Systemic Morphine Analgesia Research Articles

Comparison of systemic morphine, nalbuphine, and epidural analgesia on acute and chronic postoperative pain in laparoscopic colorectal surgery: a randomized controlled trial

Comparison of systemic morphine, nalbuphine, and epidural analgesia on acute and chronic postoperative pain in laparoscopic colorectal surgery: a randomized controlled trial

Investigating the Role of the Locus Coeruleus in Periaqueductal Gray-mediated Antinociception

Activity in the ventrolateral periaqueductal gray (vlPAG) has been shown to be antinociceptive and is considered to be a major component in the expression of opioid drug-induced analgesia. Canonically, opioids disinhibit vlPAG activity, which modulates neuronal responses in the rostroventral medulla (RVM) and ultimately gates spinal outflow of nociceptive information via serotonergic and opioidergic mechanisms in the spinal dorsal horn. Fundamental pharmacological studies, however, indicate that spinal noradrenergic signaling is consistently implicated in opioid antinociception, suggesting that there is a gap in our knowledge of how the vlPAG may control the release of antinociceptive neuromodulators in the dorsal horn through different output regions. Although the locus coeruleus (LC) has been shown to modulate nociception, its role in and recruitment by the canonical descending circuitry is unclear. Using genetically-encoded and anatomically-targeted viral tools, immunohistochemistry, and acute pain behavior assays in conjunction with intrathecal pharmacology in mice, we show that activity in the vlPAG is necessary for the expression of systemic morphine analgesia at low doses, and that both systemic morphine-induced and PAG-driven antinociception require opioidergic and noradrenergic signaling in the spinal cord. Additionally, we find that vlPAG projection neurons send branching axons to both the RVM and LC, which may account for the LC activation we observed in both opioid-induced and PAG-driven antinociception. These findings reveal a previously underappreciated architecture of the descending pain modulatory circuitry and advance our understanding of the circuit mechanisms by which morphine produces analgesia. Grant support from NIDA R00 DA034648, Rita Allen Foundation (non-profit), Klingenstein-Simons Foundation (non-profit).

Preventive skin analgesia with lidocaine patch for management of post-thoracotomy pain: Results of a randomized, double blind, placebo controlled study.

BackgroundTo evaluate whether pre‐emptive skin analgesia using a lidocaine patch 5% would improve the effects of systemic morphine analgesia for controlling acute post‐thoracotomy pain.MethodsThis was a double‐blind, placebo controlled, prospective study. Patients were randomly assigned to receive lidocaine 5% patch (lidocaine group) or a placebo (placebo group) three days before thoracotomy. Postoperative analgesia was induced in all cases with intravenous morphine analgesia. The intergroup differences were assessed in order to evaluate whether the lidocaine patch 5% would have effects on pain intensity when at rest and after coughing (primary end‐point) on morphine consumption, on the recovery of respiratory function, and on peripheral painful pathways measured with N2 and P2 laser‐evoked potential (secondary end‐points).ResultsA total of 90 patients were randomized, of whom 45 were allocated to the lidocaine group and 45 to the placebo group. Lidocaine compared with the placebo group showed a significant reduction in pain intensity both at rest (P = 0.013) and after coughing (P = 0.015), and in total morphine consumption (P = 0.001); and also showed a better recovery of flow expiratory volume in one second (P = 0.025) and of forced vital capacity (P = 0.037). The placebo group compared with the lidocaine group presented a reduction in amplitude of N2 (P = 0.001) and P2 (P = 0.03), and an increase in the latency of N2 (P = 0.023) and P2 (P = 0.025) laser‐evoked potential.ConclusionsThe preventive skin analgesia with lidocaine patch 5% seems to be a valid adjunct to intravenous morphine analgesia for controlling post‐thoracotomy pain. However, our initial results should be corroborated/confirmed by larger studies.

