The nociceptive and anti-nociceptive effects of bee venom injection and therapy: a double-edged sword

Abstract

Bee venom injection as a therapy, like many other complementary and alternative medicine approaches, has been used for thousands of years to attempt to alleviate a range of diseases including arthritis. More recently, additional theraupeutic goals have been added to the list of diseases making this a critical time to evaluate the evidence for the beneficial and adverse effects of bee venom injection. Although reports of pain reduction (analgesic and antinociceptive) and anti-inflammatory effects of bee venom injection are accumulating in the literature, it is common knowledge that bee venom stings are painful and produce inflammation. In addition, a significant number of studies have been performed in the past decade highlighting that injection of bee venom and components of bee venom produce significant signs of pain or nociception, inflammation and many effects at multiple levels of immediate, acute and prolonged pain processes. This report reviews the extensive new data regarding the deleterious effects of bee venom injection in people and animals, our current understanding of the responsible underlying mechanisms and critical venom components, and provides a critical evaluation of reports of the beneficial effects of bee venom injection in people and animals and the proposed underlying mechanisms. Although further studies are required to make firm conclusions, therapeutic bee venom injection may be beneficial for some patients, but may also be harmful. This report highlights key patterns of results, critical shortcomings, and essential areas requiring further study.

Fig. 1

Amino acid sequences of bee venom polypeptides: melittin, apamin, mast cell degranulating peptide and secapin.

Fig. 2

Activation of dorsal root ganglion (DRG) cells in response to direct application of melittin. (A) Whole cell recording of a DRG cell in response to 2 M melittin under current-clamp. Following 50 s melittin perfusion, the cell is evoked to fire immediately with occasional action potentials that is followed by a tonic period of firing for more than 10 min. Onset latency is 26 s. (B) Whole cell recording of another DRG cell in response to 2 M melittin under voltage-clamp (Vh = −70 mV). Following 50 s melittin perfusion, the cell is evoked to produce an inward current with a slow decay time. The onset latency is 20 s. The membrane potentials: cell in A = −60 mV, cell in B = −61 mV.

Fig. 3

A schematic drawing of proposed underlying mechanisms of the bee venom induced persistent nociception and primary hyperalgesia to heat and mechanical stimuli applied in the periphery. On the left column, venom sac and sting apparatus is shown at the tip of a honeybee abdomen. The major polypeptides and enzymes of the bee venom are listed below (also see Table 1). Subcutaneous injection of bee venom by a syringe is shown on the left top, while a nerve terminal of primary afferent is shown on the bottom right. The direct and indirect actions of each ingredients of the bee venom are proposed. Color symbols representing each ingredient of the bee venom (left) can be clearly seen on the right where melittin (dark red double strand), MCD peptide (red colored circle), apamin (green colored circle) and tertiapin (light blue rectangle) bind directly to the membrane of a nociceptor cell leading to activation of it. Meanwhile, melittin, MCD peptide, bv PLA2 (light green ‘H’), and hyaluronidase (dark green double balls) cause tissue damage (grey) and release ATP and H⁺ that activate P2X3 (thick blue arrow and paired channel)/P2Y (thin red arrow and paired channel), TRPV1 (green arrow and paired channel) and ASIC (light geen dashed arrow and paired channel). Indirect actions of melittin, MCD peptide and bv PLA2 cause degranulation of mast cells (purple) and release histamine, BK and 5-HT that activate H1 receptor (pink thick arrow and paired receptor), 5-HT3 receptor (blue arrow and paired receptor) and BK1/2 receptors (dark green arrow and paired receptor). The firing of nociceptor terminals will be mediated by voltage-dependent sodium channels (TTXr Nav1.8/1.9), VDCC, VDPC, Kir and Ca²⁺–K⁺. Dorsal root reflex and axon reflex may cause release of glutamate and neuropeptides (SP and CGRP) that further activate their autoreceptors on the nociceptor terminals or blood vessels causing inflammatory extravasation (neurogenic) with infiltration of macrophage, immune cells and platelets and many cytokines (TNFalpha, IL1beta, PAF, etc.). The syringe indicates transcutaneous injection of bee venom. Abbreviations: 5-HT3, 5-hydroxytryptamine receptor 3; 12-HETE, 12-hydroxyeicosatetraenoic acids; AA, arachidonic acid; ASIC, acid-sensing ionic channel; ATP, adenosine triphosphate; BK1/2, bradykinin receptors 1/2; bv PLA₂, bee venom phospholipase A2; Ca²⁺–K⁺, calcium-dependent potassium channel; CGRP, calcitonin-gene related peptide; COX-1/2, cyclooxygenases1/2; Glu, glutamate; H1, histamine receptor type 1; iGluRs, ionotropic glutamate receptors; IL1β, interleukin 1β; IL6, interleukin 6; Kir, inward-rectifier potassium channel, LOXs, lipoxygenases; MAPKs, mitogen-activated protein kinases; MCD peptide, mast cell degranulating peptide; MCL peptide, mastocytolyitic peptide; NK1, neurokinin 1; NOS, notric oxide synthase; P2X3, P2-purinoreceptor X3; P2Y, P2-purinoreceptor Y; PAF, platelet-activated factor; PGs, prostaglandins; PKA, protein kinase A; protein kinase C; protein kinase G; SP, substance P; TNFα, tumor-necrosis factor α; TRPV1, transient receptor potential vanilloid receptor 1; TTXr, tetrodotoxin-resistant; VDCC, voltage-dependent calcium channel, VDPC, voltage-dependent potassium channel.

