G. Picolo - Academia.edu (original) (raw)

Papers by G. Picolo

Research paper thumbnail of Animal toxins as analgesics - an overview

Drug News & Perspectives, 2006

Pain is a multidimensional sensory experience, and multiple mechanisms are involved in the genera... more Pain is a multidimensional sensory experience, and multiple mechanisms are involved in the generation of pathophysiological nociceptive pain. Identification of the mechanisms and molecular components responsible for pain generation has not only advanced our understanding of pain and its control, but has also led to the selection of new targets for designing novel analgesic drugs. The high selectivity and specificity of animal toxins have enabled their use as potential therapeutics in the treatment of pain and candidates for the development of new analgesic drugs. This review focuses on the use of animal toxins for pain control and examines the possible analgesic mechanisms of these molecules.

Research paper thumbnail of Harnessing the knowledge of animal toxins to generate drugs

Pharmacological Research, 2016

Research paper thumbnail of delta-opioid receptors and nitric oxide mediate the analgesic effect of Crotalus durissus terrificus snake venom

European journal of pharmacology, Jan 10, 2000

The antinociceptive effect of Crotalus durissus terrificus venom was investigated in a model of i... more The antinociceptive effect of Crotalus durissus terrificus venom was investigated in a model of inflammatory hyperalgesia induced by carrageenin. The rat paw pressure test was applied before and 3 h after the intraplantar (i.pl.) injection of carrageenin. The venom administered per os before and 1 or 2 h after carrageenin blocked hyperalgesia. When carrageenin was injected in both hind paws and naloxone into one hind paw, antinociception was abolished only in the paw injected with naloxone. D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP) and nor-binaltorphimine, antagonists of micro- and kappa-opioid receptors, respectively, did not alter the effect of the venom. N,N-diallyl-Tyr-Aib-Aib-Phe-Leu (ICI 174,864), an antagonist of delta-opioid receptors, antagonised this effect. Prolonged administration of the venom did not induce tolerance to this antinociceptive effect. N(G)-methyl-L-arginine (L-NMMA) and methylene blue, inhibitors of nitric oxide synthase and soluble guanylate cyclas...

Research paper thumbnail of The antinociceptive effect of Crotalus durissus terrificus snake venom is mainly due to a supraspinally integrated response

Toxicon, 1998

The antinociceptive effect of Crotalus durissus terrificus snake venom, previously demonstrated i... more The antinociceptive effect of Crotalus durissus terrificus snake venom, previously demonstrated in the hot-plate test, was investigated in mice using the tail-flick model. The venom, administered by the intraperitoneal, subcutaneous or oral route, did not modify the basal latency time to the noxious stimulus and the association of the venom with morphine did not alter the opioid analgesic effect of this drug. These data indicate that the antinociceptive effect of the venom is mainly due to a supraspinally integrated response.

Research paper thumbnail of Analog compounds of analgesic peptides derived from the venom of crotalus durissus terrificus snakes, their uses, compositions, methods of preparation and purification

Research paper thumbnail of Crotalphine: fluorescent analogues, structural analysis and its effect on co-cultures of peritoneal macrophages and DRG neurons (LB615)

Research paper thumbnail of Crotalphine, a highly potent analgesic peptide from the venom of the South American rattlesnake Crotalus durissus terrificus

Research paper thumbnail of Periaqueductal gray μ and κ opioid receptors determine behavioral selection from maternal to predatory behavior in lactating rats