Ultrasound-guided continuous thoracic paravertebral analgesia with bupivacaine versus continuous intravenous morphine infusion for unilateral multiple fracture ribs

Background Rib fractures are common, and pain from rib fractures can be difficult to control, particularly in first few days. This pain may affect the pulmonary functions, morbidity, and mortality. Objective The aim of this study was to compare and evaluate the efficacy of ultrasound-guided continuous thoracic paravertebral block (USG-TVPB) using bupivacaine versus continuous intravenous morphine infusion (IVMI) in pain relief for patients with unilateral multiple fractured ribs (UMFRs) and on pulmonary function improvement. Patients and methods The study included 70 ICU patients of both sexes, aged 18–60 years with ASA physical status class I to III who had unilateral three or more ribs fracture. According to the conducted method for relief of fracture rib pain, these patients were assigned into two equal groups with 35 patients in each. The first group patients (USG-TPVB) received ultrasound-guided thoracic paravertebral analgesia using bupivacaine. The second group patients (IVMI group) received intravenous morphine infusion. The recorded data included patients demographic variables, pain severity, pulmonary mechanics, arterial blood gases, hemodynamic changes, analgesic request/day, total rescue morphine analgesic dose, and total ketorolac dose over 4 days of ICU stay, and hospital stay durations, and adverse effects. Results After the start of analgesic regimen, the patients who received continuous thoracic paravertebral bupivacaine infusion (USG-TPVB group) were significantly better than those received continuous IV morphine infusion (IVMI group), where the forced vital capacity was significantly higher in USG-TPVB group than in IVMI group at 30 min, 24 h, and 48 h (P Conclusion Ultrasound-guided continuous thoracic paravertebral analgesia with bupivacaine provided better pain control with improved pulmonary functions than continuous systemic intravenous morphine analgesia in unilateral multiple rib fractures with less rescue analgesic requests, shorter length of ICU stay, and less adverse effects.

Neuron-restrictive silencer factor-mediated downregulation of μ-opioid receptor contributes to the reduced morphine analgesia in bone cancer pain.

Bone cancer pain has been reported to have unique mechanisms and is resistant to morphine treatment. Recent studies have indicated that neuron-restrictive silencer factor (NRSF) plays a crucial role in modulating the expression of the μ-opioid receptor (MOR) gene. The present study elucidates the regulatory mechanisms of MOR and its ability to affect bone cancer pain. Using a sarcoma-inoculated murine model, pain behaviors that represent continuous or breakthrough pain were evaluated. Expression of NRSF in the dorsal root ganglion (DRG) and spinal dorsal horn was quantified at the transcriptional and translational levels, respectively. Additionally, chromatin immunoprecipitation assays were used to detect NRSF binding to the promoter of MOR. Furthermore, NRSF was genetically knocked out by antisense oligodeoxynucleotide, and the expression of MOR and the effect of morphine were subsequently analyzed. Our results indicated that in a sarcoma murine model, NRSF expression is upregulated in dorsal root ganglion neurons, and the expression of NRSF mRNA is significantly negatively correlated with MOR mRNA expression. Additionally, chromatin immunoprecipitation analysis revealed that NRSF binding to the neuron-restrictive silencer element within the promoter area of the MOR gene is promoted with a hypoacetylation state of histone H3 and H4. Furthermore, genetically knocking down NRSF with antisense oligodeoxynucleotide rescued the expression of MOR and potentiated the systemic morphine analgesia. The present results suggest that in sarcoma-induced bone cancer pain, NRSF-induced downregulation of MOR is involved in the reduction of morphine analgesia. Epigenetically, up-regulation of MOR could substantially improve the effect of system delivery of morphine.

Histone deacetylase inhibitors relieve morphine resistance in neuropathic pain after peripheral nerve injury

Neuropathic pain is often insensitive to morphine. Our previous study has demonstrated that neuron-restrictive silencer factor represses mu opioid receptor (MOP) gene expression in the dorsal root ganglion (DRG) via histone hypoacetylation-mediated mechanisms after peripheral nerve injury, thereby causing loss of peripheral morphine analgesia. Here, we showed that histone deacetylase (HDAC) inhibitors, such as trichostatin A and valproic acid, restored peripheral and systemic morphine analgesia in neuropathic pain. Also, these agents blocked nerve injury-induced MOP down-regulation in the DRG. These results suggest that HDAC inhibitors could serve as adjuvant analgesics to morphine for the management of neuropathic pain.