Fig. 4

A schematic drawing of proposed underlying mechanisms of the bee venom (BV)-induced chemically relevant persistent nociception (CRPN) in the spinal cord dorsal horn. The BV-induced thermally relevant secondary hyperalgesia (TRSH) and thermally relevant mirror-image hyperalgesia (TRMIH) are proposed to share the mechanisms similar to the CRPN. Shown is a synaptic structure between a pre-synaptic component (central terminal of primary afferents, left) and a post-synaptic component (membrane of a pain-signaling neuron, right). Astrocytes and microglia are not fully activated at this stage. At the synaptic cleft, in response to the coming of tonic firing action potentials, excitatory amino acids (EAAs, glutamate and aspartate, small colored clear vesicles) are selectively activating ionotropic glutamate receptors (NMDA and AMPA/KA) and metabotropic glutamate receptor group I (mGluR I), while substance P (large dense-cored vesicles) are activating neurokinin 1 (NK1) receptors. At this process, mGluR II and III are not activated. At pre-synaptic component, vanilloid receptor TRPV1, voltage-dependent calcium channel (VDCC), and NK1 are activated. ATP (green clear vesicles) released from glial cells or damaged cells due to cytotoxic effects are activating ATP P2X receptors. On the other hand, glycinergic and GABAergic modulations become weak due to lack of inhibitory amino acids. Intracellularly, extracellular signaling-regulated kinase (ERK) and p38 MAPK, protein kinases (PKA and PKC and PKG) are phosphorylated and recruited as enhancing modulators of membrane receptors and ion channels. Cyclooxygenases 1/2 (COX-1/2) are also recruited as enzymes catalyzing arachidonic acids to prostaglandins. The inset on the right top shows involvement of descending nociceptive facilitatory pathway from rostral medial medulla (RMM) in the development and maintenance of TRMIH due to the centrally sensitized state.

Fig. 5

A schematic drawing of proposed underlying mechanisms of the bee venom (BV)-induced thermally relevant primary hyperalgesia (TRPH) in the spinal cord dorsal horn. Shown is a synaptic structure between a pre-synaptic component (central terminal of primary afferents, left) and a post-synaptic component (membrane of a pain-signaling neuron, right). Astrocytes and microglia are fully activated at this stage. At the synaptic cleft, in response to thermally nociceptive heat stimuli, excitatory amino acids (EAAs, glutamate and aspartate, small colored clear vesicles) are selectively activating group I, II and III of metabotropic glutamate receptors but without activation of ionotropic glutamate receptors (NMDA and AMPA/KA). Substance P (large dense-cored vesicles) are also activating neurokinin 1 (NK1) receptors. At pre-synaptic component, vanilloid receptor TRPV1, voltage-dependent calcium channel (VDCC), and NK1 are activated. ATP (green clear vesicles) released from glial cells or damaged cells due to cytotoxic effects are activating ATP P2X receptors. Intracellularly, extracellular signaling-regulated kinase (ERK) and p38 MAPK, protein kinases (PKC and PKG, but not PKA), are phosphorylated and recruited as enhancing modulators of membrane receptors and ion channels. Cyclooxygenases 1/2 (COX-1/2) are also recruited as enzymes catalyzing arachidonic acids to prostaglandins.

Fig. 6

A schematic drawing of proposed underlying mechanisms of the bee venom (BV)-induced mechanically relevant primary hyperalgesia (MRPH) in the spinal cord dorsal horn. Shown is a synaptic structure between a pre-synaptic component (central terminal of primary afferents, left) and a post-synaptic component (membrane of a pain-signaling neuron, right). Astrocytes and microglia are fully activated at this stage. At the synaptic cleft, in response to mechanically von Frey filament stimuli, excitatory amino acids (EAAs, glutamate and aspartate, small colored clear vesicles) are selectively activating metabotropic glutamate receptors (mGluR) group I, but without activation of ionotropic glutamate receptors (NMDA and AMPA/KA) and mGluR group II and III. Neurokinin 1 (NK1) receptors are not activated. At pre-synaptic component, vanilloid receptor TRPV1, voltage-dependent calcium channel (VDCC), and NK1 are inactivated. ATP (green clear vesicles) released from glial cells or damaged cells due to cytotoxic effects are still activating ATP P2X receptors. Intracellularly, only protein kinase A (PKA) and PKG, but not PKC, are phosphorylated. Cyclooxygenases 1/2 (COX-1/2) are recruited as enzymes catalyzing arachidonic acids to prostaglandins.