c.), nor-binaltorphimine (10 mg/kg, s.c.), naltriben (0.6 mg/kg, s.c.) or BNTX (0.6 mg/kg s.c.). The endomorphin-2-induced paw-withdrawal inhibition was blocked by the pretreatment with an antiserum against dynorphin A-(1-17) or [Met(5)]enkephalin, but not by antiserum against dynorphin B-(1-13). Pretreatment with these antisera did not affect the endomorphin-1-induced paw-withdrawal inhibition. Our results indicate that endomorphin-2 given i.t. produces its antinociceptive effects via the stimulation of mu (1)-opioid receptors (naloxonazine-sensitive site) in the spinal cord. The antinociception induced by endomophin-2 contains additional components, which are mediated by the release of dynorphin A-(1-17) and [Met(5)]enkephalin which subsequently act on kappa-opioid receptors and delta(2)-opioid receptors to produce antinociception.

Topics: Analgesics; Animals; Benzylidene Compounds; Dose-Response Relationship, Drug; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalin, Methionine; Immune Sera; Injections, Spinal; Injections, Subcutaneous; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain; Pain Measurement; Pain Threshold; Peptide Fragments; Time Factors

The duration of the somatostatin-, bradykinin- or prostaglandin F2alpha-induced nociceptive response was significantly less in diabetic mice than in non-diabetic mice. Subcutaneous injection of 7-benzylidenenaltrexone (0.1, 0.3 and 1 mg/kg), an antagonist of delta1-opioid receptors, had no significant effect on either somatostatin-, bradykinin- or prostaglandin F2alpha-induced nociceptive responses in non-diabetic mice. 7-Benzylidenenaltrexone (0.1 and 0.3 mg/kg, s.c.) also had no significant effect on somatostatin- or prostaglandin F2alpha-induced nociceptive responses in diabetic mice. However, the bradykinin-induced nociceptive response in diabetic mice was dose-dependently and significantly increased when 7-benzylidenenaltrexone (0.1, 0.3 and 1 mg/kg, s.c.) was injected 10 min before the injection of bradykinin. These results suggest that a spinal delta1-opioid receptor-mediated endogenous antinociceptive system may inhibit the bradykinin-mediated nociceptive responses in the second phase of the formalin-induced nociceptive response in diabetic mice.

Topics: Animals; Benzylidene Compounds; Bradykinin; Diabetes Mellitus, Experimental; Dinoprost; Dose-Response Relationship, Drug; Formaldehyde; Injections, Subcutaneous; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Pain; Receptors, Opioid, delta; Somatostatin

CD-1 mice were treated intravenously with streptozotocin, 200 mg/kg, and tested 2 weeks later or treated with 60 mg/kg and tested 3 days later. Both treatments changed the tail flick response of heroin and 6-monoacetylmorphine (6 MAM) given intracerebroventricularly from a mu- to delta-opioid receptor-mediated action as determined by differential effects of opioid receptor antagonists. The response to morphine remained mu. Heroin and 6 MAM responses involved delta1 (inhibited by 7-benzylidenenaltrexone) and delta2 (inhibited by naltriben) receptors, respectively. These delta-agonist actions did not synergize with the mu-agonist action of morphine in the diabetic mice. The expected synergism between the delta agonist, [D-Pen2-D-Pen5]enkephalin (DPDPE), and morphine was not obtained in diabetic mice. Thus, diabetes disrupted the purported mu/delta-coupled response. In nondiabetic CD-1 mice, heroin and 6 MAM produced a different mu-receptor response (not inhibited by naloxonazine) from that of morphine (inhibited by naloxonazine). Also, these mu actions, unlike that of morphine, did not synergize with DPDPE. The unique receptor actions and changes produced by streptozotocin suggest that extrinsic in addition to genetic factors influence the opioid receptor selectivity of heroin and 6 MAM.

Topics: Analgesics, Opioid; Animals; Anti-Bacterial Agents; Benzylidene Compounds; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Interactions; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Heroin; Injections, Intraventricular; Male; Mice; Morphine; Morphine Derivatives; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Receptors, Opioid, delta; Receptors, Opioid, mu; Streptozocin; Time Factors