Behavioural Brain Research, 2014

Every mother must optimize her time between caring for her young and her subsistence. The rostro ... more Every mother must optimize her time between caring for her young and her subsistence. The rostro lateral portion of the periaqueductal grey (rlPAG) is a critical site that modulates the switch between maternal and predatory behavior. Opioids play multiple roles in both maternal behavior and this switching process. The present study used a pharmacological approach to evaluate the functional role of rlPAG μ and κ opioid receptors in behavioral selection. Rat dams were implanted with a guide cannula in the rlPAG and divided into three experiments in which we tested the role of opioid agonists (Experiment 1), the influence of μ and κ opioid receptor blockade in the presence of morphine (Experiment 2), and the influence of μ and κ opioid receptor blockade (Experiment 3). After behavioral test, in Experiment 4, we evaluated rlPAG μ and κ receptor activation in all Experiments 1-3. The results showed that massive opioidergic activation induced by morphine in the rlPAG inhibited maternal behavior without interfering with predatory hunting. No behavioral changes and no receptor activation were promoted by the specific agonist alone. However, κ receptor blockade increased hunting behavior and increased the level of μ receptor activation in the rlPAG. Thus, endogenous opioidergic tone might be modulated by a functional interaction between opioid receptor subtypes. Such a compensatory receptor interaction appears to be relevant for behavioral selection among motivated behaviors. These findings indicate a role for multiple opioid receptor interactions in the modulation of behavioral selection between maternal and predatory behaviors in the PAG.

Research paper thumbnail of 144. Analgesic Effect of Crotalphine in a New Model of Rat Bone Cancer Pain

Research paper thumbnail of Hyperalgesia induced by Asp49 and Lys49 phospholipases A2 from Bothrops asper snake venom: pharmacological mediation and molecular determinants

Research paper thumbnail of Inflammation induced by Bothrops asper venom

Research paper thumbnail of Pharmacological modulation of hyperalgesia induced by Bothrops asper (terciopelo) snake venom

Toxicon, 2001

The ability of Bothrops asper snake venom to cause hyperalgesia was investigated in rats, using t... more The ability of Bothrops asper snake venom to cause hyperalgesia was investigated in rats, using the paw pressure test. Intraplantar injection of the venom (5-15 microg/paw) caused a dose and time-related hyperalgesia, which peaked 2h after venom injection. Bothrops asper venom-induced hyperalgesia was blocked by the bradykinin B(2) receptor antagonist HOE 140 and attenuated by dexamethasone, an inhibitor of phospholipase A(2). Inhibition of the lipoxygenase pathway by NDGA abrogated the algogenic phenomenon. The hyperalgesic response was not modified by pretreatment with indomethacin, an inhibitor of the cyclo-oxygenase pathway, by meloxicam, an inhibitor of the type 2 cyclo-oxygenase pathway, by the PAF receptor antagonist BN52021 or by anti-TNF-alpha or anti-interleukin 1 antibodies. Intraplantar injection of the venom also caused an oedematogenic response which was not modified by any of these pharmacological treatments. These results suggest that hyperalgesia induced by Bothrops asper venom is, at least partially, mediated by bradykinin, phospholipase A(2) activity and leukotrienes. Distinct mechanisms are involved in the development of hyperalgesia and oedema induced by the venom.

Research paper thumbnail of Bradykinin is involved in hyperalgesia induced by Bothrops jararaca venom

Toxicon, 2002

Bradykinin is involved in hyperalgesia (pain hypersensitivity) induced by Bothrops jararaca venom... more Bradykinin is involved in hyperalgesia (pain hypersensitivity) induced by Bothrops jararaca venom-intraplantar injection of B. jararaca venom (5microg/paw) in rats caused hyperalgesia, which peaked 1h after venom injection. This phenomenon was not modified by promethazine (H(1) receptor antagonist), methysergide (5-HT receptor antagonist), guanethidine (sympathetic function inhibitor), anti-TNF-alpha or anti-interleukin-1 antibodies or by the chelating agent CaNa(2)EDTA. Venom-induced hyperalgesia was blocked by the bradykinin B(2) receptor antagonist HOE 140. On the other hand, des-Arg(9), [Leu(8)]-bradykinin, a bradykinin B(1) receptor antagonist, did not modify the hyperalgesic response. These results suggest that bradykinin, acting on B(2) receptor, is a mediator of hyperalgesia induced by B. jararaca venom.