Attenuation of systemic morphine-induced analgesia by central administration of ghrelin and related peptides in mice

Ghrelin, an acylated 28-amino peptide secreted in the gastric endocrine cells, has been demonstrated to stimulate the release of growth hormone, increase food intake, and inhibit pro-inflammatory cascade, etc. Ghrelin mainly combines with its receptor (GHS-R1α) to play the role in physiological and pathological functions. It has been reported that ghrelin plays important roles in the control of pain through interaction with the opioid system in inflammatory pain and acute pain. However, very few studies show the effect of supraspinal ghrelin system on antinociception induced by intraperitoneal (i.p.) administration of morphine. In the present study, intracerebroventricular (i.c.v.) injection of ghrelin (0.1, 1, 10 and 100nmol/L) produced inhibition of systemic morphine (6mg/kg, i.p.) analgesia in the tail withdrawal test. Similarly, i.c.v. injection GHRP-6 and GHRP-2 which are the agonists of GHS-R1α, also decreased analgesia effect induced by morphine injected intraperitoneally in mice. Furthermore, these anti-opioid activities of ghrelin and related peptides were not blocked by pretreatment with the GHS-R1α selective antagonist [d-Lys3]-GHRP-6 (100nmol/L, i.c.v.). These results demonstrated that central ghrelin and related peptides could inhibit the analgesia effect induced by intraperitoneal (i.p.) administration of morphine. The anti-opioid effects of ghrelin and related peptides do not interact with GHS-R1a. These findings may pave the way for a new strategy on investigating the interaction between ghrelin system and opioids on pain modulation.

The Yin and Yang of pain: variability in formalin test nociception and morphine analgesia produced by the Yin Yang 1 transcription factor gene

We recently observed a reliable phenotypic difference in the inflammatory pain sensitivity of a congenic mouse strain compared to its background strain. By constructing and testing subcongenic strains combined with gene-expression assays, we provide evidence for the candidacy of the Yy1 gene - encoding the ubiquitously expressed and multifunctional Yin Yang 1 transcription factor - as responsible. To confirm this hypothesis, we used a Cre/lox strategy to produce mutant mice in which Yy1 expression was ablated in Nav 1.8-positive neurons of the dorsal root ganglion. These mutants also displayed reduced inflammatory pain sensitivity on the formalin test. Further testing of pain-related phenotypes in these mutants revealed robustly increased sensitivity to systemic and spinal (but not supraspinal) morphine analgesia, and greatly increased endogenous (swim stress-induced) opioid analgesia. None of the known biological roles of Yin Yang 1 were suggestive of such a phenotype, and thus a novel player in pain modulatory systems has been identified.

Central Administration of Neuropeptide FF and Related Peptides Attenuate Systemic Morphine Analgesia in Mice

Neuropeptide FF (NPFF) belongs to an opioid-modulating peptide family. NPFF has been reported to play important roles in the control of pain and analgesia through interactions with the opioid system. However, very few studies examined the effect of supraspinal NPFF system on analgesia induced by opiates administered at the peripheral level. In the present study, intracerebroventricular (i.c.v.) injection of NPFF (1, 3 and 10 nmol) dose-dependently inhibited systemic morphine (0.12 mg, i.p.) analgesia in the mouse tail flick test. Similarly, i.c.v. administration of dNPA and NPVF, two agonists highly selective for NPFF(2) and NPFF(1) receptors, respectively, decreased analgesia induced by i.p. morphine in mice. Furthermore, these anti-opioid activities of NPFF and related peptides were blocked by pretreatment with the NPFF receptors selective antagonist RF9 (10 nmol, i.c.v.). These results demonstrate that activation of central NPFF(1) and NPFF(2) receptors has the similar anti-opioid actions on the antinociceptive effect of systemic morphine.

Ventromedial and medial preoptic hypothalamic ibotenic acid lesions potentiate systemic morphine analgesia in female, but not male rats