Physiological as well as hormone-simulated pregnancy (HSP) is associated with opioid-mediated elevations in maternal nociceptive thresholds. Previous reports from this laboratory have demonstrated the involvement of spinal cord kappa opiate receptors in this phenomenon. The present study was undertaken in order to determine the exclusivity of this mediation. Intrathecal (i.t.) administration of the delta opiate receptor-selective antagonists naltrindole (NTI), 7-benzylidenenaltrexone (BNTX) or naltriben (NTB) substantially reduces nociceptive thresholds of gestation (day 20) and HSP (day 19). Hyperalgesic actions of these compounds following i.t. administration are not observed in non-pregnant or vehicle-treated control animals. These data indicate that delta opiate receptor activity is a prerequisite for the manifestation of a substantial portion of gestational and HSP analgesia. In contrast, i.t. application of the micro-selective antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) has no effect on nociceptive thresholds of gestational day 20, as was previously demonstrated for HSP-induced antinociception. Thus, the potent spinal mu analgesic system does not participate in gestational or HSP analgesia. During physiological pregnancy, less robust constituents of intrinsic opioid pain-attenuating systems in the spinal cord (delta and kappa opioid systems) are recruited to mediate the maternal antinociception of gestation. Furthermore, the ability of estrogen and progesterone to modulate spinal opioid antinociceptive activity emphasizes potential differences between men and women in their response to pain medication.

Topics: Animals; Benzylidene Compounds; Female; Humans; Injections, Spinal; Male; Naltrexone; Narcotic Antagonists; Pain; Pregnancy; Pregnancy, Animal; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Sensory Thresholds; Sex Characteristics; Spinal Cord; Time Factors

The purpose of this study was to determine which delta (delta) opioid receptor subtype, delta 1 or delta 2, was involved in producing the antinociceptive action of heroin and 6-monacetylmorphine (MAM) in Swiss Webster mice. Previous work from this laboratory established that heroin and MAM, given intracerebroventricularly (i.c.v.) in Swiss Webster mice, produce antinociception through activation of supraspinal delta receptors. Naltrindole, but not naloxone or nor-binaltorphimine, antagonizes the inhibitory action of heroin and MAM in the tail-flick test. Recent literature documents the occurrence of subtypes of the delta opioid receptor and the availability of selective antagonists. 7-Benzylidenenaltrexone (BNTX) antagonizes the antinociception induced by delta 1 receptor agonists without affecting that induced by delta 2 receptor agonists. Naltriben (NTB) selectively inhibits delta 2- but not delta 1-induced antinociception. In the present study BNTX and NTB were administered i.c.v. with heroin and MAM to determine the delta receptor subtype responsible for inhibition of the tail-flick response in Swiss Webster mice. The ED50 for heroin-induced antinociception was increased 19-fold by BNTX and was not altered by NTB administration. On the other hand, the ED50 value of MAM was increased 3-fold by NTB and was not altered by BNTX administration. These results suggest that heroin activated supraspinal delta 1 receptors and MAM acted on supraspinal delta 2 receptors to produce antinociception in Swiss Webster mice.

Topics: Animals; Benzylidene Compounds; Heroin; Male; Mice; Morphine Derivatives; Naltrexone; Pain; Receptors, Opioid, delta

Pharmacological evidence for the existence of delta-opioid receptor subtypes has been reported. This study was conducted to determine which type of delta-opioid receptors was involved supraspinally and spinally when antinociception was induced by the natural enkephalins, [Leu5]enkephalin and [Met5]enkephalin. In the mouse tail flick assay, the antinociceptive ED50 values of both intracerebroventricularly (i.c.v.) administered [Leu5]enkephalin and [Met5]enkephalin (together with the peptidase inhibitors, bestatin and thiorphan) were significantly increased by 7-benzylidenenaltrexone (BNTX), a selective delta 1-opioid receptor antagonist but not by naltriben, a selective delta 2-opioid receptor antagonist. On the other hand, when the enkephalins were administered intrathecally (i.t.), the antinociceptive ED50 values of both enkephalins were significantly raised by naltriben but not by BNTX. beta-Endorphin-induced (i.c.v.) antinociception was antagonized by naltriben administered i.t. or s.c. but not by BNTX administered i.t. or s.c. Different delta-opioid receptor subtypes appeared to be involved in supraspinal (delta 1) and spinal (delta 2) antinociception induced by endogenous delta-opioid receptor agonists, [Leu5] and [Met5]enkephalin. The antinociception produced by i.c.v. administered beta-endorphin has been attributed to the release of [Met5]enkephalin in the spinal cord and its antagonism by naltriben support the finding that enkephalins interact with delta 2-opioid receptors in the spinal cord to mediate antinociception. beta-Endorphin may be interacting at receptors other than delta 1- or delta 2-opioid receptors in the brain, perhaps the putative epsilon receptors, to mediate their effects because neither i.c.v. administered BNTX nor naltriben inhibited its activity.

Topics: Animals; Benzylidene Compounds; beta-Endorphin; Brain; Enkephalin, Leucine; Enkephalin, Methionine; Injections, Intraventricular; Injections, Spinal; Male; Mice; Naltrexone; Pain; Receptors, Opioid, delta; Spinal Cord