Research paper thumbnail of Bunodosines: novel analgesic acylamino acids from the venom of the sea anemone Bunodosoma cangicum

Research paper thumbnail of Analgesic Effect of He-Ne (632.8 nm) Low-Level Laser Therapy on Acute Inflammatory Pain

Photomedicine and Laser Surgery, 2005

The aim of this study was to evaluate the analgesic effect of the low level laser therapy (LLLT) ... more The aim of this study was to evaluate the analgesic effect of the low level laser therapy (LLLT) with a He-Ne laser on acute inflammatory pain, verifying the contribution of the peripheral opioid receptors and the action of LLLT on the hyperalgesia produced by the release of hyperalgesic mediators of inflammation. All analgesic drugs have undesired effects. Because of that, other therapies are being investigated for treatment of the inflammatory pain. Among those, LLLT seems to be very promising. Male Wistar rats were used. Three complementary experiments were done. (1) The inflammatory reaction was induced by the injection of carrageenin into one of the hind paws. Pain threshold and volume increase of the edema were measured by a pressure gauge and plethysmography, respectively. (2) The involvement of peripheral opioid receptors on the analgesic effect of the laser was evaluated by simultaneous injection of carrageenin and naloxone into one hind paw. (3) Hyperalgesia was induced by injecting PGE2 for the study of the effect of the laser on the sensitization increase of nociceptors. A He-Ne laser (632.8 nm) of 2.5 J/cm2 was used for irradiation. We found that He-Ne stimulation increased the pain threshold by a factor between 68% and 95% depending on the injected drug. We also observed a 54% reduction on the volume increase of the edema when it was irradiated. He-Ne LLLT inhibits the sensitization increase of nociceptors on the inflammatory process. The analgesic effect seems to involve hyperalgesic mediators instead of peripheral opioid receptors.

Research paper thumbnail of Peripheral kappa and delta opioid receptors are involved in the antinociceptive effect of crotalphine in a rat model of cancer pain

Pharmacology Biochemistry and Behavior, 2013

Research paper thumbnail of Pain and analgesia: The dual effect of nitric oxide in the nociceptive system

Research paper thumbnail of Peripheral neuronal nitric oxide synthase activity mediates the antinociceptive effect of Crotalus durissus terrificus snake venom, a <span class="katex"><span class="katex-mathml"><math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><mrow><mi>d</mi><mi>e</mi><mi>l</mi><mi>t</mi><mi>a</mi><mo separator="true">;</mo><mo>−</mo><mi>a</mi><mi>n</mi><mi>d</mi></mrow><annotation encoding="application/x-tex">delta;- and </annotation></semantics></math></span><span class="katex-html" aria-hidden="true"><span class="base"><span class="strut" style="height:0.8889em;vertical-align:-0.1944em;"></span><span class="mord mathnormal">d</span><span class="mord mathnormal">e</span><span class="mord mathnormal">lt</span><span class="mord mathnormal">a</span><span class="mpunct">;</span><span class="mspace" style="margin-right:0.1667em;"></span><span class="mord">−</span><span class="mord mathnormal">an</span><span class="mord mathnormal">d</span></span></span></span>kappa;-opioid receptor agonist

Research paper thumbnail of Crotalphine, a novel potent analgesic peptide from the venom of the South American rattlesnake Crotalus durissus terrificus

Peptides, 2008

We have shown that the venom of the South American rattlesnake Crotalus durissus terrificus induc... more We have shown that the venom of the South American rattlesnake Crotalus durissus terrificus induces a long-lasting antinociceptive effect mediated by activation of kappa- and delta-opioid receptors. Despite being mediated by opioid receptors, prolonged treatment with the crotalid venom does not cause the development of peripheral tolerance or abstinence symptoms upon withdrawal. In the present study, we have isolated and chemically characterized a novel and potent antinociceptive peptide responsible for the oral opioid activity of this crotalid venom. The amino acid sequence of this peptide, designated crotalphine, was determined by mass spectrometry and corroborated by solid-phase synthesis to be <EFSPENCQGESQPC, where <E is pyroglutamic acid and the two cysteine residues forming a disulfide bond. This 14-amino-acid residue sequence is identical to the gamma-chain sequence of crotapotin, a non-toxic component of this snake venom. Crotalphine, when orally administered (0.008-2...