Sex differences in systemic morphine analgesia occur with male rodents displaying significantly greater analgesic magnitudes and potencies than females. Neonatal androgenization, and to a lesser degree, adult ovariectomy enhance systemic morphine analgesia in female rats, implicating both organizational and activational effects of gonadal hormones. The neuroanatomical circuits sensitive to sex-related hormones by which females display a smaller opiate analgesic effect is not clear, but the ventromedial (VMH) and medial preoptic (MPOA) hypothalamic nuclei are critical in the monitoring of estradiol and other sex hormone levels. To assess the contribution of these nuclei to sex and adult gonadectomy differences in systemic morphine analgesia, intact male, intact female and adult ovariectomized (OVEX) female rats received bilateral saline (SAL) or ibotenic acid (IBO) microinjections into either the VMH or MPOA. Following surgeries, baseline tail-flick latencies over 120 minutes (min) were assessed over 4 days in all nine groups with intact females tested in the estrus phase of their cycle. All animals then received an ascending series of morphine (1.0, 2.5, 5.0, 7.5, 10.0 mg/kg) injections 30 min prior to the tail-flick test time course with 8–12 day inter-injection intervals between doses. Baseline latencies failed to differ between SAL-treated intact males and females, but were significantly higher in SAL-treated OVEX females. Both VMH IBO and MPOA IBO lesions increased baseline latencies in intact male and female rats, but not in OVEX females. SAL-treated intact males (ED 50 = 4.0 mg/kg) and SAL-treated OVEX females (ED 50 = 3.5 mg/kg) displayed significantly greater potencies of systemic morphine analgesia than SAL-treated intact females (ED 50 = 6.3 mg/kg), confirming previous gender and gonadectomy differences. Neither VMH IBO (ED 50 = 3.7 mg/kg) nor MPOA IBO (ED 50 = 4.1 mg/kg) males differed from SAL-treated males in the potency of systemic morphine analgesia. In contrast, VMH IBO (ED 50 = 4.1 mg/kg) and MPOA IBO (ED 50 = 3.5 mg/kg) intact females displayed significantly greater potencies in systemic morphine analgesia than SAL-treated intact females. However, VMH IBO OVEX (ED 50 = 3.5 mg/kg) and MPOA IBO OVEX (ED 50 = 3.9 mg/kg) failed to differ from SAL-treated OVEX females in the potency of systemic morphine analgesia. The magnitudes of systemic morphine analgesia as measured by Maximum Percentage Effect values displayed similar patterns, but lesser degrees, of effects. These data suggest that VMH and MPOA nuclei act to tonically inhibit endogenous pain-inhibitory circuits in the intact female, but not intact male brain, and that removal of circulating gonadal hormones by OVEX and/or excitotoxic destruction of these estrogen receptor accumulating nuclei disinhibit the female analgesic response to systemic morphine.

Neonatal and Adult Gonadal Hormone Manipulations Enhance Morphine Analgesia Elicited from the Ventrolateral Periaqueductal Gray in Female Rats

ABSTRACTMale rodents displayed greater magnitudes of analgesia following systemic, ventricular, and intracerebral administration of μ-opioid receptor agonists than female rodents. Whereas neonatal castration of male rat pups produced reductions in systemic and central morphine analgesia as adults, neonatal androgenization of female rat pups treated with testosterone propionate (TP) displayed enhancements in systemic and central morphine analgesia as adults. Adult gonadectomy minimally affected μ-opioid analgesia, except if less potent μ agonists were employed, or if morphine was directly administered into the ventrolateral periaqueductal gray (vlPAG). Adult ovariectomy failed to appreciably alter the enhanced analgesia following systemic morphine in female rats with neonatal androgenization. Because the vlPAG elicited morphine analgesia that was sensitive to both neonatal and adult gonadal hormone manipulations, the present study examined morphine analgesia elicited from the vlPAG in female rats receiving neonatal treatment with TP or vehicle and subsequently exposed to adult ovariectomy or sham surgery as well as intact male rats. Intact male rats displayed significantly greater magnitudes and potencies in vlPAG morphine analgesia than female rats receiving neonatal treatment with either vehicle or TP. In turn, neonatal androgenization significantly enhanced vlPAG morphine analgesia relative to neonatal vehicle treatment in females. Adult ovariectomy significantly enhanced the magnitude of vlPAG morphine analgesia in female rats receiving neonatal treatment with either vehicle or TP. This demonstrates a strong interaction between neonatal and adult gonadal hormone manipulations in the mediation of vlPAG morphine analgesia in female rats.

Organizational manipulation of gonadal hormones and systemic morphine analgesia in female rats: Effects of adult ovariectomy and estradiol replacement

Previous research has indicated the importance of sex in mediating the larger magnitude of μ-opioid receptor agonist-induced analgesia in male relative to female rodents. Whereas manipulations involving the adult activational effects of gonadal hormones minimally alter these analgesic sex differences, manipulations involving neonatal organizational effects of gonadal hormones have previously been shown to profoundly affect morphine analgesia. Thus, adult male rats neonatally castrated on the first day after birth displayed reductions in morphine analgesia relative to sham-operated males, and adult female rats neonatally treated with testosterone propionate on the first day after birth displayed enhancements in morphine analgesia relative to vehicle-treated females. Because neonatal androgenization in female rats produces an anovulatory syndrome that could change their adult hormonal milieu, the present study examined whether adult ovariectomy altered the magnitude of systemic morphine analgesia (1–5 mg/kg) in neonatal androgenized female rats relative to neonatal vehicle-treated female rats as well as gonadal steroid hormone replacement with estradiol benzoate. Intact male rats displayed significantly greater magnitudes and potencies (2- to 2.3-fold leftward shift) of systemic morphine analgesia than female rats treated neonatally with either vehicle (1–5 mg/kg) or testosterone (1.7–5 mg/kg). In turn, neonatal androgenized female rats displayed significantly greater magnitudes of systemic morphine (1, 5 mg/kg) analgesia than vehicle-treated female rats accompanied by a smaller 20% leftward shift in potency. Adult ovariectomy minimally affected morphine analgesia in neonatal vehicle-treated females, while significantly reducing the magnitude (1 mg/kg), but not the potency of morphine analgesia in neonatal androgenized female rats. Estradiol replacement therapy significantly increased the magnitude of morphine analgesia in both groups at some doses, but only changed the potency (20–30%) in females treated neonatally with vehicle. Taken together, these data suggest a limited organizational-activational gonadal hormone interaction in the mediation of systemic morphine analgesia in female rats.

Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats.

Opioid agonists such as morphine have been found to exert excitatory and inhibitory receptor-mediated effects at low and high doses, respectively. Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects, have been reported to augment systemic morphine analgesia and inhibit the development of tolerance/physical dependence. This study investigated the site of action of the paradoxical effects of naltrexone and the generality of this effect. The potential of ultra-low doses of naltrexone to influence morphine-induced analgesia was investigated in tests of nociception. Administration of intrathecal (0.05 and 0.1 ng) or systemic (10 ng/kg i.p.) naltrexone augmented the antinociception produced by an acute submaximal dose of intrathecal (5 microg) or systemic (7.5 mg/kg i.p.) morphine in the tail-flick test. Chronic intrathecal (0.005 and 0.05 ng) or systemic (10 ng/kg) naltrexone combined with morphine (15 microg i.t.; 15 mg/kg i.p.) over a 7-day period inhibited the decline in morphine antinociception and prevented the loss of morphine potency. In animals rendered tolerant to intrathecal (15 microg) or systemic (15 mg/kg) morphine, administration of naltrexone (0.05 ng i.t.; 10 and 50 ng/kg i.p.) significantly restored the antinociceptive effect and potency of morphine. Thus, in ultra-low doses, naltrexone paradoxically enhances morphine analgesia and inhibits or reverses tolerance through a spinal action. The potential of naltrexone to influence morphine-induced reward was also investigated using a place preference paradigm. Systemic administration of ultra-low doses of naltrexone (16.7, 20.0, and 25.0 ng/kg) with morphine (1.0 mg/kg) extended the duration of the morphine-induced conditioned place preference. These effects of naltrexone on morphine-induced reward may have implications for chronic treatment with agonist-antagonist combinations.

Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs.

Many peptides and transmitters found within the brain also have peripheral sites of action. We now demonstrate that the brain releases functionally active neurotransmitters/neuromodulators directly from the brain into the blood through a saturable P-glycoprotein (Pgp) transport system. Downregulating Pgp1 expression with antisense reduced the brain-to-blood transport of morphine, beta-endorphin and other opioids. Lowering Pgp expression significantly enhanced systemic morphine analgesia and prevented tolerance, but diminished the analgesic activity of centrally administered morphine, implying that supraspinal analgesia resulted from a combination of central and peripheral mechanisms activated by morphine transported from the brain to the blood. Similarly, mice with a disruption of the Mdr1a gene were more sensitive to systemic morphine and less sensitive to morphine given centrally. This ability of the Pgp transport system to pump functionally active compounds from the brain to periphery defines a potentially important mechanism for the central nervous system to modulate peripheral systems.