Research paper thumbnail of Bunodosine 391: An Analgesic Acylamino Acid from the Venom of the Sea Anemone Bunodosoma cangicum

Journal of Natural Products, 2011

Research paper thumbnail of Animal toxins as analgesics - an overview

Drug News & Perspectives, 2006

Pain is a multidimensional sensory experience, and multiple mechanisms are involved in the genera... more Pain is a multidimensional sensory experience, and multiple mechanisms are involved in the generation of pathophysiological nociceptive pain. Identification of the mechanisms and molecular components responsible for pain generation has not only advanced our understanding of pain and its control, but has also led to the selection of new targets for designing novel analgesic drugs. The high selectivity and specificity of animal toxins have enabled their use as potential therapeutics in the treatment of pain and candidates for the development of new analgesic drugs. This review focuses on the use of animal toxins for pain control and examines the possible analgesic mechanisms of these molecules.

Research paper thumbnail of Harnessing the knowledge of animal toxins to generate drugs

Pharmacological Research, 2016

Research paper thumbnail of delta-opioid receptors and nitric oxide mediate the analgesic effect of Crotalus durissus terrificus snake venom

European journal of pharmacology, Jan 10, 2000

The antinociceptive effect of Crotalus durissus terrificus venom was investigated in a model of i... more The antinociceptive effect of Crotalus durissus terrificus venom was investigated in a model of inflammatory hyperalgesia induced by carrageenin. The rat paw pressure test was applied before and 3 h after the intraplantar (i.pl.) injection of carrageenin. The venom administered per os before and 1 or 2 h after carrageenin blocked hyperalgesia. When carrageenin was injected in both hind paws and naloxone into one hind paw, antinociception was abolished only in the paw injected with naloxone. D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP) and nor-binaltorphimine, antagonists of micro- and kappa-opioid receptors, respectively, did not alter the effect of the venom. N,N-diallyl-Tyr-Aib-Aib-Phe-Leu (ICI 174,864), an antagonist of delta-opioid receptors, antagonised this effect. Prolonged administration of the venom did not induce tolerance to this antinociceptive effect. N(G)-methyl-L-arginine (L-NMMA) and methylene blue, inhibitors of nitric oxide synthase and soluble guanylate cyclas...

Research paper thumbnail of The antinociceptive effect of Crotalus durissus terrificus snake venom is mainly due to a supraspinally integrated response

Toxicon, 1998

The antinociceptive effect of Crotalus durissus terrificus snake venom, previously demonstrated i... more The antinociceptive effect of Crotalus durissus terrificus snake venom, previously demonstrated in the hot-plate test, was investigated in mice using the tail-flick model. The venom, administered by the intraperitoneal, subcutaneous or oral route, did not modify the basal latency time to the noxious stimulus and the association of the venom with morphine did not alter the opioid analgesic effect of this drug. These data indicate that the antinociceptive effect of the venom is mainly due to a supraspinally integrated response.

Research paper thumbnail of Analog compounds of analgesic peptides derived from the venom of crotalus durissus terrificus snakes, their uses, compositions, methods of preparation and purification

Research paper thumbnail of Crotalphine: fluorescent analogues, structural analysis and its effect on co-cultures of peritoneal macrophages and DRG neurons (LB615)

Research paper thumbnail of Crotalphine, a highly potent analgesic peptide from the venom of the South American rattlesnake Crotalus durissus terrificus

Research paper thumbnail of Periaqueductal gray μ and κ opioid receptors determine behavioral selection from maternal to predatory behavior in lactating rats