Gender differences in opioid-mediated analgesia: animal and human studies.

Gender differences in opioid-mediated analgesia: animal and human studies.

The role of excitatory amino acid transmission within the rostral ventromedial medulla in the antinociceptive actions of systemically administered morphine

Two classes of neurons with distinct responses to opioids have been identified in the rostral ventromedial medulla (RVM), a region with a well-documented role in nociceptive modulation. `Off-cells' are activated, indirectly, by opioids, and are likely to exert a net inhibitory effect on nociceptive processing. `On-cells' are directly inhibited by opioids, and there is evidence that these neurons can, under various conditions, facilitate nociception. We showed previously that excitatory amino acid (EAA) neurotransmission is crucial to the nocifensor reflex-related on-cell burst, but plays little role in maintaining the ongoing activity of off-cells. The aim of the present study was to determine whether EAA transmission contributes to the activation of off-cells and the concomitant behavioral antinociception that follow systemic opioid administration. The non-selective EAA receptor antagonist kynurenate was infused into the RVM (1 nmol/200 nl) of lightly anesthetized rats prior to administration of morphine (1.5 mg/kg i.v). Off-cell, on-cell and neutral cell firing, as well as, tail flick response (TF) latencies were recorded. Kynurenate, significantly attenuated the characteristic opioid activation of off-cells. As a group, off-cells in kynurenate-treated animals did not become continuously active, and continued to exhibit tail-flick related pauses in firing. On-cell and neutral cell responses to opioid administration were unchanged. Opioid inhibition of the TF was also reduced, although baseline TF latency was unaffected, by RVM kynurenate. EAA-mediated activation of off-cells, thus has an important role in opioid analgesia. The present observations underscore the importance of excitatory interactions among opioid-sensitive nociceptive modulatory circuits for systemic morphine analgesia, suggesting that such interactions are a critical factor in the synergistic relationships which have been demonstrated among these sites.

Time-Dependent Effects of In Vivo Pertussis Toxin on Morphine Analgesia and G-Proteins in Mice

Previous studies have indicated a long-duration of effect of in vivo pertussis toxin (PTX) on morphine analgesia in the mouse. However, the time-course of potency changes in morphine analgesia as determined in dose-response studies and biochemical correlates of PTX treatment have not been reported to date. Therefore, in the present studies the effects of in vivo PTX on morphine analgesia ED 50 and PTX-catalyzed incorporation of [ 32P]-ADP-ribose and synapsin content in mouse spinal cord were examined. Mice were injected IT & ICV with saline or PTX (total dose = 0.2 μg) and tested for systemic morphine analgesia (tail-flick) 1, 10, 16 & 40 days later. There was no significant decrease in morphine potency 1 day following PTX treatment, whereas PTX produced a significant decrease in morphine potency at 10, 16 & 40 days. Concurrent decreases in the incorporation of [ 32P]-ADP-ribose in spinal cord by PTX were observed on days 10, 16 & 40. No changes were observed in synapsin content which suggests that the effect was not nonspecific. This study indicates that in vivo PTX produces co-ordinate long-lasting effects in both functional (analgesia) and biochemical (G i/o-proteins) assays.

2327 Chronic salt loading and lactation upregulate the expression of synapsin IIA gene in the rat paraventricular nucleus

Previous research has indicated the importance of sex in mediating the larger magnitude of μ-opioid receptor agonist-induced analgesia in male relative to female rodents. Whereas manipulations involving the adult activational effects of gonadal hormones minimally alter these analgesic sex differences, manipulations involving neonatal organizational effects of gonadal hormones have previously been shown to profoundly affect morphine analgesia. Thus, adult male rats neonatally castrated on the first day after birth displayed reductions in morphine analgesia relative to sham-operated males, and adult female rats neonatally treated with testosterone propionate on the first day after birth displayed enhancements in morphine analgesia relative to vehicle-treated females. Because neonatal androgenization in female rats produces an anovulatory syndrome that could change their adult hormonal milieu, the present study examined whether adult ovariectomy altered the magnitude of systemic morphine analgesia (1–5 mg/kg) in neonatal androgenized female rats relative to neonatal vehicle-treated female rats as well as gonadal steroid hormone replacement with estradiol benzoate. Intact male rats displayed significantly greater magnitudes and potencies (2- to 2.3-fold leftward shift) of systemic morphine analgesia than female rats treated neonatally with either vehicle (1–5 mg/kg) or testosterone (1.7–5 mg/kg). In turn, neonatal androgenized female rats displayed significantly greater magnitudes of systemic morphine (1, 5 mg/kg) analgesia than vehicle-treated female rats accompanied by a smaller 20% leftward shift in potency. Adult ovariectomy minimally affected morphine analgesia in neonatal vehicle-treated females, while significantly reducing the magnitude (1 mg/kg), but not the potency of morphine analgesia in neonatal androgenized female rats. Estradiol replacement therapy significantly increased the magnitude of morphine analgesia in both groups at some doses, but only changed the potency (20–30%) in females treated neonatally with vehicle. Taken together, these data suggest a limited organizational-activational gonadal hormone interaction in the mediation of systemic morphine analgesia in female rats.

Histamine-induced modulation of nociceptive responses

Because previous studies suggest an antinociceptive role for the neuromodulator histamine (HA) in the periaqueductal grey or the nearby dorsal raphe (PAG/DR), a detailed pharmacological investigation of the effects of intracerebral HA on the hot-plate nociceptive test was performed in rats. Intracerebral microinjections of HA (1 μg) into the PAG/DR or into the median raphe evoked a mild, reversible antinociceptive response; injections into lateral or dorsal midbrain evoked either a delayed response or no response, respectively. In the PAG/DR, the HA dose-response curve had an inverted U-shape, showing that HA can induce both antinociceptive (0.3–3 μg) and pro-nociceptive (10–30 μg) responses. Larger doses of HA (e.g., 100 μg) produced irreversible and highly variable antinociceptive responses that were accompanied by behavioral and histopathological changes; such effects, indicative of toxicity, were not observed after 0.3 μg of HA, the peak antinociceptive dose. HA (0.3 μg) antinociception was completely inhibited by intracerebral co-administration of the opiate antagonist naloxone (1 ng), the H 1-receptor antagonist temelastine (20 pg), and the H 2-receptor antagonist tiotidine (1 ng); none of these drugs altered nociceptive scores in the absence of HA. These results show that: (1) HA, a neurotransmitter in the PAG, can evoke antinociception in the absence of other behavioral or toxic effects; and (2) HA antinociception depends on the activation of both opiate and HA receptors in the PAG/DR. Since previous studies have shown that: 1. (1) systemic morphine increases the release of HA in the PAG/DR, 2. (2) systemic morphine analgesia is inhibited by PAG/DR injections of the H 2 antagonist tiotidine, the present results (showing antagonism of HA antinociception by intracerebral tiotidine treatment) strongly support the conclusion that histaminergic mechanisms in the PAG/DR mediate a portion of systemic morphine antinociception.

Roles of gender and gonadectomy in pilocarpine and clonidine analgesia in rats

Central and systemic morphine analgesia as well as both opioid and nonopioid forms of swim analgesia display gender differences with male rats showing greater magnitudes of analgesia than female rats. Since nonopioid swim analgesia is dependent upon muscarinic cholinergic and alpha 2-noradrenergic mechanisms, the present study evaluated in rats whether gender, adult gonadectomy or estrous phase altered analgesia induced by either the muscarinic cholinergic receptor agonist, pilocarpine or the alpha 2-noradrenergic receptor agonist, clonidine. Pilocarpine (1–10 mg/kg) analgesia was significantly greater in male rats. Female rats displayed 7-fold and 3-fold rightward shifts in peak analgesia on the tail-flick and jump tests respectively. Clonidine (100–500 μg/kg) analgesia was significantly greater on both nocipeptive tests in males, but only produced a 2-fold rightward shift in peak analgesia in females on the jump test. Whereas castration failed to shift either dose-response curve, ovariectomy mitigated the gender differences in pilocarpine and clonidine analgesia. Both pilocarpine and clonidine analgesia were not altered by estrous phase changes. These data indicate that gender differences in analgesia are not specific to opioid systems.