Behavioural Brain Research, 2014

Every mother must optimize her time between caring for her young and her subsistence. The rostro ... more Every mother must optimize her time between caring for her young and her subsistence. The rostro lateral portion of the periaqueductal grey (rlPAG) is a critical site that modulates the switch between maternal and predatory behavior. Opioids play multiple roles in both maternal behavior and this switching process. The present study used a pharmacological approach to evaluate the functional role of rlPAG μ and κ opioid receptors in behavioral selection. Rat dams were implanted with a guide cannula in the rlPAG and divided into three experiments in which we tested the role of opioid agonists (Experiment 1), the influence of μ and κ opioid receptor blockade in the presence of morphine (Experiment 2), and the influence of μ and κ opioid receptor blockade (Experiment 3). After behavioral test, in Experiment 4, we evaluated rlPAG μ and κ receptor activation in all Experiments 1-3. The results showed that massive opioidergic activation induced by morphine in the rlPAG inhibited maternal behavior without interfering with predatory hunting. No behavioral changes and no receptor activation were promoted by the specific agonist alone. However, κ receptor blockade increased hunting behavior and increased the level of μ receptor activation in the rlPAG. Thus, endogenous opioidergic tone might be modulated by a functional interaction between opioid receptor subtypes. Such a compensatory receptor interaction appears to be relevant for behavioral selection among motivated behaviors. These findings indicate a role for multiple opioid receptor interactions in the modulation of behavioral selection between maternal and predatory behaviors in the PAG.

Research paper thumbnail of 144. Analgesic Effect of Crotalphine in a New Model of Rat Bone Cancer Pain

Research paper thumbnail of Hyperalgesia induced by Asp49 and Lys49 phospholipases A2 from Bothrops asper snake venom: pharmacological mediation and molecular determinants

Research paper thumbnail of Inflammation induced by Bothrops asper venom

Research paper thumbnail of Pharmacological modulation of hyperalgesia induced by Bothrops asper (terciopelo) snake venom

Toxicon, 2001

The ability of Bothrops asper snake venom to cause hyperalgesia was investigated in rats, using t... more The ability of Bothrops asper snake venom to cause hyperalgesia was investigated in rats, using the paw pressure test. Intraplantar injection of the venom (5-15 microg/paw) caused a dose and time-related hyperalgesia, which peaked 2h after venom injection. Bothrops asper venom-induced hyperalgesia was blocked by the bradykinin B(2) receptor antagonist HOE 140 and attenuated by dexamethasone, an inhibitor of phospholipase A(2). Inhibition of the lipoxygenase pathway by NDGA abrogated the algogenic phenomenon. The hyperalgesic response was not modified by pretreatment with indomethacin, an inhibitor of the cyclo-oxygenase pathway, by meloxicam, an inhibitor of the type 2 cyclo-oxygenase pathway, by the PAF receptor antagonist BN52021 or by anti-TNF-alpha or anti-interleukin 1 antibodies. Intraplantar injection of the venom also caused an oedematogenic response which was not modified by any of these pharmacological treatments. These results suggest that hyperalgesia induced by Bothrops asper venom is, at least partially, mediated by bradykinin, phospholipase A(2) activity and leukotrienes. Distinct mechanisms are involved in the development of hyperalgesia and oedema induced by the venom.

Research paper thumbnail of Bradykinin is involved in hyperalgesia induced by Bothrops jararaca venom

Toxicon, 2002

Bradykinin is involved in hyperalgesia (pain hypersensitivity) induced by Bothrops jararaca venom... more Bradykinin is involved in hyperalgesia (pain hypersensitivity) induced by Bothrops jararaca venom-intraplantar injection of B. jararaca venom (5microg/paw) in rats caused hyperalgesia, which peaked 1h after venom injection. This phenomenon was not modified by promethazine (H(1) receptor antagonist), methysergide (5-HT receptor antagonist), guanethidine (sympathetic function inhibitor), anti-TNF-alpha or anti-interleukin-1 antibodies or by the chelating agent CaNa(2)EDTA. Venom-induced hyperalgesia was blocked by the bradykinin B(2) receptor antagonist HOE 140. On the other hand, des-Arg(9), [Leu(8)]-bradykinin, a bradykinin B(1) receptor antagonist, did not modify the hyperalgesic response. These results suggest that bradykinin, acting on B(2) receptor, is a mediator of hyperalgesia induced by B. jararaca venom.

Research paper thumbnail of Bunodosines: novel analgesic acylamino acids from the venom of the sea anemone Bunodosoma cangicum

Research paper thumbnail of Analgesic Effect of He-Ne (632.8 nm) Low-Level Laser Therapy on Acute Inflammatory Pain

Photomedicine and Laser Surgery, 2005

The aim of this study was to evaluate the analgesic effect of the low level laser therapy (LLLT) ... more The aim of this study was to evaluate the analgesic effect of the low level laser therapy (LLLT) with a He-Ne laser on acute inflammatory pain, verifying the contribution of the peripheral opioid receptors and the action of LLLT on the hyperalgesia produced by the release of hyperalgesic mediators of inflammation. All analgesic drugs have undesired effects. Because of that, other therapies are being investigated for treatment of the inflammatory pain. Among those, LLLT seems to be very promising. Male Wistar rats were used. Three complementary experiments were done. (1) The inflammatory reaction was induced by the injection of carrageenin into one of the hind paws. Pain threshold and volume increase of the edema were measured by a pressure gauge and plethysmography, respectively. (2) The involvement of peripheral opioid receptors on the analgesic effect of the laser was evaluated by simultaneous injection of carrageenin and naloxone into one hind paw. (3) Hyperalgesia was induced by injecting PGE2 for the study of the effect of the laser on the sensitization increase of nociceptors. A He-Ne laser (632.8 nm) of 2.5 J/cm2 was used for irradiation. We found that He-Ne stimulation increased the pain threshold by a factor between 68% and 95% depending on the injected drug. We also observed a 54% reduction on the volume increase of the edema when it was irradiated. He-Ne LLLT inhibits the sensitization increase of nociceptors on the inflammatory process. The analgesic effect seems to involve hyperalgesic mediators instead of peripheral opioid receptors.

Research paper thumbnail of Peripheral kappa and delta opioid receptors are involved in the antinociceptive effect of crotalphine in a rat model of cancer pain

Pharmacology Biochemistry and Behavior, 2013

Research paper thumbnail of Pain and analgesia: The dual effect of nitric oxide in the nociceptive system

Research paper thumbnail of Peripheral neuronal nitric oxide synthase activity mediates the antinociceptive effect of Crotalus durissus terrificus snake venom, a <span class="katex"><span class="katex-mathml"><math xmlns="http://www.w3.org/1998/Math/MathML"><semantics><mrow><mi>d</mi><mi>e</mi><mi>l</mi><mi>t</mi><mi>a</mi><mo separator="true">;</mo><mo>−</mo><mi>a</mi><mi>n</mi><mi>d</mi></mrow><annotation encoding="application/x-tex">delta;- and </annotation></semantics></math></span><span class="katex-html" aria-hidden="true"><span class="base"><span class="strut" style="height:0.8889em;vertical-align:-0.1944em;"></span><span class="mord mathnormal">d</span><span class="mord mathnormal">e</span><span class="mord mathnormal">lt</span><span class="mord mathnormal">a</span><span class="mpunct">;</span><span class="mspace" style="margin-right:0.1667em;"></span><span class="mord">−</span><span class="mord mathnormal">an</span><span class="mord mathnormal">d</span></span></span></span>kappa;-opioid receptor agonist

Research paper thumbnail of Crotalphine, a novel potent analgesic peptide from the venom of the South American rattlesnake Crotalus durissus terrificus

Peptides, 2008

We have shown that the venom of the South American rattlesnake Crotalus durissus terrificus induc... more We have shown that the venom of the South American rattlesnake Crotalus durissus terrificus induces a long-lasting antinociceptive effect mediated by activation of kappa- and delta-opioid receptors. Despite being mediated by opioid receptors, prolonged treatment with the crotalid venom does not cause the development of peripheral tolerance or abstinence symptoms upon withdrawal. In the present study, we have isolated and chemically characterized a novel and potent antinociceptive peptide responsible for the oral opioid activity of this crotalid venom. The amino acid sequence of this peptide, designated crotalphine, was determined by mass spectrometry and corroborated by solid-phase synthesis to be <EFSPENCQGESQPC, where <E is pyroglutamic acid and the two cysteine residues forming a disulfide bond. This 14-amino-acid residue sequence is identical to the gamma-chain sequence of crotapotin, a non-toxic component of this snake venom. Crotalphine, when orally administered (0.008-2...

Research paper thumbnail of Bunodosine 391: An Analgesic Acylamino Acid from the Venom of the Sea Anemone Bunodosoma cangicum

Journal of Natural Products, 2011